Editor’s Choice – Diabetologia (2025)

Domenico Tricò, Luca Sacchetta, Eleni Rebelos, Noemi Cimbalo, Martina Chiriacò, Diego Moriconi, Lorenzo Nesti, Giulia Nesti, Silvia Frascerra, Maria T. Scozzaro, Giuseppe Daniele, Simona Baldi, Andrea Mari, Monica Nannipieri, Andrea Natali

Postprandial hypoglycaemia (PPHG) is a frequent complication of Roux-en-Y gastric bypass and is associated with negative health consequences. In this issue, Tricò et al (https://doi.org/10.1007/s00125-024-06312-3) report findings from a case–control clinical study, which identified excessive glucose clearance as the main determinant of post-bypass hypoglycaemia in people with type 2 diabetes. This was driven by high insulin sensitivity and early glucose-stimulated hyperinsulinaemia, the latter being dependent on low insulin clearance and enhanced beta cell function. PPHG was also characterised by defective counterregulatory hormone responses that hinder the compensatory increase in endogenous glucose production, and prevent the appearance of symptoms and signs of sympathetic cardiovascular activation and neuroglycopenia. The latter makes the individual unaware of hypoglycaemia and vulnerable to recurrent hypoglycaemic episodes. Consistently, the authors found that OGTT-induced hypoglycaemia was associated with more hypoglycaemic events, as assessed using continuous glucose monitoring, and with potentially (mal)adaptive dietary habits, which may repeatedly trigger PPHG. In summary, Tricò et al state that by implementing an integrated physiology approach, this study exposes the complex pathogenetic mechanisms underlying post-bypass PPHG, as well as the clinical relevance of this pathological condition in individuals with type 2 diabetes, and reveals potential therapeutic targets.

Chaitra Rao, Daniel T. Cater, Saptarshi Roy, Jerry Xu, Andre G. De Oliveira, Carmella Evans‑Molina, Jon D. Piganelli, Decio L. Eizirik, Raghavendra G. Mirmira, Emily K. Sims

Beta cell extracellular vesicle (EV) cargo differs under conditions of health and disease and may mediate extracellular interactions within the islet microenvironment. In this issue, Rao, Cater et al (https://doi.org/10.1007/s00125-024-06313-2) demonstrate that the immune checkpoint protein programmed death-ligand 1 (PD-L1) is present on the beta cell EV surface and upregulated by exposure of islets to IFN. The authors found that beta cell EV PD-L1 was able to bind PD-1 in a dose-dependent manner, and that treatment of activated CD8⁺T cells with beta cell EV PD-L1 reduced T cell proliferation and cytokine production. They also report that plasma EV PD-L1 was increased in islet autoantibody-positive individuals, especially in those who had single autoantibody positivity, as compared with an islet autoantibody-negative control group. Moreover, in both autoantibody-positive individuals, in early disease stages, and in individuals with recently diagnosed stage 3 type 1 diabetes, plasma EV PD-L1 positively correlated with plasma C-peptide. The authors conclude that these findings support a potential link between higher EV PD-L1 and beta cell survival and suggest that EV PD-L1 could be exploited as a means to inhibit immune-mediated beta cell death.

Mary R. Rooney, Amelia S. Wallace, Justin B. Echouffo Tcheugui, Michael Fang, Jiaqi Hu, Pamela L. Lutsey, Morgan E. Grams, Josef Coresh, Elizabeth Selvin

Prediabetes (classified here as HbA_1c39–47 mmol/mol [5.7–6.4%] or fasting glucose 5.6–6.9 mmol/l) is associated with elevated risks of microvascular and macrovascular complications among middle-aged adults. However, it is unknown to what extent the associations of prediabetes with long-term risks of clinical outcomes remain after accounting for their intervening progression to type 2 diabetes. In this issue, Rooney et al (https://doi.org/10.1007/s00125-024-06315-0) characterised long-term risks of macrovascular and microvascular outcomes in people with prediabetes at baseline before and after accounting for progression to incident diabetes. The authors found that progression to diabetes explained less than one-quarter of the risks of clinical outcomes associated with prediabetes. They conclude that these results highlight the importance of routine screening for prediabetes, and of primary prevention interventions to reduce the incidence of cardiovascular and kidney disease among people with prediabetes.

Rula A. Amr, Ahmed M. Al‑Smadi, Rand T. Akasheh

Diabetes mellitus poses a growing global health challenge, and effective management of this disease hinges on understanding the factors influencing diabetes knowledge and behaviour. In this issue, Amr et al (https://doi.org/10.1007/s00125-024-06304-3) report findings from a survey of 1050 Jordanian adults, which was used to explore how demographic and clinical variables shape diabetes-related knowledge and self-management behaviours. Older age, female sex and being married were strongly associated with higher diabetes knowledge and behaviour scores. Interestingly, individuals with diabetes demonstrated greater diabetes knowledge than those without but failed to exhibit corresponding behavioural improvements, highlighting systemic barriers to effective management. The authors state that these findings emphasise the need for culturally sensitive, targeted interventions that bridge the gap between diabetes knowledge and behaviour. By leveraging the knowledge-attitude-behaviour (KAB) model, which suggests that behavioural change can be achieved by targeting both knowledge and attitudes, this study offers actionable insights to inform public health strategies, aiming to improve diabetes care in Jordan and in other regions facing similar challenges. Amr et al conclude that this research underscores the importance of addressing both educational and structural barriers to diabetes management to empower individuals and promote better health outcomes.

Joreintje D. Mackenbach, Josine M. Stuber, Joline W. J. Beulens

Diabetes prevention policies that require personal resources to benefit from them may inadvertently widen socioeconomic inequalities. In a narrative review in this issue, Mackenbach et al (https://doi.org/10.1007/s00125-024-06330-1), summarise the available evidence on the effectiveness and equity of low-agency, population-based policies aimed at reducing the burden of type 2 diabetes. Where evidence on the equity effects of these policies was available, the authors found that most of the low-agency, population-based policies that they identified are equitable. However, for many policies, evidence on equity effects is lacking. Mackenbach and colleagues conclude that future research should consider the type of evidence needed to demonstrate the real-world effectiveness and equity of population-based diabetes prevention policies. The figures from this review are available as a downloadableslideset.

Nunzio Guccio, Constanza Alcaino, Emily L. Miedzybrodzka, Marta Santos‑Hernandez, Christopher A. Smith, Adam Davison, Rula Bany Bakar, Richard G. Kay, Frank Reimann, Fiona M. Gribble

Interest in the incretin hormone glucose-dependent insulinotropic polypeptide (GIP), which is secreted by small intestinal K cells and modulates insulin secretion, fat storage and bone turnover, has soared since the clinical success of tirzepatide, a dual agonist for glucagon-like peptide-1 (GLP-1) and GIP receptors. In this issue, Guccio et al (https://doi.org/10.1007/s00125-024-06293-3) used organoids generated from human intestinal biopsies, a self-regenerating model forming ‘mini guts’ in vitro that can be genetically modified by CRISPR-Cas9, to study the signalling pathways involved in human GIP release. By inserting fluorescent reporters controlled by the GIP promoter, the authors were able to identify, purify and characterise human GIP-secreting cells using techniques including RNA sequencing, live cell imaging and peptide mass spectrometry. The study identified which sensory proteins on human GIP-secreting cells are responsible for detecting different components of our diet, and how these trigger second messenger pathways to culminate in GIP secretion. The authors highlight that understanding GIP release is a crucial step in explaining how food ingestion leads to insulin release and appetite regulation and conclude that this may lead to novel therapies to modulate endogenous GIP release in metabolic diseases.

Raniero Chimienti, Silvia Torchio, Gabriel Siracusano, Valentina Zamarian, Laura Monaco, Marta Tiffany Lombardo, Silvia Pellegrini, Fabio Manenti, Federica Cuozzo, Greta Rossi, Paola Carrera, Valeria Sordi, Vania Broccoli, Riccardo Bonfanti, Giorgio Casari, Giulio Frontino, Lorenzo Piemonti

Wolfram syndrome 1 (WS1), a rare inherited disorder, severely impacts the survival of pancreatic beta cells, contributing to early-onset diabetes in affected individuals. In this issue, Chimienti and Torchio et al (https://doi.org/10.1007/s00125-024-06307-0) investigate how an acceptor splice site mutation in theWFS1gene promotes the production of both incomplete proteins and premature termination codon (PTC)-carrying transcripts. Using patient-derived induced pluripotent stem cells differentiated into pancreatic beta cells, the authors demonstrate that, under cell stress and inflammatory conditions, these PTC-carrying transcripts evade the nonsense-mediated decay (NMD) mechanism, leading to their dramatic accumulation and predisposing beta cells to the defective unfolded protein response and apoptosis. As severalWFS1gene mutations introduce a PTC, the authors conclude that NMD inhibition and the accumulation of PTC-carrying mRNAs may represent new molecular targets for effective WS1 therapies and for mitigating beta cell damage under conditions of stress and inflammation.

David Nathanson, Katarina Eeg‑Olofsson, Tim Spelman, Erik Bülow, Mattias Kyhlstedt, Fleur Levrat‑Guillen, Jan Bolinder

Intermittently scanned continuous glucose monitoring (isCGM) improves glucose management in individuals with type 1 diabetes; however, evidence regarding its effectiveness in type 2 diabetes is limited, and studies linking CGM use to reduced CVD risks in the type 2 diabetes population have been limited in size and scope, although increased time in range has been correlated with some markers of CVD. In this issue, Nathanson et al (https://doi.org/10.1007/s00125-024-06289-z) demonstrate that use of isCGM devices in adults with type 2 diabetes on insulin therapy is associated with improved glycaemic management and reductions in HbA_1c, with a greater improvement in HbA_1camong those with suboptimal glucose management. Users of isCGM devices also saw significant reductions in hospitalisations for CVD events, including acute myocardial infarction, heart failure and stroke. The authors conclude that adults with type 2 diabetes on insulin therapy may benefit from isCGM or CGM and that isCGM/CGM may be cost-effective as it reduces the risk of complications.

Eric Wang, Elisabetta Patorno, Farzin Khosrow‑Khavar, Stephen Crystal, Chintan V. Dave

Sodium–glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor antagonists (GLP-1RAs) are indicated for people with diabetes and cardiorenal complications; however, despite clinical guidelines recommending these therapies, uptake has been slow. In this issue, Wang et al (https://doi.org/10.1007/s00125-024-06321-2)highlight disparities in the adoption of these optimal second-line therapies among older Medicare beneficiaries with type 2 diabetes and comorbid cardiorenal conditions. Despite the demonstrated benefits of SGLT2is and GLP-1RAs for managing these conditions, Black participants were less likely to receive these therapies than other racial or ethnic groups. The authors examined trends over time and noted that, although disparities persisted throughout the study period examined, there was an encouraging improvement in the uptake of these therapies across racial and ethnic groups. The authors conclude that there is a need for continued efforts to address inequities in access to advanced diabetes treatments.

Daniel T. Meier, Joyce de Paula Souza, Marc Y. Donath

Increased body weight is associated with chronic low-grade inflammation, which contributes to the development and complications of diabetes. Central to this pathology is the activation of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome complex and secretion of IL-1β and IL-18. In this issue, Meier et al (https://doi.org/10.1007/s00125-024-06306-1) describe the activation of the NLRP3 inflammasome by metabolic stress, including the molecular mechanisms involved, and discuss the consequences for tissue integrity and energy metabolism. The emerging role of IL-1β in physiology and insulin secretion is compared with the apparent pathological features of inflammation. The authors outline the potential benefits of blocking the IL-1 pathway, with a focus on the comorbidities of diabetes, but also other associated diseases such as obesity, Alzheimer’s disease, rheumatoid arthritis and gout. The authors conclude by considering the safety aspects of IL-1 antagonism, as well as the prospect of using this therapeutic approach for the treatment of type 2 diabetes. The figures from this review are available as a downloadableslideset.

Sapna Sharma, Qiuling Dong, Mark Haid, Jonathan Adam, Roberto Bizzotto, Juan J. Fernandez‑Tajes, Angus G. Jones, Andrea Tura, Anna Artati, Cornelia Prehn, Gabi Kastenmüller, Robert W. Koivula, Paul W. Franks, Mark Walker, Ian M. Forgie, Giuseppe Giordano, Imre Pavo, Hartmut Ruetten, Manolis Dermitzakis, Mark I. McCarthy, Oluf Pedersen, Jochen M. Schwenk, Konstantinos D. Tsirigos, Federico De Masi, Soren Brunak, Ana Viñuela, Andrea Mari, Timothy J. McDonald, Tarja Kokkola, Jerzy Adamski, Ewan R. Pearson, Harald Grallert

Genomic and transcriptomic studies often fail to explain the complexity of a biological system, thus leaving us with a huge gap in the map from genotype to phenotype. The approach that is closest to fill this gap is metabolomics. Metabolomics is a high-throughput study of the metabolome, which includes all the small molecules (50–1500 Da) with diverse physiochemical characteristics and dynamic range of abundance, commonly known as metabolites. In this issue, Sharma, Dong and Haid et al (https://doi.org/10.1007/s00125-024-06282-6) identify key biomarkers, including branched-chain amino acids, lipids and newly discoveredN-lactoyl-amino acid metabolites, that are linked to prediabetes and diabetes. The authors provide evidence that these markers affect disease progression over time, with genetic analysis pointing to disruptions in lipid metabolism andn-3 fatty acids as major factors in the onset of type 2 diabetes. The authors conclude that their study’s findings could help classify individuals based on their risk levels, paving the way for more targeted and personalised diabetes interventions.

Noura Aldous, Ahmed K. Elsayed, Bushra Memon, Sadaf Ijaz, Sikander Hayat, Essam M. Abdelalim

Mutations in theRFX6gene (which encodes regulatory factor X6; RFX6) lead to monogenic diabetes with a hypoplastic pancreas. In this issue, Aldous et al (https://doi.org/10.1007/s00125-024-06232-2) investigate the mechanisms behind the impairment of pancreatic islet development caused byRFX6loss-of-function mutations. The authors utilise human embryonic stem cells and a gene-edited induced pluripotent stem cell model to investigate the role of RFX6 during differentiation into human pancreatic islets. The authors show that while RFX6 is present in the early stages of pancreatic development, its absence does not prevent the formation of pancreatic progenitors. Instead, its absence has two significant effects: downregulation of genes crucial for endocrine specification and the formation of smaller islet organoids due to an increased rate of cellular apoptosis (linked to reduced expression of the antioxidant enzyme catalase). These findings suggest thatRFX6mutations primarily disrupt islet cell formation through increased cell death and suppression of essential pancreatic endocrine genes. The authors conclude that these insights may pave the way for potential therapeutic strategies, such as enhancing catalase levels, to mitigate diabetes related to RFX6 defects.

Naomi Holman, Arthur C. Yelland, Bob Young, Jonathan Valabhji, William Jeffcoate, Fran Game

The management of diabetes-related foot ulcers through multi-disciplinary footcare teams tends to focus, and assess success, on ulcer healing. However, people with foot ulcers have high prevalence of cardiovascular and renal morbidity and are known to have reduced life expectancy. In this issue, Holman et al (https://doi.org/10.1007/s00125-024-06262-w) present findings from a nationwide analysis of 71,000 people presenting with diabetes-related foot ulcers in England and Wales, showing mortality rates of 8.2% and 14.4% at 26 weeks and 52 weeks, respectively. The authors highlight that whilst the severity of the ulcer at presentation to a multi-disciplinary footcare team was associated with higher mortality after 12 and 26 weeks, by 52 weeks these associations were reduced and cardiovascular and renal comorbidities were a stronger predictor of mortality. The authors conclude that in the context of high short-term mortality, teams managing people with diabetes-related foot ulcers should consider modifying the burdensome care and maximising quality of residual life, rather than an exclusive focus on healing.

Lianna W. Wat and Katrin J. Svensson

The tight regulation of energy metabolism is crucial to health and survival. Secreted factors are one key class of regulators that control this process. Approximately 9% of the human genome, or 1891 genes, encode secreted products yet only a small percentage of these have been characterised and linked to metabolism. Recent advances in open-source expression data and proteomic techniques have led to rapid identification of new metabolic secreted factors. In this issue, Wat and Svensson (https://doi.org/10.1007/s00125-024-06253-x) summarise the last decade of discoveries of novel secreted factors or functions of previously known secreted factors that control glucose and lipid metabolism. Specifically, they discuss three secreted factors that promote the development of metabolic disease (scEMC10, vimentin and CILP2) and four secreted factors that are proposed to be protective (ISM1, LCN2, NRG1 and NRG4). This review highlights the most recent insights into understanding how the secretome contributes to metabolic regulation and discusses the current challenges of functional characterisation and therapeutic development. The figures from this review are available as a downloadableslideset.

Aikaterini Eleftheriadou, Vincenza Spallone, Abd A. Tahrani, Uazman Alam

Cardiac autonomic neuropathy (CAN) is a common, yet often under-recognised, complication of diabetes, associated with significant morbidity and mortality. In this issue, Eleftheriadou et al (https://doi.org/10.1007/s00125-024-06242-0) provide a comprehensive overview of CAN, detailing its pathophysiology, clinical presentation and management, including diagnosis, to aid clinicians in effectively addressing this condition. The authors highlight recent breakthroughs in understanding of the pathophysiology of CAN, including the roles of mitochondrial dysfunction, fatty acid metabolism, genetic factors and collagen turnover. Additionally, they compare diagnostic methods and discuss the potential utility of heart rate variability compared with traditional cardiovascular autonomic reflex tests. The review also covers the latest advancements in treatment, including the putative roles of the glucose-lowering agents such as sodium–glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists. The authors conclude by discussing future research directions. The figures from this review are available as a downloadable slideset.

Lu You, Lauric A. Ferrat, Richard A. Oram, Hemang M. Parikh, Andrea K. Steck, Jeffrey Krischer, Maria J. Redondo, the Type 1 Diabetes TrialNet Study Group

Individuals at risk of type 1 diabetes represent a heterogeneous population. In this issue, You et al (https://doi.org/10.1007/s00125-024-06246-w) aim to better understand the heterogeneity of this population by identifying clusters of individuals with distinct characteristics and varying levels of risk. Using an outcome-guided clustering approach, the authors identified six clusters using demographic, metabolic, immunological and genetic markers using a dataset from the TrialNet Pathway to Prevention study. The clustering results illustrate how different combinations and levels of these risk factors can contribute to the risk of type 1 diabetes. The results also suggest that clusters with similar risk levels may exhibit distinct characteristics, which further highlights the heterogeneity within this population. The authors conclude that stratifying risk using the identified clusters may contribute to improved risk prediction in type 1 diabetes.

Isabel Hurtado, Celia Robles, Salvador Peiró, Aníbal Garcia‑Sempere, Gabriel Sanfelix‑Gimeno

The popularity of GLP-1 receptor agonists (GLP-1RAs) has risen steeply since they received approval as weight loss agents, fuelled by substantial media attention. Meanwhile, regulatory agencies are investigating a potential link between GLP-1RAs and an increased risk of suicidal ideation and self-injury (SIS), and are calling for additional pharmacoepidemiological evidence. In this issue, Hurtado et al (https://doi.org/10.1007/s00125-024-06243-z) evaluate the risk of SIS in people with diabetes and obesity who initiated either GLP-1RAs or the comparator drug class sodium–glucose cotransporter 2 inhibitors (SGLT-2i) in a southern European region with a population of 5 million, from 2015 to 2021. Across several analyses, the authors did not observe a higher risk of SIS among GLP-1RA initiators, which aligns with the most recent regulatory reports. However, the authors conclude that, because of the rarity and potential severity of SIS events, a causal link between GLP-1RAs and suicidality cannot be entirely ruled out, and cautious use and monitoring of GLP-1RAs are warranted.

Donna S.‑H. Lin, Jen‑Kuang Lee, Kuan‑Chih Huang, Ting‑Tse Lin, Hao‑Yun Lo

The introduction of sodium–glucose cotransporter 2 inhibitors (SGLT2i) has transformed the management of diabetes and chronic kidney disease (CKD), especially regarding cardiorenal outcomes. Although SGLT2i benefits in CKD are well established, individuals with advanced CKD (stages 4 and 5) have often been excluded from previous studies. In this issue, Lin et al (https://doi.org/10.1007/s00125-024-06257-7) show that continuing SGLT2i therapy, even as renal function declines to these advanced stages, provides significant benefits. Study participants saw reduced rates of major cardiovascular events, particularly myocardial infarctions, and lower all-cause hospital admissions, and those who maintained SGLT2i therapy also showed modestly higher haemoglobin and haematocrit levels. The authors highlight that the safety profile—covering risks of hypoglycaemia and diabetic ketoacidosis—was comparable between those who continued and those who discontinued therapy. They conclude that these findings suggest that SGLT2i can be safely continued in advanced CKD, presenting a valuable approach to improving outcomes in this high-risk group.

Dominic Ehrmann, Norbert Hermanns, Andreas Schmitt, Laura Klinker, Thomas Haak, Bernhard Kulzer

Diabetes distress is one of the most frequently identified mental health issues in people with type 1 or type 2 diabetes, but little is known about the role of glycaemic management and whether subjective perceptions of glucose levels or objective glycaemic parameters are more important. In this issue, Ehrmann and Hermanns et al (https://doi.org/10.1007/s00125-024-06239-9) analyse whether diabetes distress stems more from people’s interpretation of their glucose levels or from continuous glucose monitoring (CGM) data itself. Overall, in people with type 1 or type 2 diabetes, subjective perceptions of glucose levels were stronger drivers of diabetes distress than actual CGM readings. Inn-of-1 analyses, the extent to which perceptions and actual CGM readings drove distress was determined for each individual. The authors show that psychosocial well-being and glucose levels at 3 months’ follow-up differed depending on how strongly perceived glucose levels or actual CGM metrics contributed to diabetes distress. They highlight that this demonstrates the need to understand where diabetes distress comes from, as it may affect outcomes differently. The authors conclude that differentiating between the emotional impacts of perceived vs actual glucose levels would allow for more personalised therapy by selecting the most appropriate intervention strategy for reducing diabetes distress, paving the way for precision mental health in diabetes.

Dorte Glintborg, Louise L. Christensen, Marianne S. Andersen

The number of transgender people seeking gender-affirming healthcare has increased during the last few years, and the expected lifelong changes in sex hormones during gender-affirming hormone therapy raises concern about adverse outcomes. In this issue, Glintborg et al (https://doi.org/10.1007/s00125-024-06212-6) summarise evidence on metabolic and cardiovascular outcomes during gender-affirming hormone treatment. CVD risk is increased in transgender people compared with cisgender control groups, but changes in known CVD risk markers during gender-affirming hormone treatment cannot explain this higher risk. The authors highlight, therefore, that separate risk markers such as age at initiation of gender-affirming hormone treatment, assigned sex at birth, minority stress and lifestyle factors should be considered. Shared decision making is a central part of transgender care and should focus on the balance between individual wishes for gender-affirming hormone treatment and CVD risk factors. The authors conclude that future studies should address personalised screening programmes for metabolic and CVD outcomes during gender-affirming hormone treatment with the aim of optimising transgender healthcare. The figures from this review are available as a downloadableslideset

Agnete T. Lundgaard, David Westergaard, Timo Röder, Kristoffer S. Burgdorf, Margit H. Larsen, Michael Schwinn, Lise W. Thørner, Erik Sørensen, DBDS Genomic Consortium, Kaspar R. Nielsen, Henrik Hjalgrim, Christian Erikstrup, Bertram D. Kjerulff, Lotte Hindhede, Thomas F. Hansen, Mette Nyegaard, Ewan Birney, Hreinn Stefansson, Kári Stefánsson, Ole B. V. Pedersen, Sisse R. Ostrowski, Peter Rossing, Henrik Ullum, Laust H. Mortensen, Dorte Vistisen, Karina Banasik, Søren Brunak

Previous studies have shown that glucose and lipid metabolism demonstrate time-dependent changes years before type 2 diabetes is clinically diagnosed. However, little is known about other molecular changes taking place during disease development, such as inflammation, a key feature of both type 1 and type 2 diabetes. In this issue, Lundgaard et al (https://doi.org/10.1007/s00125-024-06231-3) use biobank plasma samples from Danish blood donors to investigate health-to-disease changes in 225 markers involved in inflammation, endothelial function, and glucose and lipid metabolism up to 10 years before a type 1 or type 2 diabetes diagnosis. The authors identify several new biomarkers with distinct, time-dependent trajectories, along with many biomarkers showing persistently altered levels, in the years leading up to a diabetes diagnosis, and highlight that these changes, to some extent, are specific to either type 1 or type 2 diabetes. Biomarker panels that improve the prediction of diabetes up to 10 years before a diagnosis are also described. The authors conclude that including temporal biomarkers in future risk assessment tools may improve the precision of patient-specific risk assessment.

Flora Brozzi, Cécile Jacovetti, Cristina Cosentino, Véronique Menoud, Kejing Wu, Mustafa Bilal Bayazit, Baroj Abdulkarim, Christian Iseli, Nicolas Guex, Claudiane Guay, Romano Regazzi

Immune cells that invade the islets of Langerhans during the initial phases of type 1 diabetes release proinflammatory mediators that cause beta cell dysfunction and death. In this issue, Brozzi et al (https://doi.org/10.1007/s00125-024-06207-3) report that beta cell failure in NOD mice is associated with changes in the levels of many small non-coding RNAs generated by tRNA fragmentation. The authors show that, although some of these changes are triggered by chronic exposure of beta cells to proinflammatory cytokines, others result from the direct transfer via extracellular vesicles of tRNA-derived fragments from the invading lymphocytes to insulin-secreting cells. Some of the tRNA fragments transferred to beta cells during the early phases of type 1 diabetes promote apoptosis of insulin-secreting cells. The authors conclude that that the delivery of this novel class of small non-coding RNAs produced by lymphocytes via extracellular vesicles may contribute to the autoimmune attack against insulin-secreting beta cells and the development of type 1 diabetes.

Caleb M. Grenko, Henry J. Taylor, Lori L. Bonnycastle, Dongxiang Xue, Brian N. Lee, Zoe Weiss, Tingfen Yan, Amy J. Swift, Erin C. Mansell, Angela Lee, Catherine C. Robertson, Narisu Narisu, Michael R. Erdos, Shuibing Chen, Francis S. Collins, D. Leland Taylor

Sustained hyperglycaemia, such as occurs in diabetes, is toxic to pancreatic islet beta cells and can lead to beta cell death. In this issue, Grenko, Taylor and Bonnycastle et al (https://doi.org/10.1007/s00125-024-06214-4) use single-cell RNA seq to profile >68,000 cells from islets exposed to low and high glucose for 24 h. They identify thousands of genes associated with time in culture, glucose exposure and time–glucose interaction effects and highlight that beta cells demonstrate unique association patterns across all three effects. Integrating genetic summary statistics, the authors nominate candidate effector genes and functionally characterise the effects of three genes on glucose-stimulated insulin production and secretion in a human beta cell line. The authors conclude that this study reveals transcriptional pathways activated by sustained hyperglycaemia in islet cells that may be relevant to diabetes pathogenesis.

Shutong Du, Valerie K. Sullivan, Michael Fang, Lawrence J. Appel, Elizabeth Selvin, Casey M. Rebholz

Understanding the impact of ultra-processed food consumption on diabetes risk is important for informing dietary guidelines and interventions. In this issue, Du et al (https://doi.org/10.1007/s00125-024-06221-5) investigate the association between ultra-processed food consumption and the risk of diabetes in a diverse cohort of middle-aged adults in the USA. Their findings reveal that a higher intake of ultra-processed food, particularly sugar-sweetened beverages, ultra-processed meats and sugary snacks, is significantly associated with a higher risk of diabetes. Conversely, higher consumption of minimally processed and unprocessed food is associated with a lower diabetes risk. The authors highlight the need for targeted dietary interventions aimed at reducing ultra-processed food consumption. They conclude that these findings provide compelling evidence for revising dietary guidelines to address the health impact of ultra-processed food, to reduce the burden of diabetes.

Qian Xiao, Kelsie M. Full, Martin K. Rutter, Loren Lipworth

Sleep deficiency is a well-recognised risk factor for diabetes. However, there has been limited study on long-term trajectories of sleep and diabetes risk, especially among disadvantaged populations. In this issue, Xiao et al (https://doi.org/10.1007/s00125-024-06202-8) assess long-term trajectories of sleep duration and incident diabetes in a large cohort of predominantly Black and low-income populations in the southeastern USA, finding that suboptimal sleep duration trajectories were associated with higher odds of incident diabetes. Specifically, when compared with individuals who maintained 7–9 hours of sleep over the follow-up period, people with sleep trajectories that deviated from this pattern had a significant increase in diabetes risk. In particular, the trajectories characterised by switching between the long and short sleep duration were associated with the largest elevation in risk (~50%). The authors conclude that their study highlights the importance of maintaining healthy sleep for metabolic health and suggest that suboptimal sleep patterns may be an important contributing factor to the high burden of metabolic diseases in disadvantaged populations.

Nathalie Esser, Meghan F. Hogan, Andrew T. Templin, Rehana Akter, Brendy S. Fountaine, Joseph J. Castillo, Assam El‑Osta, Lakshan Manathunga, Alexander Zhyvoloup, Daniel P. Raleigh, Sakeneh Zraika, Rebecca L. Hull, Steven E. Kahn

Islet amyloid deposition and reduced beta cell mass are pathological hallmarks of type 2 diabetes. Aggregation of human islet amyloid polypeptide (hIAPP), the main peptide component of islet amyloid deposits in humans, is toxic to beta cells. In this issue, Esser et al (https://doi.org/10.1007/s00125-024-06161-0) delineate a new role for the fibrinolytic system in modulating islet amyloidogenesis. The authors identify that a local tissue plasminogen activator (tPA)/plasmin system is specifically upregulated in vitro in amyloid-laden hIAPP transgenic mouse islets and islets from human donors with type 2 diabetes. The authors also demonstrate that plasmin is an hIAPP-degrading enzyme that protects beta cells from hIAPP-induced toxicity. Together, these findings suggest that the tPA/plasmin system serves a protective function to limit islet amyloid deposition and its cytotoxic effects. The authors conclude that interventions aimed at increasing the islet tPA/plasmin system activity may reduce or limit hIAPP aggregation, and thereby, improve beta cell survival in type 2 diabetes.

Elise Wreven, María Soledad Ruiz de Adana, Stéphan Hardivillé, Valery Gmyr, Julie Kerr‑Conte, Mikael Chetboun, Gianni Pasquetti, Nathalie Delalleau, Julien Thévenet, Anaïs Coddeville, María José Vallejo Herrera, Liad Hinden, Inmaculada Concepción Benavides Espínola, Mireia Gómez Duro, Lourdes Sanchez Salido, Francisca Linares, Francisco‑Javier Bermudez‑Silva, Joseph Tam, Caroline Bonner, Josephine M. Egan, Gabriel Olveira, Natalia Colomo, François Pattou, Isabel Gonzalez‑Mariscal

Type 1 diabetes is an autoimmune disease in which immune cells attack insulin-producing beta cells. This pathological process, called insulitis, gradually destroys these vital cells, leading to lifelong use of exogenous insulin. Recent therapies have focused on targeting immune system overactivity, but their curative capacity is limited. Because of the critical role beta cells play in the onset of type 1 diabetes, there is a need for treatments targeting both the immune system and beta cells. In this issue, Wreven et al (https://doi.org/10.1007/s00125-024-06193-6) provide evidence that the cannabinoid type 1 receptor plays a key role in the initiation of insulitis in humans, and its blockade with specific compounds ameliorates inflammation, prevents insulitis and protects beta cell function. The authors propose that targeting the cannabinoid type 1 receptor could therefore be a promising new treatment for type 1 diabetes.

Laura M. Güdemann, Katie G. Young, Nicholas J. M. Thomas, Rhian Hopkins, Robert Challen, Angus G. Jones, Andrew T. Hattersley, Ewan R. Pearson, Beverley M. Shields, Jack Bowden, John M. Dennis, Andrew P. McGovern, on behalf of the MASTERMIND consortium

Real-world use of sodium−glucose cotransporter 2 (SGLT2) inhibitors in older adults with type 2 diabetes is increasing, but these individuals are typically excluded from clinical trials. In this issue, Güdemannet al (https://doi.org/10.1007/s00125-024-06190-9) use a large UK primary care database over 2013–2020 to compare the safety and effectiveness of SGLT2 inhibitors to dipeptidyl peptidase-4 inhibitors in people with type 2 diabetes aged 70 or over. The authors use an instrumental variable approach to allow causal estimation of treatment effects. The study provides evidence that SGLT2 inhibitors effectively reduce HbA_1clevels and weight in this older age group. SGLT2 inhibitor use was associated with an increased risk of genital infections and diabetic ketoacidosis (DKA), although the incidence of DKA was low in absolute terms. Importantly, no increased risks for falls, selected osmotic symptoms or lower limb amputation were observed. The authors conclude that SGLT2 inhibitors can be an effective treatment for older adults with type 2 diabetes, although clinicians should be mindful of the heightened risks for certain adverse events.

Weiqing Wang, Stephen C. Bain, Fang Bian, Rui Chen, Sanaz Gabery, Shan Huang, Thomas B. Jensen, Bifen Luo, Guoyue Yuan, Guang Ning, for the PIONEER 11 investigators

The prevalence of diabetes in China is estimated to increase over the coming decades, highlighting a clear treatment need. However, differences in type 2 diabetes pathophysiology exist between East Asian and Western populations, which could impact treatment responses. Oral semaglutide is the first orally available glucagon-like peptide-1 receptor agonist, with demonstrated efficacy in global trials. In this issue, Wang et al (https://doi.org/10.1007/s00125-024-06142-3) show that oral semaglutide led to significant reductions in HbA_1cand body weight vs placebo in a predominantly Chinese population with type 2 diabetes insufficiently controlled by diet and exercise alone. Oral semaglutide was well tolerated. This issue also includes the PIONEER 12 trial, which demonstrated significant reductions in HbA_1cand body weight with oral semaglutide vs sitagliptin in a predominantly Chinese population with type 2 diabetes. The authors conclude that given the rising prevalence of type 2 diabetes in China, these findings provide important evidence on oral semaglutide in Chinese individuals.

Hazem Ibrahim, Diego Balboa, Jonna Saarimaki‑Vire, Hossam Montaser, Oleg Dyachok, Per‑Eric Lund, Muhmmad Omar‑Hmeadi, Jouni Kvist, Om P. Dwivedi, Väinö Lithovius, Tom Barsby, Vikash Chandra, Solja Eurola, Jarkko Ustinov, Tiinamaija Tuomi, Päivi J. Miettinen, Sebastian Barg, Anders Tengholm, Timo Otonkoski

Regulatory factor X 6 (RFX6) is crucial for the development of pancreatic beta cells. In this issue (https://doi.org/10.1007/s00125-024-06163-y), Ibrahim et al show that a pathogenic variant in theRFX6gene that is particularly enriched in the Finnish population significantly increases the risk of developing type 2 and gestational diabetes. Using advanced allelic series stem cell models, they demonstrate that heterozygous mutation results inRFX6haploinsufficiency, impairing insulin secretion in vitro and in vivo without affecting beta cell mass. Complete loss of RFX6 was associated with reduced generation of the pancreatic progenitor pool and increased apoptosis. The authors conclude that these findings enhance our understanding of how specific genetic mutations can lead to diabetes and may guide future therapies aimed at restoring normal beta cell function.

Aleksander L. Hansen, Charlotte Brøns, Leonie M. Engelhard, Mette K. Andersen, Torben Hansen, Jens S. Nielsen, Peter Vestergaard, Kurt Højlund, Niels Jessen, Michael H. Olsen, Henrik T. Sørensen, Reimar W. Thomsen, Allan Vaag

Exposure to an adverse intrauterine environment, leading to a small, vulnerable newborn, is associated with a reduction in short-term survival. In addition, survivors are vulnerable to health problems throughout life, including lower cognition and educational achievement and increased susceptibility to adult diseases such as type 2 diabetes, hypertension and CVD. In this issue, Hansen et al (https://doi.org/10.1007/s00125-024-06170-z) provide new evidence that low birthweight is not only associated with a higher risk of CVD in the general population, but also significantly elevates the risk of major cardiovascular events among individuals newly diagnosed with type 2 diabetes. The authors show that a birthweight under 3000 g, representing 25% of the study population, is associated with an elevated risk of stroke, peripheral arterial disease and cardiovascular-related death in this already high-risk group. The authors conclude that these findings underscore the need to consider birthweight in cardiovascular risk assessments and to develop more tailored preventive strategies for people with type 2 diabetes.

Jason Groegler, Aïsha Callebaut, Eddie A. James, Thomas Delong

Insulin secretory granules play a crucial role in the formation of neoepitopes targeted by autoreactive T cells in type 1 diabetes. In this review, Groegler et al (https://doi.org/10.1007/s00125-024-06164-x) highlight the unique biochemical environment within these granules, characterised by an acidic pH, high protein concentration and the presence of various enzymes, which facilitates the generation of modified epitopes that may evade thymic selection processes. The authors discuss the interactions between preproinsulin epitopes and HLA, the role of preproinsulin expression and negative selection in the thymus, and the various mechanisms of neoepitope formation within insulin granules. These neoepitopes, including hybrid insulin peptides, deamidated epitopes and citrullinated epitopes, are discussed in detail. The authors also explore the therapeutic potential of targeting mechanisms of antigen formation within insulin granules to prevent the loss of tolerance and inhibit autoimmune destruction of insulin-producing beta cells. The authors conclude that a better understanding of these processes may provide valuable insights into disease pathogenesis and reveal new opportunities for therapeutic interventions. The figures from this review are available as a downloadableslideset.

Angela Sheu, Christopher P. White, Jacqueline R. Center

People with diabetes are more likely to suffer from fragility fractures than those without diabetes, leading to worse post-fracture complications including poor fracture healing, infections and increased mortality risk. However, quantifying fracture risk in diabetes is difficult, as standard clinical measurements of bone mineral density and fracture risk calculators underestimate risk in this population. In this issue (https://doi.org/10.1007/s00125-024-06172-x), Sheu et al discuss how elucidating metabolic–bone interactions, including determining diabetes-related clinical predictors for fractures and underlying pathophysiological drivers, provides a rationale for changing from a bone-centric paradigm to a diabetes-centric approach when considering the optimal assessment and management of diabetic bone disease. The authors conclude that further clinical characterisation of diabetic osteopathy may reveal new targets for improving skeletal-related outcomes in people with diabetes. The figures from this review are available as a downloadableslideset.

Roberto Trevisan, Matteo Conti, Stefano Ciardullo

Basal insulin represents a safe and effective therapeutic option for people with diabetes. One of the barriers to insulin therapy in clinical practice is related to perceived treatment complexity, in part due to the need for daily administration. Currently, novel basal insulin molecules administered once weekly (insulin icodec and basal insulin Fc [insulin efsitora alpha]) are being studied for the treatment of both type 1 and type 2 diabetes. In this issue, Trevisan et al (https://doi.org/10.1007/s00125-024-06158-9) summarise the available evidence from RCTs on once-weekly insulins. The authors highlight that the efficacy of once-weekly insulins in terms of blood glucose levels is similar to or slightly better than that achieved with once-daily analogues. Moreover, they have a good safety profile in people with type 2 diabetes, with a similar risk of hypoglycaemia to that seen with daily insulins and no data suggesting a longer time to recovery during hypoglycaemic events. In contrast, hypoglycaemic risk may be increased in type 1 diabetes. The authors conclude that once-weekly insulin analogues may represent a promising therapeutic approach to increase adherence and improve glycaemic management in real-world clinical practice. The figures from this review are available as a downloadableslideset.

Guy S. Taylor, Kieran Smith, Jadine Scragg, Timothy J. McDonald, James A. Shaw, Daniel J. West, Lee D. Roberts

Despite the health benefits of exercise, uptake in people with type 1 diabetes is lower than in the general population, in part due to the heterogeneous metabolic responses to exercise that can lead to hypoglycaemia. Metabolomics measures the metabolites in a biofluid or tissue and is used in precision medicine to understand an individual’s molecular phenotype in response to disease. In this issue, Taylor et al (https://doi.org/10.1007/s00125-024-06153-0) use metabolomics to identify a unique metabolic response to aerobic exercise in the blood of individuals with type 1 diabetes. The authors show that this response differed depending on whether an individual’s beta cells retained the capacity to produce insulin. Two metabolites in blood, malic acid and pyruvate, were found to reciprocally correlate with VO_2peak, a metric of aerobic capacity in exercise, in individuals with type 1 diabetes. The authors conclude that the ratio of malic acid to pyruvate, key metabolites in cellular energy production, may have diagnostic potential in identifying people with type 1 diabetes with low aerobic capacity in exercise.

Cong Xie, Peter Iroga, Michelle J. Bound, Jacqueline Grivell, Weikun Huang, Karen L. Jones, Michael Horowitz, Christopher K. Rayner, Tongzhi Wu

Metformin is the first-line drug for the management of type 2 diabetes and has been shown to lower postprandial blood glucose levels via several gastrointestinal mechanisms, including the stimulation of the incretin hormone glucagon-like peptide-1 (GLP-1). In practice, it is recommended that metformin is ingested with meals to minimise potential gastrointestinal adverse effects. However, this may compromise its glucose-lowering efficacy. In this issue, Xie et al (https://doi.org/10.1007/s00125-024-06131-6) compare the effects of administering metformin at different time intervals before an enteral glucose load on subsequent blood glucose, insulin and GLP-1 responses in a group of participants with type 2 diabetes who were treated by, and tolerant to, metformin. The study had a double-blind, randomised, placebo-controlled crossover design and the authors used a naso-duodenal catheter to ensure the precise delivery of metformin and the glucose load into the small intestine. The authors found that metformin is more effective at lowering blood glucose and augmenting GLP-1 secretion when given 30–60 min before enteral glucose. The authors conclude that, in metformin-tolerant individuals with type 2 diabetes, administration of metformin before meals may enhance its efficacy for postprandial glycaemic control.

Simona Sacco, Matteo Foschi, Raffaele Ornello, Federico De Santis, Riccardo Pofi, Michele Romoli

The intertwining of diabetes mellitus and stroke extends from pathogenic mechanisms to the need for tailored care. Diabetes and hyperglycaemia worsen stroke outcomes, with hyperglycaemia in the acute ischaemic stroke phase increasing the risk of haemorrhagic transformation and poor functional recovery, emphasising the need for early severe hyperglycaemia management. Intensive glucose control within a comprehensive care bundle improves outcomes post haemorrhagic stroke. Considering the frequent micro- and macrovascular complications seen in diabetes, tailored cardiovascular prevention strategies are essential. Sodium–glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists allow tailored treatment strategies, which are particularly beneficial for individuals with heart failure and chronic kidney disease. In this issue, Sacco, et al (https://doi.org/10.1007/s00125-024-06146-z) synthesise hyperacute stroke management and cardiovascular prevention concepts in people with diabetes, informing clinicians on preferred treatments based on large studies and RCTs. The figures from this review are available as a downloadable slideset.

Martin Heni

Insulin exerts its actions not only on peripheral organs but also in the brain, where it impacts multiple brain functions. In this issue, Martin Heni (https://doi.org/10.1007/s00125-024-06104-9) provides a comprehensive overview of brain insulin’s role in human metabolism. After highlighting historical discoveries, the author describes how insulin passes into the human brain and summarises recent findings on brain insulin’s impact on whole-body metabolism, including effects on hepatic glucose production, insulin sensitivity and pancreatic insulin secretion. The effect of brain insulin on body weight and body fat distribution is also discussed, paying particular attention to brain insulin resistance and linking it to altered glucose metabolism, obesity and cognitive impairments. The author highlights that the work reviewed here provides the first indication of the potential involvement of brain insulin resistance in the pathogenesis of high-risk clusters of prediabetes and diabetes. Emerging treatment strategies for brain insulin resistance are also reviewed, highlighting their potential in addressing both metabolic and neurological disorders. The author concludes with future research perspectives and underscores the importance of further exploring brain insulin’s role in health and disease. The figures from this review are available as a downloadable slideset.

Richard I. G. Holt, Clive S. Cockram, Ronald C. W. Ma, Andrea O. Y. Luk

Interest in infections as a cause of morbidity and mortality in people with diabetes has been reignited by the COVID-19 pandemic. However, the complex bi-directional relationship between diabetes and infection is much broader than that between diabetes and COVID-19; it encompasses severe infections that occur predominantly in people with diabetes, and common infections, where the clinical course is affected by diabetes and its complications and comorbidities. In this issue, Holt et al (https://doi.org/10.1007/s00125-024-06102-x) describe the epidemiology of diabetes and infection, the mechanisms that make people with diabetes more vulnerable to infection, specific infections that clinicians need to be aware of, and the principles of treatment and prevention. Significant gaps in our knowledge about the relationship between diabetes and infection remain. Although major advances in diabetes treatments and technologies have occurred, further studies are required to determine whether improved diabetes care translates to a reduction in risk of serious infection. The figures from this review are available as a downloadable slideset.

Dakota Gustafson, Peter V. DiStefano, Xue Fan Wang, Ruilin Wu, Siavash Ghaffari, Crizza Ching, Kumaragurubaran Rathnakumar, Faisal Alibhai, Michal Syonov, Jessica Fitzpatrick, Emilie Boudreau, Cori Lau, Natalie Galant, Mansoor Husain, Ren‑Ke Li, Warren L. Lee, Rulan S. Parekh, Philippe P. Monnier, Jason E. Fish

While vascular leakiness is a prominent feature of diabetes, the mechanisms are poorly understood. Of particular concern is leak in the brain, as this is associated with cognitive impairment. In this issue, Gustafson and DiStefano et al (https://doi.org/10.1007/s00125–024–06120–9) report that circulating small extracellular vesicles contribute to cerebrovascular leak in type 2 diabetes. The authors found that the abundance of circulating extracellular vesicles is increased in diabetes and that the proteins present in these vesicles are altered. Using intravital microscopy, they show that injection of extracellular vesicles isolated from a mouse model of type 2 diabetes into non-diabetic mice can induce cerebrovascular leak. Mechanistically, these vesicles increase transcytosis and disrupt cell–cell junctions in endothelial cells, and the vascular leak is dependent on MAPK/Rho-associated protein kinase (ROCK) signalling. The authors conclude that these findings provide insights into circulating factors that drive vascular leakiness in type 2 diabetes and suggest new therapeutic approaches to prevent vascular complications, including cognitive impairment.

Alistair J. Monteyne, Kaja Falkenhain, Gráinne Whelehan, Helena Neudorf, Doaa R. Abdelrahman, Andrew J. Murton, Benjamin T. Wall, Francis B. Stephens, Jonathan P. Little

Recent studies have demonstrated the utility of ketone monoester supplements at inducing physiological ketosis and lowering blood glucose levels following a meal. In this issue, Monteyne et al (https://doi.org/10.1007/s00125–024–06122–7) address whether pre-meal ketone monoester ingestion reduces blood glucose in individuals with type 2 diabetes. The authors found that oral ingestion of the ketone monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate rapidly induced ketosis and significantly reduced post-meal blood glucose levels compared with a non-caloric placebo. This was predominantly due to a decrease in the rate that glucose from the meal, measured directly using a dual-glucose stable isotope tracer approach, appeared in circulation. The reduction in blood glucose levels with the ketone monoester occurred in concert with reduced circulating NEFA levels, but with no difference in circulating insulin between conditions. The authors conclude that these findings highlight a novel approach to mitigate postprandial glucose excursions, and underscore the therapeutic potential of ketone monoester supplements in type 2 diabetes management.

Adrian Villalba, Yorick Gitton, Megumi Inoue, Virginie Aiello, Raphaël Blain, Maryne Toupin, Séverine Mazaud‑Guittot, Latif Rachdi, Henrik Semb, Alain Chédotal, Raphaël Scharfmann

Rodent models have provided extensive insights into pancreas development; however, the mechanisms underlying human pancreas formation have not been fully elucidated. In this issue, Villalba and Gitton et al (https://doi.org/10.1007/s00125–024–06143–2) report how they integrated light-sheet fluorescent microscopy with tissue clearing to enable 3D visualisation of human embryonic and fetal pancreatic architecture. They first addressed the spatiotemporal distribution of early insulin-positive (beta) cells during the first trimester of human development. Their findings indicate that these early beta cells emerge around post-conception week 5, 2 weeks earlier than previously described. They are predominantly located in the inner part of the pancreas, suggesting a highly specialised niche for differentiation. Conversely, proliferating pancreatic progenitors are confined to the periphery, revealing a tissue regionalisation for the mechanisms of proliferation and differentiation. The authors conclude that this work represents a strong base to build a whole 3D atlas of the developing human pancreas.

Sophie Béliard, Florian Mourre, René Valéro

Dyslipidaemias are major cardiovascular risk factors, especially in people with diabetes. Over the last 10 years, a large number of next-generation therapies in the field of lipidology have been developed. In this issue, Béliard et al (https://doi.org/10.1007/s00125–024–06100-z) provide an update on these next-generation lipid-modifying therapies, with particular emphasis on their efficacy in the population with diabetes and their potential impact on glucose metabolism. Lowering LDL-cholesterol levels is usually the first goal in individuals with diabetes to reduce the risk of atherosclerotic CVD. However, the authors highlight that, beyond controlling LDL-cholesterol levels, it is necessary to improve the lipid abnormalities that are responsible for residual cardiovascular risk: elevated lipoprotein (a) levels and atherogenic dyslipidaemia. The authors describe how new drugs under development with the aim of decreasing LDL-cholesterol, triglyceride or lipoprotein (a) levels are promising to reduce the burden of CVD, particularly in those with diabetes, or reduce the risk of acute pancreatitis. These drugs have favourable, unfavourable or neutral effects on the risk of new-onset diabetes or glycaemic control. The authors conclude that further studies are needed to confirm the efficacy of these new drugs and monitor their potential side effects, particularly with regard to glycaemic control. The figure from this review is available as a downloadable slide.

Sami Qadri, Hannele Yki-Järvinen

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is a bourgeoning health issue that disproportionately affects people with type 2 diabetes. Liver fat accumulation is not merely a marker of metabolic abnormalities; it precedes and predicts progressive liver disease. However, there is significant uncertainty regarding who should be targeted for liver-related evaluations and the best methods for doing so. In this issue, Qadri and Yki-Järvinen (https://doi.org/10.1007/s00125–024–06087–7) provide a critical review of recent evidence on the importance, feasibility and methods of monitoring MASLD in type 2 diabetes. The authors highlight that, although MASLD is common among individuals with diabetes, the prevalence of advanced liver fibrosis is likely to be overestimated. Recent guidelines recommend universal fibrosis screening in type 2 diabetes, but the evidence base and appropriate tools are lacking. The proposed screening algorithms are expected to channel 20% of all individuals with diabetes to tertiary care, with a false discovery rate as high as 80%. The authors conclude that fibrosis case-finding strategies should be thoroughly reassessed and that more effective approaches to surveying the liver in type 2 diabetes are needed. The figures from this review are available as a downloadable slideset.

Pedro Cardoso, Katie G. Young, Anand T. N. Nair, Rhian Hopkins, Andrew P. McGovern, Eram Haider, Piyumanga Karunaratne, Louise Donnelly, Bilal A. Mateen, Naveed Sattar, Rury R. Holman, Jack Bowden, Andrew T. Hattersley, Ewan R. Pearson, Angus G. Jones, Beverley M. Shields, Trevelyan J. McKinley, John M. Dennis, on behalf of the MASTERMIND consortium

A central aim of type 2 diabetes precision medicine is to accurately target specific drug treatments to the individuals most likely to benefit from them. In this issue, Cardoso et al (https://doi.org/10.1007/s00125-024-06099-3)apply cutting-edge Bayesian causal forest models to develop and validate a model to predict differences in the glycaemic efficacy of glucagon-like peptide-1 (GLP-1) receptor agonists and sodium−glucose cotransporter 2 (SGLT2) inhibitors for individuals based on their routine clinical characteristics. Using large-scale UK routine clinical data (n=46,394), the authors identify robust and clinically relevant differences in glycaemic response for many individuals. Sex is identified as a major treatment response modifier, with greater glycaemic efficacy of GLP-1 receptor agonists in females, a finding confirmed in independent trial data. Beyond glycaemia, targeting of both therapies based on predicted HbA_1c response was associated with improved short-term tolerability and lower longer-term risk of new-onset microvascular complications. The authors conclude that the use of routine clinical features for type 2 diabetes treatment selection could support low-cost precision medicine worldwide.

Heikki Hyöty, Susanna Kääriäinen, Jutta E. Laiho, Gail M. Comer, Wei Tian, Taina Härkönen, Jussi P. Lehtonen, Sami Oikarinen, Leena Puustinen, Michele Snyder, Francisco León, Mika Scheinin, Mikael Knip, Miguel Sanjuan

Coxsackie B virus (CVB) infections usually cause mild common cold-type symptoms but may sometimes lead to severe life-threatening conditions. Recent epidemiological, mechanistic and preclinical studies point to CVB infections as the main environmental factor that sets into motion the autoimmune process that eliminates pancreatic beta cells in genetically susceptible individuals, triggering type 1 diabetes. There are no approved vaccines against CVB, and PRV-101, a formalin-inactivated vaccine including CVB serotypes 1–5, is the first one to progress to human testing. In this issue, Hyöty et al (https://doi.org/10.1007/s00125-024-06092-w) report that PRV-101 was well tolerated by participants in a double-blind randomised placebo-controlled Phase I trial. PRV-101 induced long-lasting, high serum concentrations of neutralising antibodies against all five CVB serotypes included in the vaccine. The authors conclude that the results of this first-in-human trial support the future development of PRV-101, which has the potential to be the first vaccine to prevent CVB infections, and could therefore potentially decrease the global incidence of type 1 diabetes.

Nigel Kurgan, Jeppe Kjærgaard Larsen, Atul S. Deshmukh

High-throughput and robust proteomic technologies have developed rapidly over the past decade. In this issue, Kurgan et al (https://doi.org/10.1007/s00125-024-06097-5) propel proteomics to the forefront of advancing precision diabetes medicine. They summarise recent advances in cutting-edge MS-based and affinity proteomic technologies and describe how they can be applied to improve accuracy in the prevention, diagnosis, prognosis and treatment of diabetes. The authors present a compelling case for proteomics in identifying predictive protein panels for type 2 diabetes subtyping and constructing clinical prediction models. Moreover, they underscore the significance of integrating proteomics with multimodal data, including genomics (proteogenomics) and clinical information, to deepen our understanding of the heterogeneity in type 2 diabetes aetiology and treatment responsiveness. The authors conclude with a call for action formed on advancing proteomics technologies, benchmarking their performance and standardising technologies across sites. The figures from this review are available as a downloadable slideset.

Olof Idevall‑Hagren, Ceren Incedal Nilsson, Gonzalo Sanchez

The cilium is probably the most elusive of the cellular organelles and its functions are only just beginning to be explored and understood. The fact that it is the only organelle exposed to the extracellular milieu and its surface is packed with receptors clearly points to its involvement as a sensory platform, including in pancreatic islets. New research on the basic structural and functional features of the cilium in beta cells is converging with genome-wide association studies to support key roles of the cilium in both cell and organ-level physiology, including regulation of cell polarity, metabolism, and production and secretion of insulin. In this issue, Idevall-Hagren et al (https://doi.org/10.1007/s00125-024-06096-6) discuss the latest findings and the challenges ahead with an eye on the potential for developing strategies to steer ciliary signalling to produce therapeutical impact. The figures from this review are available as a downloadable slideset.

Andre P Kengne, Ambady Ramachandran

The population of people with type 2 diabetes in low- and middle-income countries (LMICs) is huge and fast growing, calling for efforts to prevent further increases, while improving the detection and management of people with the condition. In this issue, Kengne and Ramachandran (https://doi.org/10.1007/s00125-023-06085-1) highlight the practical challenges in preventing type 2 diabetes and discuss the steps involved in the implementation of effective type 2 diabetes prevention programmes in LMICs. Existing evidence on type 2 diabetes prevention from both efficacy and implementation studies originates mostly from high income countries and, in LMICs, is dominated by studies from China and India. Challenges and barriers to implementing diabetes prevention programmes in LMICs include individual-, societal- and healthcare support-level factors. Going forward, steps in effectively implementing diabetes prevention programmes in LMICs while addressing the existing challenges should include awareness creation, risk screening of individuals, planning the programmes, and outcome evaluation. The authors conclude that non-invasive risk factor-based screening and information technology-based implementation strategies hold promise. The figure from this review is available as a downloadable slide.

Beibei Liu, Di Xie, Xinmei Huang, Sungho Jin, Yangyang Dai, Xiaoli Sun, Da Li, Anton M. Bennett, Sabrina Diano, Yingqun Huang

Skeletal muscle insulin resistance is a critical component of the pathogenesis of type 2 diabetes. Decreased expression of PGC-1α is among the many mechanisms implicated in insulin resistance; however, how this dysregulation occurs is yet to be elucidated. In this issue Liu, Xie, Huang et al (https://doi.org/10.1007/s00125-023-06073-5) report increased expression of ten-eleven translocation 3 (TET3) in skeletal muscle of individuals with type 2 diabetes as compared with individuals without diabetes. They show that TET3 interacts with and reduces the abundance of PGC-1α in myocytes. Specifically, TET3 was found to form protein complexes with PGC-1α, preventing its phosphorylation on sites known to promote protein stability and activity. It is proposed that this results in decreased mitochondrial respiration and insulin sensitivity in myocytes. Consistent with this theory, the authors showed that mice with skeletal muscle-specific TET3 deficiency exhibited increased PGC-1α abundance, and enhanced muscle and whole-body insulin sensitivity. Moreover, these animals remained insulin sensitive under high-fat diet challenge. The authors conclude that these findings hold promise for developing novel, TET3-targeting therapeutic agents for insulin resistance and type 2 diabetes.

Karoliina Tuomela, Megan K. Levings

Advanced genetic engineering approaches are transforming cell therapies across a number of fields, from cancer to autoimmunity. In this issue, Tuomela and Levings (https://doi.org/10.1007/s00125-023-06076-2) discuss the role and potential of immunosuppressive regulatory T cells (Tregs) in type 1 diabetes, focusing on the opportunities presented by the genetic engineering of these cells in this context. The authors highlight that although Tregs have demonstrated excellent safety in clinical trials, there has been a clear need for improved efficacy and consideration for the unique challenges in type 1 diabetes. Fortunately, genetic engineering has led to significant advancements in the areas of Treg manufacture, antigen specificity and in vivo survival, leading to promising pre-clinical results. As a result, engineered Treg therapies are on the verge of entry into clinical trial for the treatment type 1 diabetes. Nevertheless, the authors conclude that questions remain regarding the optimal strategy for designing Tregs that effectively suppress immune responses in the pancreatic islet environment. The figure from this review is available as a downloadableslide.

Amy Rothberg, Michael Lean, Blandine Laferrère

The concept of type 2 diabetes remission is gaining wide public and professional attention. In this issue, Rothberg, Lean and Laferrère (https://doi.org/10.1007/s00125-023-06069-1) discuss how substantial and sustained intentional weight loss can result in durable remission, especially if implemented early in the onset of the disease, preferably at the stage of prediabetes (defined in Europe, Australasia and Canada [and most of the world] as HbA_1c≥42 mmol/mol and <48 mmol/mol [≥6.0% and <6.5%], and in the USA as HbA_1c≥39 mmol/mol and <48 mmol/mol [≥5.7% and <6.5%]). Effective weight management also improves all features of the metabolic syndrome and reduces complications. The authors highlight that, although newer medications, such as glucagon-like peptide-1 receptor agonists and sodium–glucose cotransporter-2 receptor inhibitors, represent a formidable leap forward in the treatment of type 2 diabetes and associated obesity, and for the prevention of cardiovascular complications, their cost and side effects are still prohibitive for many. They conclude that affordable intensive lifestyle management should be provided as first-line therapy for the treatment of type 2 diabetes. According to the authors, the greatest research challenges are to improve adherence to a healthy lifestyle and long-term weight loss maintenance, and to define cost-effective approaches tailored to the preferences and needs of people living with type 2 diabetes. The figure from this review is available as a downloadableslide.

Anna G. Hoek, Elisa Dal Canto, Eva Wenker, Navin Bindraban, M. Louis Handoko, Petra J. M. Elders, Joline W. J. Beulens

Heart failure (HF) and type 2 diabetes are closely linked, and concomitantly pose an increased risk of morbidity and mortality. In this issue, Hoek et al (https://doi.org/10.1007/s00125-023-06068-2) present a comprehensive review of the epidemiology of HF in people with type 2 diabetes using both a narrative and systematic review approach. In their systematic review/meta-analysis, the authors reveal that there is a higher prevalence of left ventricular diastolic dysfunction (LVDD; 43%) and HF with preserved ejection fraction (HFpEF; 17%) in type 2 diabetes, as compared with left ventricular systolic dysfunction (LVSD; 6%) and HF with reduced ejection fraction (HFrEF; 7%). Furthermore, HFpEF incidence (7%) was shown to surpass HFrEF incidence (4%), emphasising the predominance of LVDD/HFpEF in type 2 diabetes. For LVDD, when assessed by grade (grade I, II or II) or by classification (indeterminate vs definitive), grade I and indeterminate LVDD were highly prevalent; this indicates that there is a large pre-clinical group with early LVDD that could be targeted for early disease detection, to reduce disease burden. The authors conclude that there is a need for easily accessible and reliable tools for diagnosing HF. They outline how the introduction of uniform and accessible guidelines for diagnosing HF (published by the European Society of Cardiology [ESC] in 2021) and the use of sodium–glucose cotransporter 2 inhibitors may lead to more effective treatment of HF in type 2 diabetes. The figures from this review are available as a downloadableslideset.

Nikhil R. Gandasi, Rui Gao, Lakshmi Kothegala, Abigail Pearce, Cristiano Santos, Samuel Acreman, Davide Basco, Anna Benrick, Margarita V. Chibalina, Anne Clark, Claudia Guida, Matthew Harris, Paul R. V. Johnson, Jakob G. Knudsen, Jinfang Ma, Caroline Miranda, Makoto Shigeto, Andrei I. Tarasov, Ho Yan Yeung, Bernard Thorens, Ingrid W. Asterholm, Quan Zhang, Reshma Ramracheya, Graham Ladds, Patrik Rorsman

The incretin hormone glucagon-like peptide 1 (GLP-1) stimulates insulin secretion and inhibits glucagon secretion, with both effects contributing to its blood glucose-lowering effect. GLP-1 is secreted in the gut as GLP-1(7–36), which is rapidly degraded to GLP-1(9–36) and which was previously believed to be biologically inactive. In this issue, Gandasi et al (https://doi.org/10.1007/s00125-023-06060-w) show that GLP-1(9–36), while lacking insulin releasing capacity, strongly and potently inhibits glucagon secretion. They demonstrate that circulating GLP-1(9–36) functions as a systemic inhibitor of glucagon secretion and that this effect is impaired in type 2 diabetes. The capacity of GLP-1(9–36) to inhibit glucagon secretion is prevented by glucagon receptor antagonists and the marked increase in circulating glucagon after administration of such compounds may (in part) be mediated by the removal of the glucagonostatic effects of GLP-1(9–36). The authors suggest that GLP-1(9–36) is more than just a biologically inactive metabolite and that it has many properties that qualify it as a new systemic glucagonostatic hormone.

Arunkumar Krishnan, Carolin V. Schneider, Yousaf Hadi, Diptasree Mukherjee, Bandar AlShehri,·Saleh A Alqahtani

Current evidence highlights a strong association between CVD and non-alcoholic fatty liver disease (NAFLD). The presence of NAFLD in association with type 2 diabetes worsens the metabolic profile and exacerbates the risk of CVD. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been reported to effectively reduce the incidence of major adverse cardiovascular events (MACE) in individuals with type 2 diabetes or NAFLD. However, the specific impact of GLP-1RAs on cardiovascular risk in individuals with both NAFLD and concurrent type 2 diabetes remains unclear. In this issue, Krishnan et al (https://doi.org/10.1007/s00125-023-06057-5) reveal that, among people with both NAFLD and type 2 diabetes, new GLP-1RA users experienced a lower incidence of MACE, cerebrovascular events, heart failure and mortality than those taking other glucose-lowering medications, with outcomes comparable to those in users of sodium-glucose cotransporter-2 (SGLT2) inhibitors. The findings suggest that early initiation of GLP-1RAs or SGLT2 inhibitors in individuals with NAFLD and type 2 diabetes has potential cardioprotective benefits. The authors conclude that regular cardiovascular risk assessments and prompt incorporation of either of these drugs are crucial for mitigating risks in these individuals. In addition, comparison of the effects of these two drugs may allow drug selection to be personalised based on individual patient needs.

Sonia Fernandez‑Veledo, Anna Marsal‑Beltran, Joan Vendrell

Succinate, traditionally associated with the tricarboxylic acid (TCA) cycle, has now emerged as a key player in cellular signalling via its receptor, succinate receptor 1 (SUCNR1). In this issue, Fernández-Veledo et al (https://doi.org/10.1007/s00125-023-06063-7) explore the role of succinate in diabetes, shedding light on its evolution from a conventional intracellular metabolite to a potent extracellular signalling molecule. Succinate’s multifaceted nature, with origins in both mitochondria and the microbiome, opens doors to understanding and managing complex metabolic diseases such as diabetes. Recent insights into succinate’s biology highlight its potential as both a biomarker in and a therapeutic target for managing diabetes and its related complications, presenting exciting prospects for future research and clinical interventions. The figure from this review is available as a downloadable slide.

José L. Peñalvo

The global prevalence of type 2 diabetes is rapidly rising, posing significant health and economic challenges, alongside evident disparities. The obesity epidemic exacerbates this issue, with sugar-sweetened beverages (SSBs) contributing to an excess intake of sugar and increased diabetes risk. In this issue, José Peñalvo (https://doi.org/10.1007/s00125-023-06064-6) discusses the implementation of SSB taxes as a promising public-health strategy to curb consumption of these beverages and alleviate the burden of type 2 diabetes. The author highlights how research indicates that such taxes lead to higher prices and reduced consumption of SSBs, particularly among lower socioeconomic groups, potentially reducing health inequalities. Ongoing tax schemes demonstrate positive effects on consumption patterns, with modelling studies predicting health benefits by preventing type 2 diabetes and related conditions. However, empirical evaluation of the impact of SSB taxes remains limited. Peñalvo concludes that continued research and tailored policies, coupled with complementary approaches to reduce diabetes and its risk factors, are crucial to effectively address the global type 2 diabetes crisis. The figure from this review is available as a downloadable slide.

Jeremy Basset‑Sagarminaga, Tineke van de Weijer, Patricia Iozzo, Patrick Schrauwen, Vera Schrauwen‑Hinderling

The liver, a pivotal organ in maintaining glucose balance, has emerged as a focal point in the quest to understand the pathogenesis of type 2 diabetes. Hepatic glucose uptake (HGU), a critical aspect of liver metabolism, can be measured using positron emission tomography (PET), but there are unique challenges related to the physiology and metabolic complexity of the liver. In this issue, Basset-Sagarminaga et al (https://doi.org/10.1007/s00125-023-06055-7) provide a comprehensive perspective on the array of protocols available for the measurement of HGU using [18F]-2-fluoro-2-deoxy-d-glucose (FDG) PET and delve into the current state of knowledge concerning HGU and its dysregulation in the context of type 2 diabetes. The authors conclude that FDG PET techniques hold the potential to reshape our understanding of metabolic diseases and advance therapeutic strategies. The figures from this review are available as a downloadable slideset

Judit Castillo‑Armengol, Flavia Marzetta, Ana Rodriguez Sanchez‑Archidona, Christian Fledelius, Mark Evans, Alison McNeilly, Rory J. McCrimmon, Mark Ibberson, Bernard Thorens

Repeated insulin-induced hypoglycaemia in individuals with diabetes progressively leads to defective counterregulation to restore normoglycaemia, particularly resulting in a decrease in glucagon secretion. This defect is thought to be caused by impaired hypoglycaemia sensing by hypothalamic neurons, although the precise mechanisms are mostly unknown. In this issue, Castillo-Armengol et al (https://doi.org/10.1007/s00125-023-06043-x) report findings from a study in which they developed a mouse model of type 2 diabetes with defective glucagon secretion caused by repeated hypoglycaemic episodes. Using this mouse model, they analysed hypothalamic gene expression via single-nuclei RNA sequencing and performed proteomic analysis of hypothalamic synaptosomal fractions. The authors show that repeated exposure to hypoglycaemia induces changes in neurons, oligodendrocytes and astrocytes that point to reduced sensing of hypoglycaemia, decreased activity of tripartite synapses, and impaired myelination. They also demonstrate increased signs of neurodegeneration with a high propensity for amyloid beta production in these cells. In summary, the authors state that the findings from this study help to define the hypothalamic causes of defective counterregulation and may lead to measures aimed at preventing hypoglycaemic episodes in insulin-treated individuals with diabetes.

Emilie Moens de Hase, Audrey M. Neyrinck, Julie Rodriguez, Miriam Cnop, Nicolas Paquot, Jean‑Paul Thissen, Yining Xu, Ana Beloqui, Laure B. Bindels, Nathalie M. Delzenne, Matthias Van Hul, Patrice D. Cani

Dysosmobacter welbionis is a commensal intestinal bacterium, the abundance of which is inversely associated with HbA_1c in individuals with obesity and type 2 diabetes. In this issue, Moens de Hase et al (https://doi.org/10.1007/s00125-023-06032-0) report that individuals who respond positively to prebiotic treatment, marked by a reduction in BMI after 3 months of intervention, had higher levels of D. welbionis at baseline compared with non-responders. Furthermore, participants treated with metformin exhibited significantly increased levels of this bacterium, while it was inversely linked to fasting blood glucose levels. The authors also show that, mechanistically, D. welbionis appeared to boost the secretion of key hormones, like glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). In mice, D. welbionis treatment not only curtailed weight gain and improved glucose tolerance but also outperformed metformin. The authors conclude that these findings hint at the pivotal role that D. welbionis might play in shaping our metabolic health, with the evidence suggesting that the abundance of D. welbionis is influenced by metformin treatment and associated with prebiotic response and glucose metabolism in individuals with obesity and diabetes. They conclude that their findings may have implications for the development of personalised approaches for the treatment of obesity and diabetes.

Gianluigi Savarese, Felix Lindberg, Gerasimos Filippatos, Javed Butler, Stefan D. Anker

Overactivation of the mineralocorticoid receptor (MR) has pathophysiological implications in multiple organ systems. In this issue, Savarese and Lindberg et al (https://doi.org/10.1007/s00125-023-06031-1) provide a comprehensive review of the role of MR overactivation in cardiac and renal disease, and summarise the evidence related to old and new methods of pharmacologically targeting the MR. The authors describe how traditional steroidal MR antagonists (MRA) are a cornerstone of therapy in heart failure but remain underused due to real and perceived risks of side effects, particularly in patients with renal failure and/or at risk of hyperkalaemia. Novel non-steroidal MRA have distinct properties that might enable inhibition of the MR with an improved safety profile. The authors highlight how the Phase III programme on one such novel non-steroidal MRA, finerenone, demonstrated improved renal and cardiovascular outcomes in patients with diabetic kidney disease, potentially setting the stage for a new paradigm in targeting MR overactivation. The figures from this review are available as a downloadable slideset.

Johan Jendle, Peter Adolfsson, Pratik Choudhary, Klemen Dovc, Alexander Fleming, David C. Klonoff, Julia K. Mader, Nick Oliver, Jennifer L. Sherr, Jan Šoupal, Lutz Heinemann

People living with diabetes often use a large variety of medical devices to assist their day-to-day diabetes management. In this issue, Jendle et al (https://doi.org/10.1007/s00125-023-06049-5) summarise the current understanding of interoperability in medical devices and data used in diabetes therapy. The authors highlight that a critical aspect of interoperability is how diabetes technology, such as systems for integrated continuous glucose monitoring and automated insulin delivery (AID) systems, communicate with each other. Furthermore, they state that how the data generated by these devices are not only effectively downloaded, integrated and presented, but also effectively and safely used by the individuals living with diabetes and their healthcare providers are also important aspects. As well as the practical challenges, the authors report that connected devices must also adhere to regulatory and legal frameworks, with key issues relating to data ownership and the integrity of connected devices. The authors conclude that an open and transparent standard for data handling remains to be established and only when data can be assessed in a standardised manner can the data generated be integrated into electronic medical records. The figures from this review are available as a downloadable slideset.

Scott C. Mackenzie, Chris A. R. Sainsbury, Deborah J. Wake

The rise of artificial intelligence (AI) has brought both promise and apprehension across numerous industries, and healthcare is no exception. In the context of diabetes care, current AI technologies predominantly target type 1 diabetes, representing just the tip of the iceberg in terms of potential. In this review, Mackenzie et al (https://doi.org/10.1007/s00125-023-06038-8) provide a comprehensive perspective on how AI stands poised to revolutionise the entire spectrum of diabetes care. This transformation encompasses empowering self-management, delivering personalised educational support, and leveraging diverse data sources for predictive analytics and clinical-decision support. The authors state that the ultimate objectives are to enhance the quality of clinical care whilst streamlining its delivery. However, the rapid pace of diabetes AI innovation, coupled with a limited evidence base, presents challenges to achieving safe, integrated and ethically responsible adoption. Mackenzie et al suggest that, to unlock the full potential of AI-enabled diabetes care, stakeholders must collaborate to address issues concerning clinical safety, technological readiness, health equity and user acceptance. The figures from this review are available as a downloadable slideset.

Achyut Ram Vyakaranam, Maryama M. Mahamed, Per Hellman, Olof Eriksson, Daniel Espes, Gustaf Christoffersson, Anders Sundin

The pancreatic islets of Langerhans are highly innervated, especially from the sympathetic nervous system. Unravelling the complex interplay among neural signals, hormonal regulation and immune responses through quantifiable non-invasive imaging, such as positron emission tomography/computerised tomography (PET/CT) techniques, has been a longstanding pursuit in understanding the pathophysiology of both type 1 and type 2 diabetes. In this issue, Vyakaranam et al (https://doi.org/10.1007/s00125-023-06039-7) explore PET/CT as a potential imaging method for the pancreatic sympathetic nervous system in humans. The PET tracer ¹¹C-hydroxy ephedrine (¹¹C-HED), previously employed to assess cardiac innervation, was used by the authors for diagnosing tumours with a sympathetic origin. Among these individuals examined by ¹¹C-HED-PET in the oncological setting, a lower degree of tracer uptake in the pancreas was found in those with type 2 diabetes, along with regional differences suggesting nerve mass losses. The authors conclude that this study provides a proof of concept for future investigations into pancreatic innervation in both type 1 and type 2 diabetes.

Laura J. Corbin, David A. Hughes, Caroline J. Bull, Emma E. Vincent, Madeleine L. Smith, Alex McConnachie, Claudia‑Martina Messow, Paul Welsh, Roy Taylor, Michael E. J. Lean, Naveed Sattar, Nicholas J. Timpson

The Diabetes Remission Clinical Trial (DiRECT) demonstrated that a structured weight management programme, implemented in a primary care setting, can deliver both meaningful weight loss (24% of participants with more than 15kg weight loss) and type 2 diabetes remission (46% of participants at 12 months). In this issue, Corbin et al use (https://doi.org/10.1007/s00125-023-06019-x) high-throughput metabolomics technologies to explore the wider metabolic consequences of the same intervention. The authors investigated over 1000 metabolites in serum samples collected from 261 participants of the DiRECT trial before and 1 year after beginning the intervention (or control) treatment. Around 14% of all metabolites measured, including many associated with fat metabolism, were found to be altered in the intervention arm. The authors conclude that dietary weight loss reverses many important metabolomic changes previously associated with increased risk of type 2 diabetes, suggesting that excess weight is upstream of many of these metabolic aberrations.

Willemijn E. Corpeleijn, Wouter J. de Waal, Henk S. Schipper, Albert Wiegman

Children with onset of type 1 diabetes under 10 years of age have an 11.4-fold increased risk of premature atherosclerotic cardiovascular disease (ASCVD) compared with matched controls. Part of their ASCVD risk is attributed to dyslipidaemia and, similar to children with familial hypercholesterolaemia (FH), lipid-lowering therapy may lower their ASCVD risk. In this issue, Corpeleijn et al (https://doi.org/10.1007/s00125-023-06041-z) describe how, in a 20 year follow-up study of statins in children with FH, early initiation slowed the progression of carotid intima–media thickness and reduced the risk of ASCVD in adulthood. The authors report that, in their 30 years’ experience of statin use in children with FH they have not observed any serious side effects, such as rhabdomyolysis. Notably, statins have been associated with disease progression in type 2 diabetes, which is likely to be due to an increase in peripheral insulin resistance, a hallmark of type 2 diabetes but less of an issue in type 1 diabetes. The authors conclude that there is a strong rationale for early ASCVD risk management in children with type 1 diabetes, including a potential role for statins. The figure from this review is available as a downloadable slide.

Vikas S. Sridhar, Christine P. Limonte, Per‑Henrik Groop, Hiddo J. L. Heerspink, Richard E. Pratley, Peter Rossing, Jay S. Skyler, David Z. I. Cherney

Over the past 20 years, the treatment of chronic kidney disease (CKD) in type 1 and type 2 diabetes has focused on glycaemic and blood pressure control, especially, in the latter case, using renin–angiotensin system (RAS) blockers. However, little progress has been made since RAS inhibitor trials demonstrated a slowing of CKD progression, especially in type 1 diabetes. Consequently, individuals with type 1 or type 2 diabetes have a high residual risk of CKD and CVD, and life expectancy for children with type 1 diabetes is reduced, highlighting the urgent need to make progress. However, there is optimism for people with type 2 diabetes. In type 2 diabetes, sodium–glucose cotransporter-2 inhibitors, glucagon-like peptide 1 receptor agonists and non-steroidal mineralocorticoid receptors antagonists have become the standard of care for reducing adverse kidney and cardiovascular outcomes, shifting the focus from a ‘glucose-centric’ to a ‘cardiorenal risk-centric’ approach. In this issue, Sridhar and Limonte et al (https://doi.org/10.1007/s00125-023-06015-1) evaluate the potential translation of these type 2 diabetes therapeutics to individuals with type 1 diabetes, with the lens of preventing the development and progression of CKD. The authors conclude that, considering the mechanistic overlap in the development and progression of CKD in type 1 and type 2 diabetes, there is a strong rationale for developing novel CKD therapies for use in both type 1 and type 2 diabetes and for repurposing existing type 2 diabetes CKD therapies for the treatment of CKD in people with type 1 diabetes. The figure from this review is available as a downloadable slide

Jian‑Ming Li, Xianyu Li, Lawrence W. C. Chan, Ruinian Hu, Tian Zheng, Haojie Li, Sijun Yang

Insulin resistance plays a key role in the development of type 2 diabetes and experimental and clinical studies have shown that insulin resistance can be exacerbated by sustained lipotoxicity-induced mitophagy deficiency. Emerging evidence suggests that exosomes (Exos) from macrophages play an essential role in regulating metabolic homeostasis. In this issue, Li et al (https://doi.org/10.1007/s00125-023-05992-7) show that lipopolysaccharide and palmitic acid-induced macrophages produce M1 Exos, which couple to the mitochondrial transport and fusion machinery and lead to abnormal mitophagy that can promote insulin resistance. The authors report that miR-27-3p is responsible for the effects of lipotoxicity-polarized macrophage-derived M1 Exos both in vitro and in vivo. They show that M1 Exos modulate mitochondrial fitness through upregulation of dynamin-related protein 1 and mitochondrial fission factor and downregulation of mitofusin 2 and optic atrophy protein 1, affecting mitochondrial transport and leading to mitochondrial fission rather than fusion. The authors identify the miR-27-3p–mitochondrial rho GTPase 1 (Miro1) axis as a key insulin-supressing pathway leading to the accumulation of fragmented dysfunctional mitochondria, resulting in a decrease in insulin sensitivity and triggering NOD-like receptor 3-dependent proinflammatory responses. The authors conclude that the miR-27-3p–Miro1 axis could be a new therapeutic target for drug development in type 2 diabetes.

Emily K. Sims, Susan M. Geyer, S. Alice Long, Kevan C. Herold

Heterogeneity exists in type 1 diabetes progression, even within the different stages of the disease. In this issue, Sims et al (https://doi.org/10.1007/s00125-023-06003-5) show that, in individuals with stage 2 type 1 diabetes, an elevation in proinsulin:C-peptide (PI:C) ratio, a biomarker reflecting beta cell stress, is highly predictive of progression to stage 3 type 1 diabetes. They report that teplizumab weakened this relationship between beta cell stress and progression, and participants with a high baseline ratio treated with the drug showed reduced progression rates compared with participants who were treated with placebo. The authors conclude that the PI:C ratio may identify subgroups of individuals who are most likely to benefit from rapid consideration for teplizumab treatment, given their imminent risk of clinical presentation with stage 3 type 1 diabetes.

Merel M. Ruissen, José D. Torres‑Pena, Bas S. Uitbeijerse, Antonio P. Arenas de Larriva, Sasja D. Huisman, Tuncay Namli, Eckhard Salzsieder, Lutz Vogt, Manuela Ploessnig, Bob van der Putte, Armelle Merle, Gustavo Serra, Gustavo Rodríguez, Albert A. de Graaf, Eelco J. P. de Koning, Javier Delgado‑Lista, Jacob K. Sont, POWER2DM Consortium

Diabetes self-management is complex and poses a large burden on individuals. E-health and mobile-health/wireless technologies can be helpful tools to support individuals in their daily diabetes self-management, aiming to reduce this burden. In this issue, Ruissen et al (https://doi.org/10.1007/s00125-023-06006-2) report on the results of a novel e-health support system (POWER2DM) that provides personalised, bidirectional support for both individuals with diabetes and clinicians. The authors describe how POWER2DM integrates biomedical, psychological and behavioural aspects. They show that it is a safe and effective tool that enables both individuals with type 1 diabetes and those with type 2 diabetes to improve glycaemic control, quality of life and diabetes self-management. The authors conclude that e-health and mobile-health support systems that acknowledge the complexity of diabetes care and provide personalised support are helpful tools for improving quality of care and quality of life.

Nicholas J. Thomas, Angus G. Jones

Type 1 diabetes occurs at any age, but diagnosis in adults is difficult as type 2 diabetes predominates. In this issue, Thomas and Jones (https://doi.org/10.1007/s00125-023-06004-4) review the challenges of robustly identifying type 1 diabetes in older adults and outline how these can be addressed. The authors also discuss the potential implications of misclassification for our understanding of type 1 diabetes presenting in adults. The phenotype of type 1 diabetes is commonly reported to be different at older onset ages, overlapping with that of type 2 diabetes. Studies suggest that misclassification of clinically diagnosed type 1 diabetes is increasingly common with older age. The authors state that the inadvertent study of participants with and without autoimmune aetiology diabetes may explain many of the reported changes in the characteristics of those with type 1/autoimmune diabetes with older age. However, when robust disease definitions are used, the phenotype of older-onset type 1 diabetes appears broadly similar to that of type 1 diabetes occurring earlier in life, without differences in presentation, genotype or progression across adult-onset ages. The authors conclude that, in the clinic, biomarker investigation is essential for the diagnosis of adult-onset type 1 diabetes, while, in research, use of high-specificity approaches to define type 1 diabetes in adults is critical to understanding the phenotype of adult-onset autoimmune aetiology diabetes. The figures from this review are available as a downloadable slideset

Alfonso Galderisi, Alice L. J. Carr, Mariangela Martino, Peter Taylor, Peter Senior, Colin Dayan

The recent approval by the US Food and Drug Administration of the use of teplizumab in preclinical (stage 2) type 1 diabetes represents a paradigm shift in our therapeutic approach to this disease. Rather than focusing on improvements in insulin replacement, the development of low-risk agents to preserve beta cell function in the preclinical phases of the disease may avert the need for insulin, providing years of burden-free life with near-perfect glucose control. However, to develop new drugs in this space, it is of pivotal importance to be able to accurately measure changes in beta cell function before significant rises in glucose occur, using methods that can be applied in large clinical trial populations. In this issue, Galderisi et al (https://doi.org/10.1007/s00125-023-06011-5) describe the metabolic changes occurring during the preclinical stages of type 1 diabetes and discuss the pros and cons of the available methodologies to quantify beta cell function in these early disease phases. They state that metabolic modelling of the data derived from standard tests, such as the OGTT or mixed meal tolerance test, may provide more accurate estimates of insulin secretion and insulin sensitivity in early-stage type 1 diabetes than C-peptide measurement alone. The authors conclude that such models should be validated in large longitudinal cohorts to confirm their value as effective measures of beta cell function in the early stage of the disease. The figures from this review are available as a downloadable slideset

Deyan Yavorov‑Dayliev, Fermín I. Milagro, Josune Ayo, María Oneca, Ignacio Goyache, Miguel López‑Yoldi, Paula Aranaz

In the recent past, the importance of the gut microbiota in the regulation of glucose and insulin homeostasis has been demonstrated. This has led to the emergence of probiotics and synbiotics as alternative therapies to ameliorate metabolic diseases-related disturbances, including those associated with diabetes mellitus, insulin resistance and inflammation. In this issue, Yavorov-Dayliev et al (https://doi.org/10.1007/s00125-023-05981-w) fully characterise the glycaemia-normalising activity of a synbiotic containing Pediococcus acidilactici, oat β-glucans and chromium picolinate in both Caenorhabditis elegans and mice. The authors demonstrate that supplementation with this synbiotic counteracted diabetes-related disturbances in C. elegans following exposure to high glucose and in mice with diet-induced obesity. Specifically, the synbiotic counteracted the effect of the high glucose/diet-induced obesity by modulating the insulin–IGF-1 signalling pathway, and by ameliorating glucose tolerance, excess visceral adiposity, insulin resistance, hepatic steatosis and liver damage. The authors propose that the synbiotic induced these affects by altering the intestinal microbiota, affecting the insulin signalling pathway, activating fatty acid β-oxidation and reducing the low-grade inflammation. In summary, Yavorov‑Dayliev and colleagues suggest that the synbiotic used in their study could provide an alternative strategy for the prevention of type 2 diabetes and its comorbidities.

Hitoshi Iida, Tatsuyoshi Kono, Chih‑Chun Lee, Preethi Krishnan, Matthew C. Arvin, Staci A. Weaver, Timothy S. Jarvela, Renato C. S. Branco, Madeline R. McLaughlin, Robert N. Bone, Xin Tong, Peter Arvan, Iris Lindberg, Carmella Evans‑Molina

Impaired processing of proinsulin into mature insulin is a key pathological feature of both type 1 and type 2 diabetes. In this issue, Iida and Kono et al (https://doi.org/10.1007/s00125-023-05979-4) investigate the link between endoplasmic reticulum (ER) Ca²⁺ levels and proinsulin processing using a mouse model with beta cell-specific sarcoendoplasmic reticulum Ca²⁺ ATPase-2 (SERCA2) deletion (βS2KO mice). βS2KO mice exhibited age-dependent glucose intolerance and elevated plasma and pancreatic proinsulin levels, whilst, in βS2KO islets, ER Ca²⁺ levels were reduced and glucose-stimulated Ca²⁺ synchronicity was impaired. In addition, expression of connexin-36, which is involved in the coordination of Ca²⁺ oscillations and glucose-stimulated insulin secretion, was reduced in βS2KO islets. Mechanistic studies showed that SERCA2 loss was associated with reduced maturation and activity of proinsulin processing enzymes and resulted in aberrant accumulation of proinsulin in the proximal secretory pathway. Treatment of islets from human donors without diabetes with high glucose and palmitate concentrations partially phenocopied the observations in βS2KO islets. The authors conclude that their findings suggest that chronic ER Ca²⁺depletion due to SERCA2 deficiency impairs the spatial regulation of prohormone trafficking and processing within the beta cell.

Charlotte Skriver, Søren Friis, Lotte B. Knudsen, Andrei‑Mircea Catarig, Alice J. Clark, Christian Dehlendorff, Lina S. Mørch

Findings from preclinical and epidemiological studies have suggested that glucagon-like peptide-1 receptor agonists (GLP-1RAs) may protect against prostate cancer, but the evidence is inconclusive. In this issue, Skriver et al (https://doi.org/10.1007/s00125-023-05972-x) report findings from a large population-based study employing data from Danish nationwide prescription, cancer, health and administrative registries. Using these data, the authors examined the risk of prostate cancer in a large sample of men aged ≥50 years with diabetes who commenced use of GLP-1RAs or basal insulin during 2007–2019. They show that men treated with GLP-1RAs had a lower incidence of prostate cancer compared with men treated with basal insulin. This association was observed particularly among older men (≥70 years) and men with cardiovascular disease. The authors conclude that their results may indicate that GLP-1RA use could have protective properties against prostate cancer but that further studies are needed to confirm these findings.

Peter J. Thompson, Jasmine Pipella, Guy A. Rutter, Herbert Y. Gaisano, Pere Santamaria

Islet autoimmunity results from a complex dialogue between the immune system and islets, eventually leading to symptomatic type 1 diabetes. In this issue, Thompson and colleagues (https://doi.org/10.1007/s00125-023-05970-z) summarise the various ways in which beta cells influence the onset and progression of islet autoimmunity in type 1 diabetes in humans. Recent work suggests that islet autoimmunity in genetically predisposed individuals results from environmental triggers that may affect beta cells early in life. Beta cells present novel antigens, undergo diverse stress responses and exhibit a functional hierarchy within the islet. Emerging work also points to alpha cells as a potential therapeutic target for arresting islet autoimmunity. Although there are many questions remaining, continued efforts to understand islet autoimmunity through the lens of the beta cell will undoubtedly improve the diagnosis and treatment of type 1 diabetes. The figures from this review are available as a downloadable slideset.

Claire L. Meek

Over 20 million infants per year are born to mothers with diabetes, and are at high risk of childhood obesity, attributed primarily to developmental influences in utero. The early onset of obesity in children with existing environmental and genetic susceptibilities to diabetes should be a major public health concern. In this issue, Claire Meek (https://doi.org/10.1007/s00125-023-05965-w) summarises the current understanding of the pathophysiology of obesity in children after intrauterine exposure to maternal hyperglycaemia. Meek proposes a new hypothesis for the mechanisms underlying childhood obesity in infants born to mothers with diabetes, involving subtle upregulation of de novo lipogenesis pathways and pancreatic beta cell function, which is initiated in utero and persists into childhood. The author also highlights possible opportunities for intervention and concludes that effective intervention will require a new focus on maternal health before, during and after pregnancy to halt the intergenerational cycle of obesity. The figure from this review is available as a downloadable slide.

Yael Riahi, Aviram Kogot‑Levin, Liat Kadosh, Bella Agranovich, Assaf Malka, Michael Assa, Ron Piran, Dana Avrahami, Benjamin Glaser, Eyal Gottlieb, Fields Jackson III, Erol Cerasi, Ernesto Bernal‑Mizrachi, Aharon Helman, Gil Leibowitz

Diabetes is characterised by hyperglucagonemia as well as insulin deficiency, making it a dual hormone disease; however, the mechanisms involved in alpha cell dysfunction are unclear. In this issue, Riahi et al (https://doi.org/10.1007/s00125-023-05967-8) highlight the nutrient sensor mammalian target of rapamycin complex 1 (mTORC1) as a key player in diabetes-related hyperglucagonemia. They show that mTORC1 activity was increased in alpha cells from type 1 and type 2 diabetes models, and its inhibition by inducible Rptor knockout in alpha cells from a type 1 diabetes model dampened glucagon secretion and ameliorated diabetes. Metabolomics, metabolic flux and gene expression studies revealed that alpha cell exposure to hyperglycaemia enhanced glucose-derived amino acid synthesis and transport, culminating in increased glutamate, branched-chain amino acid and methionine cycle activity, all contributing to stimulation of mTORC1 activation. The authors highlight that prolonged high glucose exposure therefore alters amino acid metabolism, which may drive persistent mTORC1 activation and subsequent excessive glucagon secretion. They conclude that early normalisation of blood glucose levels is crucial to prevent alpha cell dysfunction in diabetes and suggest targeting nutrient(s) metabolism and mTORC1 signalling in alpha cells as an appealing avenue for diabetes treatment.

Yukari Kobayashi, Jin Long, Shozen Dan, Neil M. Johannsen, Ruth Talamoa, Sonia Raghuram, Sukyung Chung, Kyla Kent, Marina Basina, Cynthia Lamendola, Francois Haddad, Mary B. Leonard, Timothy S. Church, Latha Palaniappan

Previous studies in people with overweight/obesity and type 2 diabetes have shown that a combination of aerobic and resistance training is superior to either type of exercise alone for lowering HbA_1c levels. In this issue, Kobayashi et al (https://doi.org/10.1007/s00125-023-05958-9) describe the STRONG-D study, which aimed to determine the impact of different exercise regimens on glycaemic control in people with ‘normal-weight type 2 diabetes’ (BMI <25 kg/m²). The study compared strength training alone, aerobic training alone, and combined strength and aerobic training. In contrast to previous trials in individuals with overweight/obesity, the authors show that strength training alone was more effective at reducing HbA_1c levels than aerobic training alone, with combination training showing intermediate effects. The authors highlight that increased lean mass relative to fat mass, observed only in the strength training group, independently predicted lower HbA_1c levels. The authors emphasise the significance of strength training for managing type 2 diabetes in normal-weight individuals and highlight the importance of considering body composition in exercise recommendations for this population. They conclude that these findings could contribute to personalised care for different diabetes phenotypes.

Matthew Anson, Sizheng S. Zhao, Philip Austin, Gema H. Ibarburu, Rayaz A. Malik, Uazman Alam

The beneficial extra-glycaemic effects of SGLT2i and GLP-1 RA on weight, renal protection and major adverse cardiovascular events are well established and make them attractive therapies in type 2 diabetes compared with other more traditional glucose-lowering agents. People with type 1 diabetes share many of the same cardiovascular risk factors as those with type 2 diabetes. Such novel agents are not approved for type 1 diabetes but are still prescribed off-label, with a paucity of robust data underpinning their safety and efficacy in this cohort. In this issue, Anson et al (https://doi.org/10.1007/s00125-023-05975-8) undertake a retrospective analysis of individuals with type 1 diabetes adjunctively treated with either an SGLT2i or a GLP-1 RA, with outcomes analysed 5 years after initiation of therapy. The authors show that individuals treated with an SGLT2i had a reduced risk of developing heart failure and chronic kidney disease and of being hospitalised for any cause compared with those adjunctively treated with a GLP-1 RA, despite an increased risk of diabetic ketoacidosis. They conclude that the findings suggest a net overall benefit of SGLT2i in type 1 diabetes compared with GLP-1 RA therapy and that dedicated long-term randomised trials are warranted to validate these findings.

In our October 2023 issue, we feature a series of reviews that focus on incretin-based therapies. These drugs were developed following the discovery of a peptide, exendin-4, in the Gila monster’s venom in the 1990s. Being structurally similar to the incretin hormone glucagon-like peptide-1 (GLP-1), exendin-4 was found to mimic the glucose-regulating effects of incretins. The decades following this discovery have seen the generation of several incretin-based therapies and, in this issue of Diabetologia, we are excited to include eight reviews summarising the state-of-the-art knowledge about these agents. Drucker and Holst (https://doi.org/10.1007/s00125-023-05906-7) start by describing the function of GLP-1, namely glucose-dependent potentiation of insulin secretion and glucoregulatory actions, appetite reduction and cardioprotection. Nauck and Müller (https://doi.org/10.1007/s00125-023-05956-x) go on to discuss another incretin hormone: glucose-dependent insulinotropic polypeptide (GIP). GIP was not initially considered an obvious drug candidate; however, a novel drug, tirzepatide, has demonstrated that dual agonism of GLP-1 and GIP receptors produces more substantial reductions in HbA_1c and body weight than selective GLP-1 receptor agonists (GLP-1RAs). Tirzepatide is but one example of a novel incretin-based therapy, with this and other advances in incretin pharmacology and drug development being summarised in the review by Tschöp et al (https://doi.org/10.1007/s00125-023-05929-0). These therapies, old and new, not only have therapeutic potential in type 2 diabetes, but also may be beneficial in other types of diabetes. In their review, Mathieu and Ahmadzai (https://doi.org/10.1007/s00125-023-05980-x) discuss the evidence for the beneficial effects of incretin-based therapies in type 1 diabetes, monogenic forms of diabetes and other conditions leading to hyperglycaemia. In terms of diabetic complications, Solini et al (https://doi.org/10.1007/s00125-023-05973-w) delve into the cardiovascular protection offered by incretin-based therapies, while Goldney et al (https://doi.org/10.1007/s00125-023-05988-3) discuss their effects on microvascular complications. Andreasen et al (https://doi.org/10.1007/s00125-023-05966-9) highlight the use of these drugs in the treatment of other metabolic diseases, specifically obesity and non-alcoholic fatty liver disease (NAFLD). Thus, the potential benefits of incretin-based therapies are clearly extensive. In contrast, however, as discussed by Karagiannis et al (https://doi.org/10.1007/s00125-023-05962-z), their uptake is restricted due to socioeconomic factors, such as affordability, accessibility, health literacy and provider bias. To extend their benefits at a societal level, a concerted effort must be made to address these issues. Looking ahead, the future holds great promise for incretin-based therapies to expand the treatment options available for individuals with metabolic disorders, offering new avenues for effective management and improved quality of life. This review set is accompanied by an editorial by Krook and Mulder (https://doi.org/10.1007/s00125-023-05987-4).

Sandra S. Hammer, Tim F. Dorweiler, Delaney McFarland, Yvonne Adu‑Agyeiwaah, Natalia Mast, Nicole El‑Darzi, Seth D. Fortmann, Sunil Nooti, Devendra K. Agrawal, Irina A. Pikuleva, George S. Abela, Maria B. Grant, Julia V. Busik

With the advancement of spectral-domain optical coherence tomography imaging, hyperreflective crystalline deposits have been identified in retinal pathologies, including diabetic retinopathy. In this issue, Hammer and Dorweiler et al (https://doi.org/10.1007/s00125-023-05949-w) uncover the nature of crystalline deposits in retina from human donors with diabetes as cholesterol crystals. Using cell culture- and animal model-based studies, cholesterol crystals were shown to recapitulate all major pathogenic mechanisms leading to diabetic retinopathy, including inflammation, cell death and breakdown of the blood–retinal barrier. Fibrates, statins and α-cyclodextrin effectively dissolved cholesterol crystals and prevented endothelial pathology. The authors conclude that the formation of cholesterol crystals represents a unifying pathogenic mechanism in the development of diabetic retinopathy and strategies for removal of cholesterol crystals may have therapeutic value in the treatment of diabetic retinopathy.

Rasmus Wibaek, Gregers S. Andersen, Allan Linneberg, Torben Hansen, Niels Grarup, Anne Cathrine B. Thuesen, Rasmus T. Jensen, Jonathan C. K. Wells, Kasper A. Pilgaard, Charlotte Brøns, Dorte Vistisen, Allan A. Vaag

Over the past three decades, longitudinal studies have consistently found lower birthweight to be associated with higher risk of type 2 diabetes, but prospective data on diabetes incidence are lacking. In this issue, Wibaek et al (https://doi.org/10.1007/s00125-023-05937-0) used data on objectively measured birthweight from original midwife records dating back to 1939−1971, and in a large sample of middle-aged to older adults examined the influence of birthweight on age- and sex-specific incidence of type 2 diabetes over two decades, from 1999−2020. The authors show that type 2 diabetes incidence rate increased with age, was higher in male participants, and that the absolute rate of increase was markedly higher in individuals born with lower birthweight compared with higher birthweight in a dose−response manner. Altogether, birthweight, genetic susceptibility of type 2 diabetes and adult adiposity (BMI) were found to be strong and independent risk factors for type 2 diabetes. The authors conclude that, within the era of precision medicine, birthweight holds strong potential to be used as a feasible marker to guide clinical care and treatment in type 2 diabetes.

Daniela Zanetti, Laurel Stell, Stefan Gustafsson, Fahim Abbasi, Philip S. Tsao, Joshua W. Knowles, RISC Investigators, Björn Zethelius, Johan Ärnlöv, Beverley Balkau, Mark Walker, Laura C. Lazzeroni, Lars Lind, John R. Petrie, Themistocles L. Assimes

The euglycaemic−hyperinsulinaemic clamp (EIC) is a reference standard for directly assessing insulin sensitivity but is invasive and time-consuming. In this issue, Zanetti et al (https://doi.org/10.1007/s00125-023-05946-z) assess the incremental value of high-throughput plasma proteomic profiling, using the proximity extension assay, in developing signatures that correlate with the M value derived from the EIC. The authors use two cohorts, the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) and the Uppsala Longitudinal Study of Adult Men (ULSAM), to show that plasma proteomic signatures of up to 67 proteins substantially improve the cross-sectional estimation of the M value over routinely available clinical variables. A smaller subset of proteins afforded much of this improvement, especially when considering predictive models applied across both cohorts. IGF-binding protein 2 was the single most consistently selected protein across all analyses and models. Zanetti and colleagues state that their approach provides opportunities to improve the identification of individuals at risk of adverse health consequences related to insulin resistance.

Valeriya Lyssenko, Allan Vaag

The diabetes epidemic has resulted in an epidemic of diabetes-associated complications. Systemic monitoring of individuals with diabetes and new insights into biological mechanisms leading to the progression of complications are necessary to halt this escalation. In this issue, Lyssenko and Vaag (https://doi.org/10.1007/s00125-023-05964-x) summarise state-of-the-art discoveries in the genetic predisposition to kidney, eye and nerve damage in individuals with diabetes. They also provide a critical view on the existing gaps in the current clinical definitions of organ damage that might hinder discovery of genomic factors that trigger or cause associated disease. Knowledge about environmental perinatal exposures may shed light on adaptive changes responsible for the intrauterine programming of metabolic mechanisms that may underlie organ vulnerability. Profiling genetic susceptibility to diabetes-associated metabolic risk factors, including high blood glucose levels, impaired insulin secretion and action, obesity, hypertension, reduced liver function and dysregulated immune system, may aid in pathophysiology-based classification of complications and identification of individuals at high risk for these complications for early prevention in individuals with diabetes. The figure from this review is available as a downloadable slide

Amber M. Luckett, Michael N. Weedon, Gareth Hawkes, R. David Leslie, Richard A. Oram, Struan F. A. Grant

Advances in genetic research have greatly expanded our understanding of the genetic contribution to type 1 diabetes, facilitating the development of genetic risk scores (GRSs) for type 1 diabetes risk. In this review, Luckett et al (https://doi.org/10.1007/s00125-023-05955-y) summarise the utility of type 1 diabetes GRSs, specifically for disease classification and prediction. They highlight how progression from simplistic models to models that incorporate HLA interactions have allowed us to capture disease risk and discriminate type 1 diabetes from other forms of diabetes. Alongside other factors, such as family history and autoantibody status, GRSs have been integrated into combined risk scores for type 1 diabetes onset prediction. Within newborn population screening, type 1 diabetes GRSs have the potential to identify infants at risk of future presentation of the disease so that they can receive additional clinical care. The authors conclude that the integration of GRSs into healthcare has huge potential for identifying and informing treatment in individuals with type 1 diabetes. The figures from this review are available as a downloadable slideset

Karis Little, Aditi Singh, Angel Del Marco, María Llorian‑Salvador, Maria Vargas‑Soria, Mireia Turch‑Anguera, Montse Solé, Noëlle Bakker, Sarah Scullion, Joan X. Comella, Ingeborg Klaassen, Rafael Simó, Monica Garcia‑Alloza, Vijay K. Tiwari, Alan W. Stitt, on behalf of the RECOGNISED consortium

People with type-2 diabetes are at higher risk of cognitive decline and dementia; however, the cellular changes that occur in the brain as type 2 diabetes progresses remain poorly understood. In this issue, Little, Singh and Del Marco et al (https://doi.org/10.1007/s00125-023-05935-2) describe using single-cell RNA sequencing to investigate changes to the neurovascular unit (NVU) within the cerebral cortex in a mouse model of type 2 diabetes. The authors identified distinct transcriptional signatures in a number of key neuronal, glial vascular and immune cells, demonstrating that metabolic and inflammatory processes are dysregulated in the cortical glia of diabetic mice. In parallel, they report that neuronal maturation was significantly affected in the type 2 diabetes cortex, with these changes occurring alongside evident cognitive decline and vascular damage. They further demonstrate that post-mortem cortex from individuals with type 2 diabetes showed comparable changes to what was observed in the mouse model. The authors conclude that altered metabolic function, neuroinflammation and changes to neuronal maturation may play an integral role in NVU damage and thus cognitive decline in type 2 diabetes.

Arturo Roca-Rivada, Sandra Marín-Cañas, Maikel L. Colli, Chiara Vinci, Toshiaki Sawatani, Lorella Marselli, Miriam Cnop, Piero Marchetti, Decio L. Eizirik

TNF-α inhibition delays the progression of type 1 diabetes and circulating TNF-α is associated with aggressive forms of the disease. In this issue, Roca-Rivada et al (https://doi.org/10.1007/s00125-023-05908-5) describe the molecular mechanisms triggered by TNF-α that lead to human beta cell dysfunction and death when the type 1 diabetes candidate gene PTPN2 is silenced. Cells silenced for PTPN2 are more susceptible to the deleterious effect of TNF-α and IFN-α, showing increased beta cell apoptosis. The authors demonstrate that beta cell apoptosis is abolished by the parallel blocking of Bcl-2-like protein 2 (BIM) or c-Jun N-terminal kinase (JNK1), indicating an unexpected common pathway between TNF-α and IFN-α. They further identify JNK1 as a substrate for PTPN2 in beta cells. The authors conclude that people with type 1 diabetes carrying risk-associated PTPN2 polymorphisms may benefit from therapies that inhibit TNF-α.

Per-Ola Carlsson, Daniel Espes, Sofia Sisay, Lindsay C. Davies, C. I. Edvard Smith and Mathias G. Svahn

Mesenchymal stromal cells (MSCs) have been shown to modulate the immune system and dampen inflammatory and autoimmune responses in numerous diseases. In this issue, Carlsson et al (https://doi.org/10.1007/s00125-023-05934-3) report their findings from a Phase I/II dose escalation and double-blind placebo-controlled clinical trial investigating the Wharton’s jelly MSC drug product, ProTrans, for the treatment of new-onset type 1 diabetes. In the dose escalation safety study, the authors demonstrate that ProTrans can be safely administered intravenously with no serious adverse events. A fixed dose of 200 million MSCs preserved the production of endogenous insulin and reduced exogenous insulin replacement compared with placebo 1 year after treatment. The authors conclude that a single treatment with ProTrans could potentially delay type 1 diabetes disease progression, thereby reducing the associated complications and improving quality of life.

Nicolai J. Wewer Albrechtsen, Jens J. Holst, Alan D. Cherrington, Brian Finan, Lise Lotte Gluud, Danielle Dean, Jonathan E. Campbell, Stephen R. Bloom, Tricia M.-M. Tan, Filip K. Knop, Timo D. Müller

More than 100 years ago, scientists were on the path to discovering a central novel metabolic regulator, now known as glucagon. Although the role of glucagon in diabetes has been studied intensively, its place in physiology and pathophysiology is still debated. In this issue, Wewer Albrechtsen et al (https://doi.org/10.1007/s00125-023-05947-y) capture the fundamentals of glucagon biology and its role in metabolic diseases. Key questions on how glucagon secretion is controlled, not only by glucose but also by amino acids and lipids, are addressed. In addition, the authors discuss how a new concept, termed ‘glucagon resistance’, may explain the diabetogenic hyperglucagonaemia observed in metabolic diseases. The authors propose that future glucagon research may help to uncover the molecular backbone of inter-organ dysfunction in individuals with diabetes and liver disease. They conclude that, as well as treating hypoglycaemia, glucagon-based therapies may also provide benefits for weight loss and the treatment of fatty liver disease. The figures from this review are available as a downloadable slideset

Caroline B. Terwee, Petra J. M. Elders, Marieke T. Blom, Joline W. Beulens, Olaf Rolandsson, Alize A. Rogge, Matthias Rose, Nicola Harman, Paula R. Williamson, Frans Pouwer, Lidwine B. Mokkink, Femke Rutters

Patient-reported outcomes (PROs) are important for shared decision making and standardisation of outcomes in research. However, in the field of diabetes, the use of PROs and associated patient-reported outcome measures (PROMs) is heterogeneous. A core outcome set for clinical trials and an International Consortium for Health Outcomes Measurement (ICHOM) standard set for clinical practice have been developed, but they, as well as other initiatives, recommend different PROs and PROMs. Standardisation of relevant outcomes and outcome measures is therefore needed. In this issue, Terwee et al (https://doi.org/10.1007/s00125-023-05926-3) provide recommendations on the selection of relevant PROs and PROMs for use in clinical practice and research in people with diabetes. The figure from this review is available as a downloadable slide

Vyron Gorgogietas, Bahareh Rajaei, Chae Heeyoung, Bruno J. Santacreu, Sandra Marín-Cañas, Paraskevi Salpea, Toshiaki Sawatani, Anyishai Musuaya, María N. Arroyo, Cristina Moreno-Castro, Khadija Benabdallah, Celine Demarez, Sanna Toivonen, Cristina Cosentino, Nathalie Pachera, Maria Lytrivi, Ying Cai, Lode Carnel, Cris Brown, Fumihiko Urano, Piero Marchetti, Patrick Gilon, Decio L. Eizirik, Miriam Cnop, Mariana Igoillo-Esteve

Wolfram syndrome is an autosomal recessive disorder caused by mutations in the WFS1 gene. Individuals affected by Wolfram syndrome develop diabetes mellitus, optic nerve atrophy, hearing loss and other neurological problems. There are currently no treatments to prevent or delay the disease. However, glucagon-like peptide 1 receptor (GLP-1R) agonists have been shown to preserve glucose tolerance and reduce neuroinflammation and vision loss in Wfs1-deficient mice and rats. In this issue, Gorgogietas et al (https://doi.org/10.1007/s00125-023-05905-8) report that GLP-1R agonists also improve the function and survival of WFS1-deficient human pancreatic beta cells and neurons. The authors conclude that these data provide a strong preclinical basis to test GLP-1R agonists in individuals with Wolfram syndrome in clinical trials.

Mi Huang, Melina Claussnitzer, Alham Saadat, Daniel E. Coral, Sebastian Kalamajski, Paul W. Franks

Genetic association studies have correlated hundreds of loci with metabolic disorders, but the functional basis of these loci is rarely explored. A well-known common genetic polymorphism in PPARGC1A (rs8192678, C/T, Gly482Ser) has been reproducibly associated with obesity and type 2 diabetes in various ancestries, highlighting the need to examine its allele-specific effects and pinpoint its clinical relevance. In this issue, Mi Huang et al (https://doi.org/10.1007/s00125-023-05915-6) report the use of a state-of-the-art CRISPR/Cas9 technique to generate isogenic adipose cell lines with different rs8192678 genotypes. They show that the rs8192678 T allele causally enhances adipogenic differentiation and mitochondrial function in an allele dosage-dependent manner. They also demonstrate that the T allele is associated with higher levels of the PPARGC1A-encoded peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) protein and of the adipogenesis master regulator peroxisome proliferator-activated receptor γ (PPARγ). These findings provide experimental insights into adipocyte-specific mechanisms underlying epidemiological correlations between rs8192678 and metabolic disorders. The authors conclude that this may prove useful for the development of genotype-based precision medicine for obesity.

Christian Laugesen, Ajenthen G. Ranjan, Signe Schmidt, Kirsten Nørgaard

Consumption of excess carbohydrate to manage hypoglycaemia can lead to rebound hyperglycaemia and promote weight gain. Previous inpatient studies have demonstrated that s.c. low-dose glucagon can be used to effectively treat non-severe hypoglycaemia in people with type 1 diabetes, but studies in outpatient settings are limited. In this issue, Laugesen et al (https://doi.org/10.1007/s00125-023-05909-4) report the findings of a randomised clinical study comparing the efficacy of pen-administered low-dose dasiglucagon with that of usual care for the prevention and treatment of non-severe hypoglycaemia during free-living conditions. The authors show that use of low-dose dasiglucagon was safe, fast and efficacious while significantly reducing the total daily carbohydrate intake and yielding high treatment satisfaction. The authors conclude that their results add to existing evidence suggesting that pen-administered low-dose dasiglucagon has the potential to become a new and non-caloric method of managing non-severe hypoglycaemia for individuals with type 1 diabetes.

Simon Helleputte, Jane E. Yardley, Sam N. Scott, Jan Stautemas, Laura Jansseune, Joke Marlier, Tine De Backer, Bruno Lapauw, Patrick Calders

In people with type 1 diabetes, blood glucose management around exercise can be very challenging, especially if exercise is performed shortly (within 2 h) after a meal (i.e. in the early postprandial period) when circulating insulin levels are high. In this issue, Helleputte, Yardley et al (https://doi.org/10.1007/s00125-023-05910-x) summarise the available data on the glycaemic effects of postprandial exercise in people with type 1 diabetes. They state that an enhanced understanding of the effects of postprandial exercise on blood glucose can help to improve blood glucose management around physical activity in this population. The studies included in this review show that prandial status is an important determinant of the blood glucose response to exercise in type 1 diabetes, as several modalities of postprandial exercise (walking and continuous and interval exercise) resulted in a decline in blood glucose concentration. The authors suggest that mealtime insulin reductions are needed to provide safe glycaemic profiles during exercise and, thereby, avoid exercise-induced hypoglycaemia. However, they highlight that issues remain concerning hyperglycaemia around exercise and late-onset post-exercise hypoglycaemia. The authors conclude that more research is needed into strategies to improve blood glucose management around postprandial exercise in people with type 1 diabetes. The figure from this review is available as a downloadable slide

Anette-Gabriele Ziegler

The first years of life are characterised by an enormous number of new exposures that challenge and shape our immune system and metabolism. It is during this period that genetically susceptible children have the highest risk of developing autoimmunity against beta cells. In this issue, Anette-Gabriele Ziegler (https://doi.org/10.1007/s00125-023-05927-2) reviews the interplay between the environment, immunity and metabolism in an attempt to explain why this fertile period for the development of islet autoimmunity in early childhood is critical for the development of type 1 diabetes. The figures from this review are available as a downloadable slideset

Paola S. Apaolaza, Diana Balcacean, Jose Zapardiel-Gonzalo, Teresa Rodriguez-Calvo

Immune infiltration in the islets of Langerhans is a hallmark of type 1 diabetes. However, there is a lack of understanding of infiltration dynamics in terms of magnitude (i.e. how many immune cells are present) and extent (i.e. in how many islets). In this issue, Apaolaza et al (https://doi.org/10.1007/s00125-023-05888-6) characterise T cell infiltration by investigating islets with moderate and high levels of infiltration in the human pancreas. The authors show that about a third of islets have moderate infiltration in double autoantibody-positive and type 1 diabetic donors, while islets with high infiltration are less abundant. Likewise, these donors have high islet and exocrine T cell density, suggesting that, as disease progresses, T cell infiltration extends throughout the pancreas, reaching both the islets and exocrine compartment. The authors conclude by presenting new analytical tools with the aim of modelling how T cells infiltrate the pancreas, and estimating pancreatic infiltration in living individuals.

Juliette A. de Klerk, Joline W. J. Beulens, Hailiang Mei, Roel Bijkerk, Anton Jan van Zonneveld, Robert W. Koivula, Petra J. M. Elders, Leen M. ’t Hart, Roderick C. Slieker

Individuals with diabetes are a heterogenous group and therefore further stratification is key. It has previously been shown that individuals with type 2 diabetes can be organised into five clusters based on five clinical variables: age, HbA_1c, BMI, C-peptide level and HDL-cholesterol level. While clusters differ in terms of clinical outcomes, the differences at the molecular level are largely unclear. In this issue, de Klerk et al (https://doi.org/10.1007/s00125-023-05886-8) compare whole blood gene expression profiles between the different clusters of people with diabetes. The authors show that relatively young people with a high BMI have an altered blood transcriptome profile compared with the other clusters. Using Mendelian randomisation, they demonstrate that the differentially expressed mRNAs may have a causal effect on multiple traits, including anthropometric characteristics and lipid metabolism. The authors conclude that the clusters may help to further stratify people with diabetes, highlighting the different underlying pathophysiologies and providing a more holistic view of type 2 diabetes.

Jacqueline M. Ratter-Rieck, Michael Roden, Christian Herder

Climate change and associated environmental risk factors, such as extreme weather events, air pollution and altered host–pathogen interactions, are a threat to human health. In this issue, Ratter-Rieck et al (https://doi.org/10.1007/s00125-023-05901-y) summarise recent evidence on how climate change may affect people with diabetes. The authors discuss how impaired responses to heat stress, diabetes-associated comorbidities and specific clinical characteristics make people with diabetes particularly vulnerable to climate-change-associated health risks, leading to increased risks of morbidity and mortality, for instance during heatwaves or after extreme weather events. They highlight that studies identifying additional predisposing factors and high-risk groups will support the development of targeted interventions. The authors conclude that implementation of climate change adaptation and mitigation strategies at governmental, clinical and individual levels will help to limit the detrimental health effects of climate change on people with diabetes. The figures from this review are available as a downloadable slideset

Alexandra Kautzky-Willer, Michael Leutner, Jürgen Harreiter

Our understanding of the sex and gender differences in type 2 diabetes has increased over the past decade. In this issue, Kautzky-Willer et al (https://doi.org/10.1007/s00125-023-05891-x) summarise recent advances in our knowledge of sex-specific clinical features of type 2 diabetes, and the differences between women and men in risk, diagnosis, management and outcomes of type 2 diabetes. The authors discuss how, overall, men have a slightly higher prevalence of type 2 diabetes diagnosis at a younger age while being less obese. Psychosocial stress is a more prominent diabetes risk factor for women than men, and women have a greater cardiometabolic risk factor burden than men at the time of diagnosis. Pregnancy complications, especially gestational diabetes, and early menopause increase the risk of type 2 diabetes in women, while low testosterone levels are associated with a higher risk in men. The authors conclude that more aggressive risk management needs to be implemented for both men and women who are at increased risk of type 2 diabetes, as well as for those with established diabetes. The figures from this review are available as a downloadable slideset

The Diabetes and Nutrition Study Group (DNSG) of the European Association for the Study of Diabetes (EASD)

Diabetes management relies on effective evidence-based guidance to inform individuals and support them to improve their health. In this issue, the Diabetes and Nutrition Study Group (DNSG) of the European Association for the Study of Diabetes (EASD) (https://doi.org/10.1007/s00125-023-05894-8) provides an update to its 2004 recommendations on the dietary management of diabetes. These guidelines are primarily for health professionals and consider nutrients, foods, food groups, patterns and some of the broader lifestyle aspects of what we eat. The guidelines draw on a substantial body of published work, much of which was conducted to inform this update, and include recommendations on prevention, management and remission. The guidelines provide effective evidence-based advice to inform the conversation between health professionals and their patients, and empower individuals to manage their health.

Shao-Wen Weng, Jian-Ching Wu, Feng-Chih Shen, Yen-Hsiang Chang, Yu-Jih Su, Wei-Shiung Lian, Ming-Hong Tai, Chia-Hao Su, Jiin-Haur Chuang, Tsu-Kung Lin, Chia-Wei Liou, Tian-Huei Chu, Ying-Hsien Kao, Feng-Sheng Wang, Pei-Wen Wang

Heat shock protein 60 (HSP60) is a mitochondrial chaperonin that plays an important role in escorting unfolded proteins. Mice deficient in HSP60 develop mitochondrial dysfunction and insulin resistance; however, the biological role of this chaperonin in nutrient metabolism and the development of non-alcoholic fatty liver disease (NAFLD) remains unclear. In this issue, Wang et al (https://doi.org/10.1007/s00125-023-05869-9) report that HSP60 deficiency was correlated with severe steatosis in human NAFLD biopsies. In contrast, transgenic mice overexpressing Hsp60 (Hsp60-Tg) developed less body fat, showed amelioration of dyslipidaemia, hepatic steatosis and M1/M2 macrophage dysregulation and exhibited lower levels of insulin resistance than wild-type mice when fed a high-fat diet. The respiratory quotient profile indicated that fat in Hsp60-Tg mice may be metabolised to meet energy demands. The authors demonstrate that, mechanistically, HSP60 promoted fatty acid oxidation by preserving sirtuin 3 (SIRT3)/AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor α (PPARα) signalling. The authors conclude that gain of mitochondrial HSP60 function may be a promising avenue for the development of therapeutic interventions for NAFLD and type 2 diabetes.

René van Tienhoven, Maria J. L. Kracht, Arno R. van der Slik, Sofia Thomaidou, Anouk H. G. Wolters, Ben N. G. Giepmans, Juan Pablo Romero Riojas, Michael S. Nelson, Françoise Carlotti, Eelco J. P. de Koning, Rob C. Hoeben, Arnaud Zaldumbide, Bart O. Roep

In type 1 diabetes, insulin-producing beta cells in the pancreatic islets of Langerhans contribute to their own demise in various ways. Under stress, beta cells can generate so-called neoantigens that result from misreads from insulin mRNA (e.g. insulin defective ribosomal product [INS-DRiP]) and which strongly provoke the immune system. In this issue, van Tienhoven et al (https://doi.org/10.1007/s00125-023-05882-y) report on the surprising finding that an antibody generated against these new beta cell stress proteins selectively stains delta cells. The authors show that the target of this antibody is another insulin gene product, resulting from alternative splicing of insulin mRNA (referred to as INS-splice), that partly overlaps with INS-DRiP. Islet delta cells express this insulin gene product, INS-splice, which contains important targets of diabetes-causing T cells. The authors highlight that this finding may point to some delta cells being potential targets of autoimmunity. The authors conclude that insulin splicing may also play a role in islet development and senescence.

Søren Gullaksen, Liv Vernstrøm, Steffen S. Sørensen, Steffen Ringgaard, Christoffer Laustsen, Kristian L. Funck, Per L. Poulsen, Esben Laugesen

Diabetes mellitus is the leading cause of chronic kidney disease. Kidney hypoxia has been suggested as a unifying pathophysiological pathway in the development of chronic kidney disease in diabetes. Renoprotective effects have been documented for the sodium−glucose cotransporter 2 inhibitor empagliflozin whereas positive effects for the glucagon-like peptide-1 receptor agonist semaglutide await confirmation in dedicated kidney outcome trials. The underlying mechanisms of action of the two drugs are unclear, but it has been suggested that they may improve kidney oxygenation. In this issue, Gullaksen et al (https://doi.org/10.1007/s00125-023-05876-w) report that treatment with empagliflozin for 32 weeks, in contrast to previous assumptions, decreases kidney medullary oxygenation in people with type 2 diabetes. Semaglutide did not affect kidney medullary oxygenation nor was there any additional effect on oxygenation with combination therapy. The authors suggest that empagliflozin-induced medullary hypoxia may stimulate erythropoietin production, leading to kidney protection. They conclude that these findings improve our understanding of the differential kidney protective effects of empagliflozin and semaglutide.

Shuai Yuan, Jordi Merino, Susanna C. Larsson

Exploration of causal factors underlying diabetes is of great importance not only for the development of more effective prevention strategies but also to provide insight into the molecular processes underlying disease risk. Mendelian randomisation is an epidemiological method that can strengthen causal inference based on the use of genetic variation. In this issue, Yuan et al (https://doi.org/10.1007/s00125-023-05879-7) summarise the evidence on potential causal risk factors for diabetes by integrating published Mendelian randomisation studies on type 1 and 2 diabetes, and reflect on future perspectives of Mendelian randomisation studies on diabetes. The authors highlight that, despite the influence of genetics on type 1 diabetes, few Mendelian randomisation studies have been conducted to identify causal exposures or molecular processes leading to increased disease risk. For type 2 diabetes, Mendelian randomisation analyses support causal associations of somatic, mental and lifestyle factors with development of the disease. The authors discuss how studies on circulating protein biomarkers, metabolites and gut microbiota provide valuable data to better understand disease pathophysiology and explore potential therapeutic targets. They conclude that more Mendelian randomisation studies in multi-ancestry cohorts are needed to examine the role of different types of physical activity, dietary components, metabolites, protein biomarkers and gut microbiome in diabetes development The figure from this review is available as a downloadable slide.

Nita G. Forouhi

Diet and nutrition are critical for the prevention and mitigation of type 2 diabetes. However, the research evidence and its implementation have been challenging, partly because of the plethora of information and apparently conflicting dietary strategies. In this issue, Nita Forouhi (https://doi.org/10.1007/s00125-023-05873-z) reviews the evidence on the role of dietary components in the prevention and management of type 2 diabetes and obesity. The review cuts through the complexity of, and challenges of measuring, diet and investigates the impact of diet using robust study designs. The author concludes that it is unhelpful to play off one nutrient against another, such as favouring a low-fat or a low-carbohydrate diet. Instead, the review suggests the importance of nutrient type or quality, nutrient food sources in food-based guidelines and the relevance of overall dietary patterns, as well as taking into account dietary adherence and longer term effects. Important areas of consensus on effective dietary strategies are highlighted and future directions are considered. The figure from this review is available as a downloadable slide.

Katia K. Mattis, Nicole A. J. Krentz, Christoph Metzendorf, Fernando Abaitua, Aliya F. Spigelman, Han Sun, Jennifer M. Ikle, Swaraj Thaman, Antje K. Rottner, Austin Bautista, Eugenia Mazzaferro, Marta Perez-Alcantara, Jocelyn E. Manning Fox, Jason M. Torres, Agata Wesolowska-Andersen, Grace Z. Yu, Anubha Mahajan, Anders Larsson, Patrick E. MacDonald, Benjamin Davies, Marcel den Hoed, Anna L. Gloyn

Genome-wide association studies have identified multiple independent signals at the RREB1 locus associated with type 2 diabetes. However, how altered expression or function of the transcription factor Ras-responsive element binding protein 1 (RREB1) influences diabetes risk was previously unknown. In this issue, Mattis and Krentz et al (https://doi.org/10.1007/s00125-022-05856-6) describe how a combination of zebrafish and human cellular models was used to identify disease-causing mechanisms at the RREB1 locus. The authors show how RREB1 loss-of-function reduced insulin gene expression and insulin content in zebrafish as well as in human beta cell models. Transcriptomic analysis identified RREB1 as a regulator of several genes involved in beta cell development and function, including the RFX family of transcription factors. Consistent with these findings, the authors show how isolated islets from human carriers of RREB1 diabetes-risk alleles exhibited altered glucose-stimulated insulin secretion. The authors conclude that the genetic association of RREB1 with type 2 diabetes is mediated, in part, by a transcriptional role for RREB1 in normal beta cell development and function.

Suping Ling, Francesco Zaccardi, Eyad Issa, Melanie J Davies, Kamlesh Khunti, Karen Brown

Owing to improvements in cardiovascular disease prevention and treatment in the past few decades, mortality rates in people with type 2 diabetes have declined substantially in some high-income countries. Given the increased incidence and mortality for some cancers associated with diabetes, it is unclear whether cancer has overtaken cardiovascular disease as the key cause of death in this population and whether inequalities exist in cancer mortality trends. In this issue, Ling et al (https://doi.org/10.1007/s00125-022-05854-8) report that, in contrast to declining all-cause mortality rates in people with type 2 diabetes at all ages between 1998 and 2018, there were decreasing trends in all-cancer mortality rates at younger ages but increasing trends at older ages (75+). In addition, they show that there were persistent inequalities in cancer mortality rates by gender and socioeconomic status and widening disparities by smoking status. The authors conclude that these findings highlight that cancer deserves a similar level of attention as other diabetes-related complications, such as cardiovascular disease, and that public health policies are needed to address persistent and widening inequalities.

Jedidiah I. Morton, Clara Marquina, Jonathan E. Shaw, Danny Liew, Kevan R. Polkinghorne, Zanfina Ademi and Dianna J. Magliano

Sodium–glucose co-transporter 2 inhibitors (SGLT2is) and glucagon-like peptide‑1 receptor agonists (GLP-1 Ras) reduce the incidence of cardiovascular and kidney disease in addition to their effects on blood glucose. However, it is unclear if they are cost-effective on the basis of their cardiovascular and kidney benefits alone, which may be why many payers/governments have HbA_1c-based restrictions on their use. In this issue, Morton et al (https://doi.org/10.1007/s00125-022-05832-0) report that, based solely on their cardiovascular benefits at current prices, SGLT2is are cost-effective for anyone with type 2 diabetes from the Australian healthcare perspective, while GLP-1 RAs are unlikely to be cost-effective, even in a population with pre-existing cardiovascular disease. The authors conclude that these findings suggest that existing HbA_1c-based restrictions on SGLT2i use may not be justified from a health economic perspective.

Deirdre K. Tobias

Systematic reviews and meta-analyses are respectable research tools when used correctly. In this issue, Deirdre Tobias (https://doi.org/10.1007/s00125-022-05862-8) describes, however, that the quality of systematic reviews today is highly variable, despite standard operating procedures and best practices, warranting serious concerns about over-reliance on their findings without paying careful attention to potential bias. She discusses how this has undoubtedly led to some arguments against their use and value to the scientific community (see the counter-debate by Enzo Bonora in this issue). However, she goes on to highlight that dismissing this critical and growing evidence base altogether would be a disservice to rigorous scientific progress. She concludes that researchers should instead be encouraged to improve their proficiency in reading, conducting and interpreting systematic review research so that these reviews better serve their intended role as efficient synthesisers of accumulating evidence and gatekeepers of redundant original research.

Enzo Bonora

Progress in medicine relies on scientific literature because journals are the main peer-reviewed medium of discoveries, achievements, concepts and ideas, inspiring further research as well as establishing best clinical practices. In this issue, Enzo Bonora (https://doi.org/10.1007/s00125-022-05808-0) illustrates the huge increase in diabetes-related literature over the last few decades but highlights what he believes is an excess of ‘nothing-to-add’ papers and, in particular, redundant meta-analyses and repetitive narrative reviews. He also emphasises the enthusiasm that meta-analyses and reviews receive from some journals and some scientists, anxious to improve their own metrics. He concludes that the scientific relevance of papers and the scientific achievements of investigators and journals are more important for medical progress than their respective metrics. See the counter-debate by Deirdre Tobias in this issue.

Aicha Saadane, Alexander A. Veenstra, Martin S. Minns, Jie Tang, Yunpeng Du, Fatima Abubakr Elghazali, Emma M. Lessieur, Eric Pearlman, Timothy S. Kern

Inflammation has been implicated in the pathogenesis of the early stages of diabetic retinopathy but the molecular mechanisms are unclear. In this issue, Saadane et al (https://doi.org/ 10.1007/s00125-022-05860-w) that deletion of CC chemokine receptor 2 (CCR2)-positive cells (largely monocytes) in a mouse model of diabetes or generation of chimeric mice lacking Ccr2 only from myeloid cells significantly inhibited the diabetes-induced increase in retinal capillary degeneration. The authors highlight how these results in monocytes reflect previous studies that have shown that neutrophils have direct cytotoxic effects on retinal endothelial cells, thus providing at least one mechanism by which leucocytes contribute to diabetes-induced vascular damage in diabetes. They conclude that abnormalities in multiple cell types in the innate immune system contribute to the development of the early stages of diabetic retinopathy, providing potential therapeutic targets for inhibiting retinopathy.