Metabolism is key in the pathogenesis of type 2 diabetes in both children and adults, and large-scale metabolomic studies offer a unique source for discovery of biomarkers for these conditions. Leveraging human genetics, we explored whether altered levels of circulating metabolites in the blood are causally linked to type 2 diabetes in youth across different ancestries. Our Mendelian randomization analysis identified causal associations for 34 metabolites, and, among these, Mendelian randomization replication and colocalization prioritized 23 metabolites. Observational evidence from the Avon Longitudinal Study of Parents and Children (ALSPAC) study validated effects on glucose homeostasis for six of these metabolites, among which phosphatidylcholine ae C42:3 emerged as the most promising biomarker. These findings highlight the role of metabolism in glucose homeostasis pathophysiology in youth.

In this study, we investigated a consanguineous family in whom normal-weight individuals had hepatic steatosis and cirrhosis. Using whole-exome sequencing we found two rare homozygous variants in the glucagon receptor (GCGR) gene that cosegregated with the phenotype. In cells, the GCGR mutations result in a loss of function and increased lipid accumulation. These results highlight the potential risks associated with GCGR antagonists and the benefits of GCGR agonists, currently in clinical trials.

Pancreatic β-cell function declines with age, but the underlying mechanism is poorly understood. In this study, we attempted to address how to reverse β-cell aging. Our data showed that sirtuin 6 (SIRT6) overexpression can reduce age-associated DNA damage, cell death, and functional decline in β-cells. Our findings suggest that improving Sirt6 gene expression and function may slow down β-cell decline in older patients.

We use the newly developed fluorescence angiography with dual fluorescence imaging method to longitudinally investigate associations between vascular leakage and visual acuity during early-, intermediate-, and late-stage diabetic retinopathy (DR) in diabetic mice. We demonstrate the onset and progression of vascular leakage, association of leakage with reduced visual acuity, and alteration of macrophage and vascular densities in late-stage DR. We confirm the sensitivity of fluorescence angiography with dual fluorescence in assessing retinal vascular leakage in conjunction with other functional measures in longitudinal studies in the same animals and demonstrate inflammatory changes in late-stage DR.

Maternal hyperglycemia is linked to 19 cord blood DNA methylation biomarkers that predict offspring metabolic dysfunction. These methylation changes, associated with maternal glycemic status, improved the prediction of β-cell dysfunction at 7, 11, and 18 years of age compared with clinical factors alone. Validation in human β-cells and pancreatic ductal epithelial cells confirmed that hyperglycemia influences methylation-dependent gene expression. These findings highlight the role of epigenetic modifications at birth as early indicators of diabetes risk, suggesting that in utero hyperglycemic exposure may mediate long-term metabolic outcomes in offspring.

Diabetes has a large medical and public health impact in American Indians. Studies have used genetic data to distinguish type 1 diabetes (T1D) and type 2 diabetes (T2D) and uncover biologic mechanisms underlying T2D clinical heterogeneity. We applied a T1D polygenic score (PS) to 3,084 American Indians (mean age 56 years, 58% women, 39% diabetes). We also calculated partitioned PS for eight clusters of T2D-associated variants and evaluated their association with 20 cardiometabolic traits and five clinical outcomes. The profile of T1D PS for individuals with diabetes was consistent with T2D. A total T2D PS was significantly associated with early age of T2D onset (P = 3.5 × 10-11). Partitioned PS for T2D clusters were significantly associated with cardiometabolic traits for the obesity cluster (increased measures of body fat and total triglycerides but lower HDL cholesterol), while the lipodystrophy cluster was associated with increased fasting insulin, waist-to-hip ratio, triglycerides, and blood pressure, and lower body fat percentage and HDL cholesterol. T2D clusters were not associated with cardiovascular and kidney outcomes. Our findings support a relationship of cluster-specific T2D partitioned PS with cardiometabolic traits described in other populations, but there are opportunities for developing improved clustering methods using genetic variation from American Indians.

Diabetes exacerbates cardiomyocyte senescence, leading to an accelerated decline in cardiac function. The systemic levels of activated protein C (aPC) were reduced, which correlated with deterioration of cardiac diastolic function in diabetic cardiomyopathy (DbCM), while the underlying mechanisms remained unclear. We aim to identify the role of aPC in ameliorating cardiomyocyte senescence in DbCM. We highlighted that aPC ameliorated cardiomyocyte senescence in DbCM via the PAR1/PAR3-P85-CaMKIIδ axis with genetic (TMP/P) and interventional (PC injection) diabetic mouse models. These findings could lead to increased insight into the pathogenesis and innovative therapeutic approaches of diabetic cardiomyopathy.

Changes in blood lipid profiles in type 2 diabetes, particularly when complicated by metabolic dysfunction-associated steatotic liver disease (MASLD), have not been fully elucidated. Does MASLD influence the plasma lipidome in patients with type 2 diabetes? Patients with MASLD exhibited elevated levels of myristic acid (FA 14:0) in plasma triglycerides, which significantly decreased after comprehensive diabetes treatment. Elevated FA 14:0 levels in triglycerides may be associated with MASLD pathogenesis in type 2 diabetes.

Treatment options for childhood obesity are expanding, but precision medicine approaches, including strategies for precision risk assessment, are needed to appropriately target treatment intensity. Parameters of adipose tissue dysfunction are better predictors of metabolic syndrome than body size, and therefore adipose tissue represents a prime candidate for research approaches in understanding the pathophysiology of insulin resistance and in identifying biomarkers of future prognosis. Expanded developmental research on pediatric adipose tissue in both mice and humans is needed to understand the pathophysiology of childhood-onset obesity and to develop precision treatment approaches.

Single-cell transcriptomics provides a powerful solution for dissecting diabetes-induced cell-type-specific responses in mammalian retina. This article summarizes key findings from recent single-cell transcriptomic studies regarding the mechanisms of diabetic retinopathy, with a particular emphasis on the neural retina. Specific retinal neuronal types/subtypes exhibit heightened sensitivity to diabetes at the transcriptional level. Retinal Müller glial cells are key contributors to diabetic retinopathy and promising therapeutic targets for retinal protection against diabetes.

The "omnigenic" hypothesis postulates that polygenic effects of common variants on typical complex traits coalesce via trans effects on the expression of a relatively sparse set of "core" effector genes and their encoded proteins in relevant tissues. The objective of this study was to identify core proteins for type 1 diabetes. We used summary statistics for single nucleotide polymorphism associations with plasma levels of 5,130 proteins in three large cohorts, including the UK Biobank, to compute genome-wide aggregated trans effects (GATE) scores for protein levels in two type 1 diabetes case-control studies (6,828 case individuals, 416,000 control individuals). GATE scores for 27 proteins were associated with type 1 diabetes. Of these, 14 were replicated between data sets, 11 had support in Mendelian randomization analysis, and 9 had experimental support in mouse models of autoimmune diabetes. The strongest associations were for immune checkpoints (PDCD1, CD5, TIGIT, and LAG3), chemokines, and innate immune system proteins (NCR1 and KLRB1). While PDCD1 is a known cause of monogenic autoimmune diabetes, neither it nor most of the core proteins identified here were previously reported as genome-wide association study hits for type 1 diabetes. These results identify possible drug targets with genetic support for causality and suggest that programmed cell death protein 1 agonists under development for other indications should be trialed for type 1 diabetes prevention.

An accurate genetic diagnosis of maturity-onset diabetes of the young (MODY) is critical for personalized treatment. To avoid misdiagnosis, only genes with strong evidence of causality must be tested. Heterozygous variants in NEUROD1, PDX1, APPL1, and WFS1 have been implicated in MODY, but strong genetic evidence supporting causality is lacking. We therefore assessed their existing genetic evidence and performed gene-level burden tests in a large MODY cohort, alongside two established MODY genes as positive controls (HNF1A- high penetrance, RFX6 -low penetrance). The first reported MODY-associated variants in NEUROD1, PDX1, APPL1, and WFS1 were <1:20,000 frequency. Based on the small number of large published pedigrees per gene (n < 3), MODY-associated variants showed only modest cosegregation in these genes. Crucially, ultra-rare (minor allele frequency <1:10,000) protein-truncating and predicted-damaging missense variants in APPL1 and WFS1 were not enriched in a MODY cohort (n = 2,571) compared with population control individuals (n = 155,501; all P > 0.05). In contrast, variants in NEUROD1 and PDX1 were enriched, albeit at levels comparable to RFX6. Multiple sensitivity analyses corroborated these findings. In summary, rare heterozygous variants in NEUROD1 and PDX1 are low-penetrance causes of MODY, while those in APPL1 and WFS1 lack robust genetic evidence for causality and should not be included in MODY testing panels.

Metabolic stress elicits functional changes in pancreatic islets, contributing to the pathogenesis of type 2 diabetes. However, the molecular mechanisms underlying overnutrition stress in islet cells is not well understood. In our study, we subjected human islets to overnutrition with 25 mmol/L glucose and 0.5 mmol/L palmitic acid (glucolipotoxicity) or to a control culture condition with 5.1 mmol/L glucose. We used single-cell RNA sequencing to comprehensively characterize the gene expression changes between these two conditions in a cell type-specific manner. We found that among all islet endocrine cell types, α-cells were the most resilient to glucolipotoxicity, while β-cells were the most susceptible. We also observed a reduction in cell-cell interactions within islet endocrine cells under glucolipotoxicity, alongside alterations in gene regulatory networks linked to type 2 diabetes genetic risk. Finally, targeted drug screening underscored the critical role of histone H3K9 methyltransferases G9a (EHMT2) and GLP (EHMT1) in modulating the β-cell cellular response to overnutrition.

In the article cited above, TG was incorrectly introduced as transforming secretory granules in the main text. The correct term is thapsigargin. The editors apologize for the error. The online version of the article (https://doi.org/10.2337/db24-0720) has been updated to correct the error.

Survivors of childhood cancers who received high doses (40-60 Gy) of cranial irradiation (CI) have increased risks of developing obesity, type 2 diabetes, and metabolic syndrome (MetS). Here, we subjected mice to CI of 0, 0.5, or 2 Gy directed to the hypothalamus to explore the effects of low-to-moderate doses of CI on MetS risks. Despite targeting the hypothalamus as a major metabolic control center, we did not detect hypothalamic astrocyte or microglia activation at 2 or 7 days, or at 3 months post-CI. Indirect calorimetry at 2 months post-CI showed no metabolic alterations between groups, yet female mice subjected to CI were unresponsive to leptin compared with sham. Follow-up monitoring over 2 years revealed accelerated weight gain in the 2-Gy female group and glucose intolerance in both sexes following CI. Insulin sensitivity, plasma insulin, and triglycerides remained unaltered, but both male and female 2-Gy groups showed elevated VLDL and lowered HDL cholesterol levels and aberrant hypothalamic mRNA levels of genes involved in synaptic and neuronal function, neuroinflammation, and endoplasmic reticulum stress. Mortality remained unaffected by all doses of CI. These data strongly suggest a significant risk for developing MetS following low-to-moderate doses of CI, and they support tailored clinical risk assessment and monitoring strategies for patients undergoing CI, especially when the hypothalamus is included.

This study adds mechanistic insight to the association between excess iron and insulin resistance and identifies an effective intervention strategy. Using a cellular skeletal muscle cell model and a preclinical animal model, we show that iron elicits endoplasmic reticulum (ER) stress and impairs insulin signaling. The adiponectin receptor agonist peptide ALY688 counteracts iron-induced ER stress and maintains insulin sensitivity. Loss-of-function approaches indicated that ALY688 acts via an autophagy-dependent, and specifically ER-phagy-dependent, mechanism.

Transcription factor Islet-1 (Isl1) and ubiquitin ligase Ring Finger 20 (Rnf20) complexes regulate insulin secretion and β-cell gene expression in vitro. Loss of Rnf20 in adult β-cells disrupts β-cell identity and insulin processing, production, and secretion. In complex with Isl1, Rnf20 influences the β-cell regulome and supports proper glucose homeostasis.

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.

In type 1 diabetes (T1D), insulin (INS) deficiency results from immune-mediated destruction of β-cells. The majority of functional β-cell mass is typically lost within months to years of disease diagnosis, but the timing and nature of this loss, particularly in early disease stages, remain unclear. We developed a whole-slide scanned image analysis pipeline for semiautomated quantitation of endocrine area, islet frequency, interislet distance, and endocrine object size distribution in 145 human pancreata from 60 donors without diabetes, 19 donors with single autoantibody positivity, 10 with multiple autoantibody positivity (mAAb+), and 16 with recent-onset (duration 0-1 year), 23 with medium-duration (1-7 years), and 17 with long-duration T1D (7+ years). We observed age-related differences in endocrine composition and islet frequency in pancreata from donors without diabetes. Age-corrected data revealed decreased islet frequency and greater interislet distance in the T1D pancreas. INS+ single cells (≤10 μm), cell clusters (>10 to <35 μm), small- and medium-sized islets (35-100 and 100-200 μm, respectively) were significantly lost at T1D onset, whereas large INS+ islets (>200 μm) were preserved. Moreover, changes in endocrine composition also occurred in pancreata from mAAb+ donors, including a significant decrease in the INS+ islet fraction. These data suggest preferential loss of INS+ small endocrine objects early in T1D development.

An acute increase of lipids in the upper small intestine (USI) of rodents and humans triggers lipid-sensing pathways to reduce food intake. However, USI lipid sensing does not reduce feeding in high-fat (HF) fed conditions, and the underlying mechanism remains elusive. Here, we report that HF feeding in male rats impaired USI lipid infusion to stimulate glucose-dependent insulinotropic polypeptide (GIP) secretion and decrease refeeding, and the defects of USI lipid sensing were restored by metformin. Next, we found that infusion of GIP receptor (GIPR) agonist in the nucleus of the solitary tract (NTS), but not mediobasal hypothalamus or area postrema, resulted in decreased refeeding in chow-fed rats. The anorectic effect of NTS GIPR agonist remained intact in HF rats and was inhibited by a genetic knockdown of GIPR. Finally, an inhibition of NTS GIPR also negated the ability of USI lipid sensing with metformin to decrease refeeding despite an increase in plasma GIP levels in HF rats. Thus, USI lipid sensing in HF rats is enhanced by metformin to trigger an endocrine GIP to NTS GIPR axis to reduce food intake, thereby unveiling small intestinal lipid-sensing pathways as potential targets to enhance GIP action and reduce weight in obesity.