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.

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.

Iron overload (IO) is a common contributing factor to aspects of the metabolic syndrome (MetS), including insulin resistance. Mechanisms of IO-induced insulin resistance include elevated oxidative stress, endoplasmic reticulum (ER) stress and impaired autophagy. Using an Akt biosensor L6 skeletal muscle cell line, we found that the adiponectin receptor agonist ALY688 prevented impaired insulin signaling in response to IO. Mechanistically, ALY688 counteracted IO-dependent effects on ER stress, the unfolded protein response (UPR), and autophagic flux. Importantly, we found that ALY688 induced FAM134B-dependent ER-phagy (reticulophagy) to ameliorate ER stress. The beneficial effects of ALY688 were attenuated in cells lacking Atg7 or FAM134B, highlighting the importance of selective autophagy of the ER by FAM134B in mitigating IO-induced impaired insulin signaling. These findings translated to a mouse model of IO in which ALY688 improved glucose tolerance, insulin sensitivity, UPR activation, FAM134B expression, and autophagy flux. Collectively, our results demonstrate that ALY688 effectively attenuated IO-induced ER stress and insulin resistance in both mice and cellular skeletal muscle models via stimulation of the UPR and ER-phagy.

Diabetes is characterized by a loss of functional β-cell mass; therefore, identifying factors involved in establishing and preserving β-cells is critical to combat rising diabetes incidence. While transcription factors are crucial β-cell regulators, knowledge of coregulators facilitating gene expression is limited. Previously, we demonstrated that the islet-1 (Isl1) transcription factor forms complexes with ubiquitin ligases ring finger 20 (Rnf20) and Rnf40 to regulate β-cells in vitro. Here, we investigated whether Rnf20-mediated complexes are required for β-cell function in adult islets by characterizing a novel β-cell-enriched Rnf20 knockout mouse model. Tamoxifen induction of Rnf20 recombination prompted a robust loss of histone 2B monoubiquitination, imparted severe hyperglycemia and glucose intolerance, and elicited an overall reduction in insulin content. Expression of mRNAs and proteins involved in glucose-stimulated insulin secretion and β-cell identity were also dysregulated in Rnf20Δβ-cell mice. Comparative analyses of the loss of either Rnf20 or Isl1 yielded similar changes in the β-cell regulome, supporting that Isl1::Rnf20 complexes are critical regulators of β-cell identity and function. Isl1::Rnf20 complexes are maintained in human tissues wherein they regulate insulin expression, secretion, and content. These findings increase our understanding of key players in β-cell maintenance, which is crucial for the advancement of β-cell derivation diabetes therapeutics.

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+), 16 with recent-onset T1D (duration 0-1 year), 23 with medium-duration T1D (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), and 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.

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.

Branched-chain amino acids (BCAAs) are essential nutrients for humans. An elevated circulating BCAA level has been associated with obesity and type 2 diabetes (T2D), but the causal role of BCAAs in metabolic health remains unclear. Using a two-sample bidirectional Mendelian randomization (MR) approach, we assessed the bidirectional causal effects of circulating BCAAs on body composition, lipids, glucose metabolism, and insulin sensitivity in ∼250,000 UK Biobank participants. In MR models, a higher circulating level of BCAAs seemed to be the outcome of poor metabolic health, including higher BMI, more circulating triglycerides (TGs), lower HDL cholesterol (HDL-C), greater insulin resistance, and higher T2D risk (all P < 6 × 10-4). Conversely, a higher level of BCAAs as the exposure seemed causally associated with more TGs and lower HDL-C (indicating dyslipidemia), independent of BMI and T2D risk. Our bioinformatic and functional analyses further identified PDE3B as a potential regulator of BCAAs and lipid metabolism in adipocytes. These findings confirm the role of circulating BCAAs as a biomarker reflecting metabolic health and identify a potential bidirectional causal link with lipid dysregulation. Additional studies should explore how BCAAs affect lipid metabolism in both insulin-resistant and metabolically healthy individuals.

Several transcription factors regulate the fasting response in liver. They include FoxO1 and FoxO3, CREB, C/EBP α/β, glucocorticoid receptor (GR), peroxisome proliferator-activated receptor-α (PPARα), FoxA2, hepatocyte nuclear factor-α (HNF4α), and others. Genome-wide chromatin occupancy studies revealed an unexpected overlap of FoxO1 and PPARα DNA binding sites at active intergenic and intron enhancers, yet their functional significance remains unknown. To address this gap in knowledge, we conducted molecular interaction analyses of these transcription factors and generated combined hepatocyte-specific ablation of the respective genes. Integrated analysis of hepatic RNA sequencing from these mice by FoxO1 and PPARα chromatin immunoprecipitation sequencing revealed a concerted regulation of glucose metabolism, with additive effects on in vivo glucose tolerance. Synergistic effects on glycogenesis were observed when PPARα was ablated in the absence of FoxO1, particularly following a high-fat diet. Free fatty acids increased following FoxO1 and were normalized by PPARα ablation, while liver triglyceride content increased in PPARα knockouts and was normalized by FoxO1 ablation. The findings highlight a functional relay between FoxO1 and PPRAα, linking insulin signaling with hepatic lipid metabolism, and offer insight into potential therapeutic strategies for metabolic diseases.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) cause an increase in hepatic glucose production (HGP). We previously showed that SGLT2i cause a rapid (within 4 h) increase in the total-body norepinephrine (NE) turnover rate, which could explain the increase in HGP. Because the increase in HGP caused by SGLT2i is long-lasting, we examined the long-term effect of SGLT2i on the NE turnover rate. Empagliflozin caused a decrease in total-body NE turnover at 1 day and at 12 weeks after starting therapy, despite an increase in glucose production, and the magnitude of decrease in NE turnover inversely correlated with the increase in HGP caused by empagliflozin.

Hypercortisolism as a causative factor in the development of type 2 diabetes has received scant attention. Studies from Europe, South America, and the U.S. have demonstrated that a significant percentage of individuals with poorly managed type 2 diabetes, despite treatment with multiple glucose-lowering agents, have endogenous hypersecretion of cortisol as a causative factor for their hyperglycemia. In vivo and in vitro studies in animals and humans have demonstrated that excess exposure to glucocorticoids can promote insulin resistance in muscle, liver, and adipocytes and impair insulin secretion. We propose a reverberating cycle in which hypercortisolism disrupts the normal circadian rhythm causing insulin resistance and hyperinsulinemia, which in turn further disrupts the hypothalamic-pituitary-adrenal axis.

Metabolic and energy reprogramming significantly affects renal cell function in diabetic kidney disease (DKD). We developed unique metabolic mouse models with varying levels of lipoic acid synthase (Lias) gene expression and correspondingly varying levels of protein lipoylation and metabolic activity. Using these metabolic mouse models, our study demonstrates that increased protein lipoylation can alleviate DKD through metabolic and energetic regulation. Our unique metabolic mouse models can serve as a preclinical platform to evaluate new therapeutic strategies, ultimately guiding translational studies for patients with DKD.

Glucagon-like peptide-1 receptor agonists are promising therapies in treating various obesity-associated diseases; however, the mechanisms are convoluted with the benefits of weight loss. Dulaglutide has weight-independent therapeutic effects on the liver, reducing hepatic steatosis and improving liver function. Dulaglutide reduces de novo lipogenesis, lipid droplet stability, inflammation, and oxidative stress in the liver and lipolysis in adipose tissue. Weight loss may play an important role in glucagon-like peptide-1 receptor agonists' effect on decreasing coronary vascular disease risk.

Current research and development are ushering in a new era of novel islet β-cell replacement therapies that can no longer be considered solely a rescue treatment for those with unstable glucose management. Clinical trial design must ensure that the application of islet β-cell replacement is broadened beyond the indication of severe hypoglycemia given the potential for establishing insulin-independent normoglycemia. It is imperative that people with type 1 diabetes and their clinicians are at the center of the risk-benefit equipoise as evidence for the safety of cellular products, transplant sites, and immune protection strategies accumulates and an increasing number of options for intervention become available.