Immunosenescence, characterized by functional decline and altered phenotypes of immune cells with age, can disturb immune tolerance and promote autoreactive responses. Type 1 diabetes (T1D) has traditionally been viewed as a disease of immune dysregulation that leads to the autoimmune destruction of pancreatic β-cells. Emerging evidence suggests that senescence contributes to both the onset and progression of T1D. Autoreactive T cells are associated not only with β-cell death but also with the induction of β-cell senescence. In parallel, senescent β-cells acquire a senescence-associated secretory phenotype that amplifies local inflammation and increases β-cell vulnerability. These interlinked processes position senescence as a mechanistic bridge between aging, immune dysfunction, and autoimmunity. Importantly, a bidirectional loop appears to exist, in which T1D accelerates immune aging while immunosenescence further exacerbates autoimmunity. Recognizing this interplay highlights senescence as a promising and underexplored therapeutic target. Here, we synthesize current knowledge on immunosenescence and cellular senescence, examine their convergence in T1D pathogenesis, and outline future directions where interventions against senescent pathways could open new opportunities for treatment and prevention.

Type 1 diabetes (T1D) impacts more than 9 million individuals globally. Despite a century since the isolation and clinical introduction of insulin, exogenous insulin injections remain the primary form of treatment for T1D. While continuous glucose monitoring systems and optimized insulin delivery reduce life-threatening hypoglycemic events, they do not provide a permanent cure. Transplantation of pancreatic islets offers a potential long-term solution. Recent advances in stem cell-derived islets (SC-islets) have shown remarkable promise in both clinical and research settings. This article highlights recent clinical reports in the use of SC-islets to restore islet function and their versatility as a platform for disease modeling and drug screening while emphasizing current strategies aimed at overcoming their limitations and enhancing their therapeutic potential. We also discuss exciting emerging approaches that expand investigations beyond pancreatic endocrine cells to encompass nonendocrine cell types in the pancreas, offering a unique bird's-eye view into pancreatic biology and insights into cellular cross talk in health and disease. Our aim is for this article to serve as a resource for up-to-date advances in SC-islet research and to highlight novel platforms for studying diabetes pathogenesis in unprecedented ways, accelerating progress toward a permanent cure.

One-third of patients with diabetes will develop end-stage kidney disease, and approximately one-half of the patients requiring kidney transplantation in the U.S. suffer from diabetes. In 2002, Yamada, Sachs, and their colleagues explored the renal subcapsular site for islet implantation in a partially inbred miniature swine model. All pancreatectomized pigs that received autologous islets under the renal capsule maintained normoglycemia. The transplantation of a composite islets-kidney (i.e., the kidney with the revascularized autologous islets) into another pancreatectomized, bilaterally nephrectomized pig provided successful renal and islet function. In 2011, this model was extended successfully to nonhuman primates (NHPs). There are several hurdles to be overcome if this model is to be successfully translated into clinical practice, and xenotransplantation might resolve this problem. Pancreases harvested from gene-edited pigs could be sources of islets that could be isografted beneath the renal capsule of an identical cloned littermate. After allowing the islets to become vascularized over a period of 6-12 weeks, during which no immunosuppressive therapy would be required, the composite islets-kidney would then be transplanted into an immunosuppressed NHP or human recipient. On reperfusion of the graft, both renal and islet function should rapidly return. If sufficient islets have been transplanted with the kidney and the immunosuppressive regimen is successful, normoglycemia and normal renal function should be quickly achieved. However, a large number of genetically engineered neonatal donor piglets will be required to manufacture one therapeutic patient dose of islets, which may prove to be a logistical problem. Alternative approaches are discussed.

Infections represent major but underrecognized complications of type 1 diabetes (T1D), type 2 diabetes (T2D), and prediabetes. This recent overview includes use of linked U.K. primary care, hospitalization, and mortality data to examine infection risk for >800,000 individuals with diabetes or prediabetes, compared with an age-, sex-, and ethnicity-matched group without diabetes. We assessed 1) infections in primary care and requiring a prescription, 2) infections leading to hospitalization, and 3) infection-related mortality, over 5 years (2015-2019). Infection risks were consistently elevated across all forms of diabetes, compared with risk for those without diabetes. The highest relative risks were observed in T1D and lowest in prediabetes. While relative risks were similar across different ethnicities, the population burden of infections attributable to diabetes was highest among South Asians. There were independently strong graded associations for average HbA1c level and visit-to-visit HbA1c variability with infection risk, particularly for hospitalization infections. Among individuals with T1D, the strongest associations with infection risk were seen for elevated HbA1c levels, whereas for T2D, variability contributed more to the excess burden of infections. Infection-related mortality across all ICD-10 chapters was substantial, representing the third leading cause of death in T2D after cardiovascular disease and cancer. Further, it might be underreported, as sepsis is rarely coded as the underlying cause of death. These findings highlight the importance of improved glycemic control, earlier recognition and treatment of infections, and stronger emphasis on infection management in clinical guidelines. Incorporation of HbA1c variability into diabetes risk algorithms, and evaluation of interventions that might stabilize control, such as continuous glucose monitoring, may enhance infection prevention and reduce complications.

Accumulating evidence indicates that diabetes is associated with increased risk of several cancers. The strongest evidence has been reported for cancers of the breast, colorectum, endometrium, liver, pancreas, and gallbladder. However, distinguishing causal relationships from associations driven by shared risk factors such as obesity, aging, and lifestyle behaviors remains challenging. Several biological mechanisms have been proposed to explain these associations. Key pathways include the effects of insulin resistance and compensatory hyperinsulinemia on mitogenic signaling pathways, including PI3K/AKT/mTOR and MAPK, as well as the influence of adiposity, chronic inflammation, and altered metabolic substrates on tumor initiation and progression. Hyperglycemia may also contribute by promoting tumor metabolism and cellular proliferation, although its independent contribution remains debated. These mechanisms likely interact to create a protumorigenic metabolic environment in individuals with diabetes. Obesity, which frequently co-occurs with diabetes, further amplifies these risks through altered adipokine secretion and increased estrogen production, highlighting the interrelated contributions of metabolic and hormonal factors. The relationship between diabetes and cancer has important clinical implications. Diabetes has been associated with worse cancer prognosis and higher cancer-related mortality, highlighting the importance of integrated management strategies. The impact of antihyperglycemic therapy on cancer risk and progression has been extensively studied, and ongoing research continues to evaluate potential protective or tumor-modifying effects. In this article, we summarize the epidemiologic and pathophysiologic evidence describing the relationship between diabetes and cancer and discuss strategies for risk mitigation, screening, and management.

Worldwide metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease. Despite high global prevalence, MASLD is not yet recognized as a noncommunicable disease, although all of the criteria are fulfilled for such a classification. MASLD is strongly associated with type 2 diabetes, cardiovascular disease, chronic kidney disease, and certain extrahepatic cancers. At 65% and 37% the prevalence of MASLD is extremely high in adults and children with type 2 diabetes, respectively. The pathogenesis of MASLD is closely related to that of type 2 diabetes, and diabetes-associated hyperglycemia, hyperinsulinemia, and hyperlipidemia promote progression from simple steatosis to hepatic inflammation and fibrosis. Thus, MASLD is now considered a complication of diabetes. However, there is still a great deal of work to be done to implement screening for and treatment of MASLD in everyday clinical diabetes management. In this article, the major mechanisms involved in the pathogenesis of MASLD and type 2 diabetes are discussed. Furthermore, the heterogeneity in the pathophysiology of MASLD and clusters in MASLD that may be relevant for future stratification of MASLD-associated risk of diseases are addressed. Finally, because of their strong hepato-, cardio-, and nephroprotective effects this article provides support as to why sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor (co)agonists should be used as first-line pharmacotherapies in people with MASLD and type 2 diabetes.

Diabetic cardiomyopathy (DbCM) is commonly defined as ventricular dysfunction in a person living with diabetes in the absence of hypertension and/or coronary artery disease (CAD). There is increasing recognition in the field that this is a poor definition to reflect the pathology of DbCM, as many individuals with diabetes (both type 1 and type 2) are often at risk of or have coexisting hypertension or CAD. On the contrary, there is increasing evidence that people living with diabetes, particularly in the early stages of disease progression, often have asymptomatic and subclinical diastolic dysfunction. Herein, we will interrogate the clinical evidence supporting the presence of diastolic dysfunction in people living with either type 1 or type 2 diabetes in the absence of hypertension and/or CAD, and whether diastolic dysfunction should be a central feature in how we clinically define DbCM. Clinical agreement on how we define and interpret the pathology of DbCM is necessary should the field aim to develop specific pharmacotherapies for this disorder. DbCM should not be confused with heart failure with preserved ejection fraction (HFpEF), despite the latter also being characterized by diastolic dysfunction. Nonetheless, it will be imperative to understand whether DbCM can be a precursor toward the progression of HFpEF in people living with diabetes, as that may further reinforce the clinical importance of managing diastolic dysfunction in the population with diabetes.

Diabetic kidney disease (DKD) and diabetic cardiomyopathy continue to drive excess morbidity and mortality in diabetes, underscoring a critical gap between mechanistic insight and clinical translation. Growth differentiation factor-15 (GDF-15), a stress-inducible cytokine of the transforming growth factor-β superfamily, has emerged as a critical biomarker and putative modulator of metabolic inflammation. Yet the field remains divided on a fundamental question: is GDF-15 simply reporting tissue distress, or does it shape disease trajectories? In this article, we explore how GDF-15 may both signal and shape DKD and cardiovascular disease. Drawing on evidence from experimental models, longitudinal clinical studies, and multi-omics analyses, we highlight the context-dependent biology of GDF-15, protective during acute metabolic or inflammatory stress but potentially pathogenic when chronically elevated in diabetes. We examine its regulation via the GFRAL-RET signaling axis, its segment-specific expression across renal tubular compartments, and its emerging role in cardiac remodeling and metabolic inflammation. Recent clinical data position circulating GDF-15 as an early and sensitive indicator of DKD progression and cardiovascular events. At the same time, mechanistic studies increasingly implicate sustained GDF-15 signaling in mitochondrial dysfunction, inflammatory amplification, and maladaptive tissue remodeling. Together, these observations place GDF-15 at a critical inflection point between risk stratification and disease mechanism. A key unresolved challenge is defining when, where, and how GDF-15 signaling exerts adaptive versus maladaptive effects-knowledge that will be essential for determining whether GDF-15 should be targeted, harnessed, or restrained in diabetes.

Active Charcot neuroarthropathy (CN) remains difficult to predict. This hypothesis-generating article proposes a deliberately restricted, testable model in which a clinically meaningful fall in HbA1c may temporally coincide with active CN in a subset of people with diabetes, established neuropathy, and a vulnerable foot. The signal is based on a sequence of observations-an initial case report, a 44-case retrospective series, and the EPiChar study-and therefore is supportive of association and biological plausibility, but not causation. Within this framework, osteocalcin should presently be regarded mainly as a candidate biomarker of a transient skeletal activation state rather than a proven pathogenic mediator. This article should therefore be read as a suggestion for prospective testing and not as confirmation of an osteocalcin-mediated pathway. We propose that this systemic signal may intersect with established local drivers-neuropathy, repetitive microtrauma, inflammation, and RANKL/OPG imbalance-and can be tested prospectively with serial bone turnover markers, neuropathy phenotyping, kidney function, and modifiable exposure data during treatment intensification.

MicroRNAs (miRNAs) are small RNAs that posttranscriptionally repress gene expression of their target mRNAs. miRNA discovery dates to 1993, when Ambros and Ruvkun identified them in nematodes. More than two decades later, their pioneering research was recognized with the Nobel Prize in Medicine, a fitting acknowledgment of the profound impact these tiny molecules exert on nearly every biological process and disease studied to date. The regulation of pancreatic islet function, critical for glucose homeostasis and diabetes development, is no exception. The identification of miR-375 as a key regulator of insulin secretion in 2004 provided the first connection between miRNAs and islets, followed by studies showing that miRNAs are essential for endocrine development. Research in this field has since expanded rapidly, yielding insights into how miRNAs influence nutrient sensing, glucose metabolism, and diabetes pathogenesis while also highlighting their potential as biomarkers and therapeutic targets. Despite this progress, the field still faces major challenges. The mechanisms controlling miRNA expression, their precise roles in islet function and diabetes progression, and strategies for their therapeutic modulation remain poorly defined. In this perspective, we summarize key findings in islet miRNA biology and diabetes and critically discuss knowledge gaps, technical challenges, and translational opportunities that define this rapidly evolving field.

In response to the lockdowns and travel bans during the coronavirus disease 2019 pandemic, Peter C. Butler at the University of California, Los Angeles (UCLA), started a virtual islet biology seminar series. After the authors of this article joined him as co-organizers, this initiative became the Islet Research Seminar Series (IRSS). Like islets of Langerhans adapt to their changing environment, the islet biology community quickly embraced this new format. The IRSS evolved into a lasting scientific forum that convenes weekly and is attended by islet biologists from the U.S., Canada, Europe, and Israel. The series covers a range of topics in islet biology, with presentations from scientists representing all career stages. It has proven particularly valuable for trainees and early-stage investigators in exposing them to a variety of topics in islet biology without travel required and facilitating more spontaneous interactions with senior scientists than at in-person meetings. While the online format is not meant to replace live scientific conferences, we believe that the IRSS plays a unique role in keeping the islet biology community connected and abreast of the most recent scientific discoveries in our field. The success of this platform stands as a testament to the scientific community to adapt and thrive through challenges. This article is dedicated to Peter C. Butler, UCLA, who initiated the IRSS.

GLP-1 receptor agonists have emerged as key pharmacological tools in the treatment of type 2 diabetes and obesity. While their anorexigenic effects are well characterized, the mechanisms by which GLP-1 modulates pancreatic β-cell function remain only partially understood. In this article, we argue that GLP-1 receptor agonists should be viewed as integrative regulators of β-cell function and explore the multifaceted actions of GLP-1 analogs on β-cell signaling. GLP-1 influences key secretagogues and intracellular mediators (calcium, glutamate, γ-aminobutyric acid, serotonin, and urocortin-3), with complex roles in insulin exocytosis. Additionally, we discuss the interplay between calcium and cAMP, and how GLP-1 modulates both pathways to coordinate insulin secretion. Emerging evidence suggests that GLP-1 analogs affect mitochondrial morphology and redox homeostasis. Considering the relatively low expression of classical antioxidant enzymes in β-cells, and their reliance on both glycolytic and mitochondrial metabolism to sustain insulin secretion, the influence of GLP-1 on mitochondrial dynamics and reactive oxygen species may play a central role in sustaining cell function and viability. Despite recent advances, critical gaps persist in the literature, particularly regarding organelle cross talk, intracellular calcium stores, and the modulation of vesicular content. Drawing on current evidence, we propose that three mechanistic dimensions (intracellular neurotransmitters, mitochondrial remodeling, and redox control) represent key areas where clarifying GLP-1 actions could most effectively advance the field. Further investigation into these mechanisms is essential for a comprehensive understanding of GLP-1 actions in β-cells. This knowledge may help refine current incretin-based therapies and identify novel molecular targets for the treatment of metabolic disorders.

Indirect calorimetry determines energy expenditure by measuring respiratory gas exchange. The approach is based on the principle that nutrient metabolism consumes O2 and produces CO2 and water in predictable ratios that can be compared with heat production. Due to the impracticality and high cost of direct calorimetry, indirect calorimetry is the major approach for modern metabolic studies in preclinical models. Despite the broad adoption of this method in rodent phenotyping, the field has lacked standardized methods for analyzing, representing, and sharing these data, limiting scientific progress. The recent review in Nature Metabolism by the International Indirect Calorimetry Consensus Committee (IICCC) addresses the lack of standardized methods by providing updated guidelines for data processing and representation and emphasizes the importance of shared data repositories tailored to these studies. These expert consensus standards aim to improve transparency, facilitate data sharing and archiving, and enhance cross-study comparability. We encourage authors submitting to Diabetes to adopt the IICCC guidelines to strengthen rigor and reproducibility in the field.

Atherosclerotic cardiovascular disease (ASCVD) risk begins increasing years before the clinical onset of type 2 diabetes, driven in part by ectopic lipid accumulation. Many individuals predisposed to diabetes often gain weight rapidly and have limited capacity to expand subcutaneous fat, leading to central fat storage and ectopic lipid deposition-especially in the liver. Hepatic fat contributes to metabolic dysfunction and elevated triglyceride-rich lipoproteins (TRLs), which are atherogenic. Alongside higher blood pressure, these factors accelerate atherosclerosis even before hyperglycemia is evident. Although traditional cardiovascular risk factors like LDL cholesterol (LDL-C) and smoking have declined, rising obesity-particularly among younger individuals-is shifting ASCVD risk more toward pathways linked to ectopic lipid accumulation and prolonged exposure to diabetes-related metabolic disturbances. Ethnic variation plays a significant role in modifying this risk. South Asians, for example, develop type 2 diabetes at lower BMIs and tend to have higher hepatic fat and TRL levels than White individuals, contributing to their increased ASCVD burden. Conversely, people of African ancestry often have lower hepatic fat and TRL levels at similar BMIs, correlating with lower ASCVD risk despite elevated diabetes risk. Risk profiles in other ethnic groups remain understudied. These findings highlight the need for early obesity prevention and ethnically tailored strategies for ASCVD risk assessment and management. Without targeted interventions, rising global rates of obesity and type 2 diabetes, especially in low- and middle-income countries, will increase ectopic lipid accumulation, TRLs, and blood pressure, ultimately accelerating ASCVD progression and reversing prior gains made in cardiovascular prevention.

There is significant evidence that acute stress, a challenge to an organism's homeostasis, has dramatic effects on metabolic control. Acute stress impairs blood glucose control in people with both type 1 and type 2 diabetes. In addition, growing evidence suggests that metabolic responses to stress in people without diabetes may be a crucial determinant of health. Acute dysregulation of blood glucose in the hospital setting, including both hyper- and hypoglycemia, predicts short- and long-term morbidity and mortality in patients with critical illnesses. Animal studies indicate that exposure to physiological and psychological stressors activates a highly conserved network of neural circuits that ultimately coordinate the functions of multiple organs to increase blood glucose. In this article, we provide an overview of the neural populations and circuits that increase blood glucose in response to acute stress, including our research funded by the American Diabetes Association Pathway to Stop Diabetes program, highlighting the impacts on clinical outcomes and opportunities for the development of therapies for diabetes. This article is part of a series of perspectives that report on research funded by the American Diabetes Association Pathway to Stop Diabetes program.

Diabetes currently affects ∼37 million adults in the U.S. and 537 million people worldwide, with type 2 diabetes (T2D) accounting for 90%-95% of the diabetes burden. The transition from normal glucose regulation (NGR) to T2D is via an intermediate stage of prediabetes, characterized by impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). Prediabetes affects ∼98 million adults in the U.S.; worldwide, more than 541 million adults have IGT and 319 million adults have IFG. Prediabetes is associated with increased risks of developing vascular and neuropathic complications, besides the risk of progression to T2D. Discussed herein are the demographic, anthropometric, biobehavioral, biochemical, and molecular factors associated with the transition from NGR to prediabetes. The natural history of prediabetes predicts time-dependent progression to T2D, as sustained recovery from prediabetes is uncommon without intervention. Lifestyle modification and certain medications interrupt the progression to T2D and may restore NGR. The landmark intervention trials are discussed, with an interpretive focus on their limitations and the need for novel approaches for durable reversal of prediabetes.

Following the trends of the adult obesity epidemic, and worsened by school disruptions during the coronavirus disease 2019 pandemic, childhood obesity prevalence has reached unprecedented levels. The health implications for this generation are especially concerning, as childhood-onset obesity has more severe health consequences than weight gain that begins in adulthood, including increased risk of type 2 diabetes and diabetes-related complications. The complexity of obesity treatment has been challenging, including remarkable heterogeneity in obesity phenotypes and treatment responses among both adults and children. Many in the field have therefore highlighted a need for precision medicine approaches in obesity treatment across age-groups. This includes a need for precision risk stratification to better target treatment intensity, which will require a better understanding of the earliest stages of metabolic syndrome pathophysiology. The health, function, and distribution of adipose tissue have been established as important determinants of metabolic health in both childhood- and adult-onset obesity, making adipose tissue a promising target for understanding phenotypic heterogeneity in obesity. Here, we provide a brief overview of the current limited understanding of adipose tissue biology during childhood development and discuss opportunities for further research into adipose-centric precision medicine approaches in childhood-onset obesity and type 2 diabetes.

Diabetes triggers cell-type-specific responses in the retina, leading to vascular lesions, glial dysfunction, and neurodegeneration, all of which contribute to the progression of diabetic retinopathy (DR). However, the specific cell types involved in disease development and the molecular mechanisms driving their responses have not yet been fully clarified, impeding the creation of effective therapeutic strategies. Recent advancements in single-cell or single-nuclei transcriptomic technologies have provided a systematic approach to profile transcript-level alterations at single-cell resolution, allowing for an in-depth analysis of diabetes-induced retinal transcriptional changes across various animal models for DR. Here, in the context of research funded by the American Diabetes Association Pathway to Stop Diabetes program, we discuss the cell-type-specific responses in the neural retina identified through single-cell transcriptomic analyses. We emphasize new insights into neural retinal responses, potential therapeutic targets, and the limitations and unresolved topics that warrant further investigation. This article is part of a series of perspectives that report on research funded by the American Diabetes Association Pathway to Stop Diabetes program.

This article summarizes the current understanding of the heterogeneity of type 1 diabetes from a June 2024 international Expert Forum organized by the editors of Diabetes, Diabetes Care, and Diabetologia. The Forum reviewed key factors contributing to the development and progression of type 1 diabetes and outlined specific, high-priority research questions. Knowledge gaps were identified, and, notably, opportunities to harness disease heterogeneity to develop personalized therapies were outlined. Herein, we summarize our discussions and review the heterogeneity of genetic risk and immunologic and metabolic phenotypes that influence and characterize type 1 diabetes progression (presented as a palette of risk factors). We discuss how these age-related factors determine disease aggressiveness (along gradients) and describe how variable immunogenetic pathways aggregate (into networks) to affect β-cell and other pancreatic pathologies to cause clinical disease at different ages and with variable severity (described as disease-related thresholds). Heterogeneity of pathogenesis and clinical severity opens avenues to prevention and intervention, including the potential of disease-modifying immunotherapy and islet cell replacement. We conclude with a call for 1) continued research to identify more factors contributing to the disease, both overall and in specific subgroups; 2) investigations focusing on both individuals who surpass metabolic and immune thresholds and develop diabetes and those who remain disease free with the same level of immunogenetic risk; and 3) efforts to identify where the current type 1 diabetes staging system may fall short and determine how it can be improved to capture and leverage heterogeneity in prevention and intervention strategies.

There is currently a revolution in the pharmacologic treatment of obesity and diabetes with newly available agonists of incretin receptors. The health benefits of these novel treatments include not only metabolic effects but also improvements in brain neurodegenerative conditions. Receptors for incretins have been described in the hypothalamic appetite regulatory center; however, their expression in the peripheral nervous system (PNS) has been largely overlooked, despite likely contributing important effects. For example, the PNS is essential for the control of numerous metabolically relevant pathways in tissues such as liver, adipose, intestine, and muscle, and incretin receptors are found on nerves innervating some, if not all, of these metabolically important tissues. In this article, we summarize the knowledge to date regarding incretin receptors and incretin drug actions in the PNS, as well as PNS control over incretin release, and the related implications for metabolic disease states that are accompanied by peripheral neuropathy.