Current imaging technologies cannot detect diabetic retinopathy until there has been significant permanent damage to patients' vision. We hypothesized that hyperglycemia causes retinal hypoxia, and hypoxia may lead to apoptosis of retinal cells. We performed experiments using a mouse model of streptozotocin (STZ)-induced diabetes to investigate the role of hyperglycemia in diabetic eye disease. Our experimental results indicate that diabetic retinas are significantly hypoxic compared with nondiabetic controls. Retinal hypoxia can be detected using HYPOX-4, an early-detection imaging probe, potentially before any detectable changes in the diabetic retina. In the early stages of diabetes, we did not observe any detectable changes in electroretinography response, vascular permeability in fluorescein angiography, or retinal thickness in optical coherence tomographic imaging. In addition, increased HYPOX-4 fluorescence in the diabetic retina was not associated with focal ischemia; rather, increased levels of HYPOX-4 fluorescence were observed throughout the entire diabetic retina. Moreover, hypoxia profiles in STZ-induced diabetic retinas were colocalized with TUNEL-positive apoptotic cells. To confirm the role of hyperglycemia in the diabetic retina, human retinal cells were treated under hyperglycemic conditions, and hypoxia was monitored using the pimonidazole-adduct immunostaining method. Surprisingly, retinal cells became hypoxic under hyperglycemic conditions within the first few hours. We conclude that the diabetic retina becomes hypoxic as a result of hyperglycemia in the early stage of diabetes, which could lead to the degeneration of retinal cells at later stages of the disease. In addition, HYPOX-4 could be used as a powerful early diagnostic imaging method to detect retinal hypoxia in the diabetic retina before any detectable retinopathy.

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.

Fibroblasts play a pivotal role in wound healing, particularly during the proliferative and remodeling phase, where they migrate to the injury site, proliferate, and synthesize essential extracellular matrix (ECM) components such as collagen and fibronectin (FN). However, fibroblast functionality is compromised because of factors such as vascular dysfunction and oxidative stress in diabetic wounds, leading to chronic inflammation and delayed healing. This study investigates the role of mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH), a key enzyme in energy metabolism, in regulating fibroblast function during diabetic wound healing. We demonstrate that mGPDH is overexpressed in diabetic wounds and in fibroblasts cultured under high-glucose conditions, contributing to impaired ECM repair. Importantly, the inhibition of mGPDH restores fibroblast functionality by enhancing ECM synthesis, increasing the levels of collagen IV and α-smooth muscle actin (α-SMA) proteins, and accelerating wound healing. Mechanistically, mGPDH deficiency activates the SIRT1-c-Myc-TGF-β1 signaling axis, resulting in reduced c-Myc protein stability, alleviation of its inhibitory effects on TGF-β1 signaling, and subsequent activation of ECM synthesis pathways. This study highlights the role of mGPDH in regulating fibroblast migration and ECM secretion, without affecting apoptosis or proliferation, thereby underscoring its selective regulatory role in wound healing. These findings establish mGPDH as a pivotal regulatory node in fibroblast function during diabetic wound healing, providing a foundation for the development of localized therapeutic strategies aimed at restoring fibroblast activity and improving wound healing outcomes in patients with diabetes.

Insulin secretion varies widely in preclinical type 1 diabetes. To understand the pathogenesis of this metabolic heterogeneity, we asked whether genetic predisposition to type 2 diabetes, quantified by a type 2 diabetes genetic risk score (T2D-GRS), modulates β-cell function and disease progression in individuals at risk of type 1 diabetes. We analyzed 4,324 islet autoantibody–positive TrialNet Pathway to Prevention participants with genome-wide genotyping and oral glucose tolerance testing. Both T2D-GRS and the type 1 diabetes genetic risk score 2 (T1D-GRS2) differed significantly across five previously described groups defined by C-peptide area under the curve (AUC; a measure of insulin secretion). The highest C-peptide AUC group, compared with the lowest, had significantly higher T2D-GRS, lower T1D-GRS2, higher BMI z-score, greater insulin resistance, older age, and lower prevalence of male participants; multiple islet autoantibody positivity; and IA-2 or insulin autoantibody positivity. Progression to clinical (stage 3) type 1 diabetes was significantly associated with T1D-GRS2 across all groups and with T2D-GRS in all but the lowest C-peptide AUC group. In conclusion, type 2 diabetes genetic burden shapes metabolic heterogeneity and accelerates progression in preclinical type 1 diabetes. These results support the evaluation of type 2 diabetes–related mechanisms as targets to improve the prediction and prevention of type 1 diabetes.

White adipose tissue (WAT) insulin resistance (IR) is a central feature of metabolic syndrome; however, data regarding defects in WAT insulin signaling in humans with IR is limited. To determine which defects in WAT insulin signaling are associated with human IR, WAT was obtained from three cohorts of patients with obesity. In a bariatric surgery cohort (RESOLVE), subcutaneous WAT (n = 24) was collected before and after weight loss, and RNA sequencing was performed. In another bariatric surgery cohort (SODA), glucose- or fructose-sweetened beverages were consumed before subcutaneous and omental WAT collection, and proteomic data were collected (n = 16). In an adolescent cohort, subcutaneous WAT (n = 14) was collected before and during hyperinsulinemic clamps, and both quantitative PCR and immunoblotting were performed. The TC10–tether containing a UBX domain for GLUT4 (TUG) pathway regulates GLUT4 translocation and glucose uptake in insulin-responsive tissues. Expectedly, in the adipose tissue from all three cohorts, GLUT4 content decreased in those with IR. TUG, which traps insulin-responsive GLUT4 vesicles in intracellular pools, was increased in the setting of IR in all three cohorts. Furthermore, expression of multiple components of the TC10–TUG pathway was altered with IR. Therefore, human WAT IR is characterized by altered molecular regulation of the TC10–TUG pathway, underscoring the importance of this pathway to WAT metabolic health.

The primary objective of this study was to investigate whether ligand-receptor interactions (LRIs) between IGHG and FCGR gene products are associated with progression to type 1 diabetes (T1D). Using two completed clinical trials (DPT-1 and TN07), we applied next-generation targeted sequencing to genotype IGHG and FCGR genes in a cohort of 1,214 individuals and assessed LRI associations with disease progression. A Cox regression model was used to quantify LRI associations. IGHG or FCGR alone was found to have weak and sporadic associations with progression. Multiple LRIs between IGHG and FCGR gene products were found to be associated with progression, especially LRIs of IGHG2 with multiple FCGR receptors that accelerate progression and those of IGHG4 with multiple FCGR receptors (some overlapping) that delay progression. Furthermore, as several crystal structures of FcγRs complexed with distinct IgG molecules are known, application of this knowledge here was hampered by the absence of any information on the subclass distribution of each of the several T1D-related autoantibodies. It cannot be excluded that their respective state of glycosylation may influence binding affinity to various FcγRs and the function of thus-formed complexes. Our findings suggest that LRIs of the IGHG and FCGR gene products probably influence progression, shedding new insights into some of the immunological mechanisms involved in progression to T1D. Our findings potentially facilitate the search for new immunotherapeutic treatment through intervening at key steps in the progression.

Glucagon-like peptide 1 receptor (GLP-1R) agonists have transformed obesity treatment, but weight loss responses to these drugs vary widely. Elucidating behavioral and metabolic phenotypes throughout GLP-1R agonist treatment could identify mechanisms underlying this response spectrum. We characterized food intake, meal patterns, energy expenditure (EE), and substrate oxidation during prolonged semaglutide treatment and posttreatment recovery in obese male mice at room temperature (RT) and thermoneutral temperature (TN). Semaglutide-induced weight loss and posttreatment weight regain were similar at RT and TN. Weight loss was divided into three stages at both temperatures: rapid initial weight loss, slower gradual weight loss, and weight maintenance. Initial weight loss was marked by reduced food intake, smaller and less frequent meals, and increased lipid oxidation. Food intake gradually returned to pretreatment levels through increased meal frequency, whereas meal size remained suppressed. Lipid oxidation gradually decreased, whereas carbohydrate oxidation increased. Weight-adjusted EE remained constant and elevated in semaglutide- versus vehicle-treated mice, and locomotor activity increased throughout semaglutide treatment. Mice rapidly regained weight after treatment cessation as a result of increased food intake, meal size and frequency, carbohydrate oxidation, EE, and activity. Thus, semaglutide-induced weight loss and regain after treatment cessation involve dynamic, stage-specific changes in feeding behavior, EE, and substrate oxidation.

We used a dual (intravenous and oral) glucose tracer protocol to evaluate rates of glucose appearance in the circulation, insulin-mediated glucose disposal (IMGD), and noninsulin-mediated glucose disposal (NIMGD) for 4 h after consumption of a mixed meal in people with obesity and type 2 diabetes before and after marked (∼20%) weight loss, induced by behavioral diet therapy (BDT, n = 11) or Roux-en-Y gastric bypass (RYGB) surgery (n = 9). Total postprandial glucose appearance rate was lower after compared with before weight loss in both the BDT and RYGB groups because of a decrease in endogenous glucose production, without a difference between groups. However, the decreases in total and incremental postprandial plasma glucose concentration areas under the curve were greater in the BDT group than the RYGB group because IMGD doubled in the BDT group but did not change in the RYGB group. These results demonstrate that the improvement in postprandial glycemia is greater after marked, matched weight loss induced by BDT compared with RYGB in people with obesity and type 2 diabetes, because of increased IMGD after BDT but not RYGB. Nonetheless, these findings do not diminish the potent therapeutic effect of RYGB surgery on glycemic control and even achieving remission of type 2 diabetes.

Metabolic dysfunction–associated steatotic liver disease (MASLD) has emerged as a global epidemic, yet its underlying molecular mechanisms remain elusive, and therapeutic options are limited. The interorgan communication between liver and adipose tissue plays a crucial role in maintaining hepatic lipid homeostasis. This study investigates the role of G-protein–coupled bile acid receptor 1 (TGR5) in adipose tissue-liver communication and its impact on hepatic lipid metabolism during the progression of MASLD. We observed that TGR5 expression in white adipose tissue was significantly upregulated under both fasting and high-fat diet (HFD) conditions, whereas its levels in brown adipose tissue remained unchanged. Notably, mice with adipocyte-specific TGR5 deletion exhibited exacerbated fasting/HFD-induced hepatic steatosis and impaired hepatic fatty acid oxidation. Mechanistically, adipose tissue TGR5 deficiency reduced adiponectin secretion, which in turn suppressed hepatic fatty acid oxidation and aggravated hepatic lipid accumulation; conversely, restoration of circulating adiponectin rescued these metabolic abnormalities. Collectively, our findings highlight a critical role for adipose tissue TGR5 in promoting adiponectin secretion, thereby enhancing hepatic fatty acid oxidation and protecting against hepatic steatosis.

Maturity-onset diabetes of the young (MODY) can present after the age of 40 years, but its prevalence and clinical characteristics, and the utility of simple clinical features for selecting cases in this age group, remain poorly defined. We analyzed whole-exome and clinical data from 51,619 individuals with diabetes diagnosed after age 40 years from one U.K. and one U.S. cohort. The prevalence of MODY due to a pathogenic variant in the 10 most common MODY genes was 1 in 191 (0.52%) in the U.K. cohort and 1 in 633 (0.16%) in the U.S. cohort. For subtypes with treatment implications (i.e., GCK, HNF1A, HNF4A, ABCC8, KCNJ11), prevalence was 1 in 234 and 1 in 935 in the U.K. and U.S. cohorts, respectively. GCK-MODY was most common, followed by HNF4A and the lower-penetrance RFX6-MODY. Clinical features of MODY largely overlapped with non-MODY diabetes either treated with insulin from diagnosis or not. Only BMI, HbA1c and HDL values were statistically different between patients with MODY and those with non-MODY diabetes in both cohorts (P < 0.0018 for all). Applying strict clinical criteria (i.e., BMI <25, noninsulin treated, and parent with diabetes) only increased the MODY diagnosis to 2.64% and 0.87% in the respective cohorts but missed >86% of cases. MODY is prevalent in later-onset diabetes and has potential for targeted therapy but is challenging to identify.

B lymphocytes are thought to drive β-cell destruction in type 1 diabetes (T1D) by activating anti-islet T cells. However, the observation that autoreactive T-cell activation and disease progression can occur without B cells challenges this view. Still, preclinical and clinical studies have shown that B-cell depletion alleviates β-cell destruction, suggesting a critical role for B cells in T1D. Our findings propose an alternative function for B cells, impairing regulatory T cells (Tregs) that would otherwise protect islets. In the NOD islet transplant model, we show that B-cell absence enables transplant tolerance, allowing Tregs to become responsive to immune therapy and confer allograft protection. Extending this to spontaneous diabetes, we have found that insulin-reactive Tregs are reduced in NOD mice in proportion to insulin-reactive B cells, while effector T cells remain unaffected. Moreover, Tregs from B-cell–deficient NOD mice better restrained β-cell destruction than those from B-cell–sufficient environments. Together, these findings indicate that autoreactive B cells primarily erode immune regulation by culling islet-protective Tregs. Thus, therapies that mobilize Tregs could be more effective when combined with B-cell–targeting strategies in islet transplant or T1D prevention.

The hypothalamus monitors blood glucose levels and regulates glucose production in the liver. In response to hypoglycemia, glucose-inhibited (GI) neurons trigger counterregulatory responses (CRRs), which stimulate the release of glucagon, epinephrine, and cortisol to elevate blood glucose. Recurrent hypoglycemia (RH), however, reduces the effectiveness of these CRRs. This study examined the role of hypothalamic prostaglandins in glucose recovery during acute hypoglycemia and RH. Imaging mass spectrometry and liquid chromatography/mass spectrometry showed phospholipid and prostaglandin levels in the hypothalamus of C57BL mice were changed after insulin or 2-deoxy-glucose administration. Ibuprofen, a nonsteroidal anti-inflammatory drug, was infused into the ventromedial hypothalamus (VMH) to analyze its effect on glucose production during hypoglycemia, revealing that prostaglandin inhibition decreased glucagon secretion. Additionally, RH-treated mice decreased glucagon release and glucose production during hypoglycemia. Inhibiting prostaglandin production via shRNA against cytosolic phospholipase A2 (cPLA2) in the hypothalamus restored CRRs diminished by RH via increasing glucagon sensitivity. These findings suggest that hypothalamic prostaglandins play a critical role in glucose recovery from acute hypoglycemia by activating VMH neurons and are also crucial for the attenuation of CRRs during RH.

For many years, brown adipose tissue (BAT) was primarily regarded as a "heat organ" for rodents. Over the past 15 years, however, research in this field has shifted significantly toward understanding of the role of BAT in metabolic health, including systemic glucose homeostasis, lipid metabolism, insulin sensitivity, and protection against cardiometabolic disease. In this award lecture, I highlight key contributions from our laboratory and others that transformed brown fat research, including molecular insights into brown and beige adipocyte biogenesis and the discovery of UCP1-independent pathways through which brown and beige fat influence metabolic health beyond thermogenesis.

TAS2R38 is a bitter taste receptor that influences bitter taste perception and diet and is also found in intestinal L cells that store and secrete glucagon-like peptide 1 (GLP-1). Preclinical studies have linked TAS2R38 activation to postprandial GLP-1 secretion, fueling interest in TAS2R38 as a therapeutic target for glucose regulation; however, evidence in humans remains limited. To further establish TAS2R38 actions in glucose homeostasis, we analyzed data from ∼220,000 European adults without type 2 diabetes in the UK Biobank to test whether functional variants conferring TAS2R38 sensitivity were associated with blood glucose. We found that individuals with two copies of a haplotype increasing receptor sensitivity (PAV) had significantly lower 0-2-h (i.e., postprandial) glucose than those with two copies of a nonfunctional haplotype (AVI), following a dose-response relationship per PAV haplotype. These associations were replicated in published genome-wide association studies of 2-h glucose, persisted after adjustment for diet and lifestyle behaviors related to bitter taste perception, and were not seen for variants in other bitter taste receptors without putative roles in glucose metabolism (TAS2R14 and TAS2R19). Collectively, these findings provide evidence in humans consistent with direct TAS2R38 actions in postprandial glycemia, supporting TAS2R38 as a novel therapeutic target for glucose regulation.

Early postprandial glucagon concentrations are higher in type 1 diabetes (T1D) than in individuals with no diabetes (ND). To determine the cause, we infused stable [13C9, 15N1]glucagon before, during, and after a mixed meal in 16 ND and 16 T1D individuals to measure glucagon turnover. In a subcohort of 9 ND and 12 T1D individuals, we estimated [13C9, 15N1]glucagon kinetics during steady state. A linear, single-compartment model described [13C9, 15N1]glucagon kinetics and allowed precise estimation of the volume of distribution (VD) and clearance rate (CL). Model parameters were similar between groups, with the VD of [13C9, 15N1]glucagon at 42.1 ± 3.3 mL/kg, implying that [13C9, 15N1]glucagon distributes in a single compartment and with VD approximating the plasma volume and CL at 10.6 ± 0.9 mL/kg/min. Higher early (0–120 min after meal ingestion) postprandial glucagon concentrations (1,907.9 ± 373.4 vs. −93.6 ± 240.5 pg/mL · 120 min P < 0.001) observed in T1D was due to higher rates of glucagon appearance (3.39 ± 2.8 vs. −3.95 ± 2.0 ng/kg · 120 min, P < 0.04) and disappearance (2.13 ± 2.6 vs. −5.28 ± 2.1 ng/kg · 120 min, P < 0.04) compared with ND. We have determined postprandial glucagon turnover in humans and have demonstrated that changes in postprandial glucagon concentrations in T1D are due to increased rates of glucagon turnover during the early postprandial period.

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.

Abatacept, a cytotoxic T lymphocyte–associated protein 4 immunoglobulin that inhibits T-cell costimulation, was evaluated for 12 months in stage 1 type 1 diabetes (T1D) to delay disease progression. Despite modest preservation of area under the curve C-peptide at 12 months, the primary end point was not met. We adopted the oral minimal model (OMM) to assess β-cell function over 48 months and explored how baseline insulin secretion (ϕtotal) modified treatment response. Using the OMM, ϕtotal was computed from oral glucose tolerance tests conducted at baseline and every 6 months. Participants were stratified into high- and low-secretor groups depending on baseline ϕtotal ≥33rd or <33rd centile, respectively. A sensitivity analysis was performed to validate threshold choice. Among 203 participants (abatacept n = 96; 107 placebo n = 107), 39% receiving abatacept and 47% receiving placebo experienced progression to stage 2 or 3 within 96 months. High secretors receiving abatacept gained 15.8 progression-free months (95% CI 4.85, 26.68; P = 0.005) and had a 54% lower hazard of progression versus those receiving placebo (hazard ratio [HR] 0.46; 95% CI 0.25, 0.84; P = 0.012). Treatment effect differed significantly by secretor status (interaction HR 2.92; 95% CI 1.23, 6.96; P = 0.015). A subgroup of responders to 12 months of abatacept was identified by ϕtotal, providing the first evidence that an immune intervention in stage 1 T1D may delay disease progression.

Polygenic scores strongly predict type 1 diabetes risk, but most scores were developed in European-ancestry populations. In this study, we leveraged recent multiancestry genome-wide association studies to create a Type 1 Diabetes Multi-Ancestry Polygenic Score (T1D MAPS). We trained the score in the Mass General Brigham (MGB) Biobank (372 individuals with type 1 diabetes) and tested the score in the All of Us program (86 individuals with type 1 diabetes). We evaluated the area under the receiver operating characteristic curve (AUC), and we compared the AUC to two published single-ancestry scores for European (EUR) and African (AFR) populations: T1D Genetic Risk Score 2 (GRS2EUR) and T1D GRSAFR. We also developed an updated score (T1D MAPS2) that combines T1D GRS2EUR and T1D MAPS. Among individuals with non-European ancestry, the AUC of T1D MAPS was 0.90, significantly higher than T1D GRS2EUR (0.82) and T1D GRSAFR (0.82). Among individuals with European ancestry, the AUC of T1D MAPS was slightly lower than T1D GRS2EUR (0.89 vs. 0.91). However, T1D MAPS2 performed equivalently to T1D GRS2EUR in European ancestry (0.91 vs. 0.91) and performed better in non-European ancestry (0.90 vs. 0.82). Overall, these findings advance the accuracy of type 1 diabetes genetic risk prediction across diverse populations.