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.

Diabetic kidney disease (DKD) progression involves intricate interactions among senescence, oxidative stress, inflammation, and fibrosis. This study systematically investigates the regulatory role and molecular mechanisms of NUAK1 in DKD pathogenesis. Bioinformatics analysis of Gene Expression Omnibus data sets identified NUAK1 as a differentially expressed gene, validated in human kidney proximal tubule epithelial (HK-2) cells, high-fat diet and streptozotocin-induced DKD mice, d-galactose-induced senescent mice, and human peripheral blood mononuclear cells. Functional studies demonstrated that NUAK1 inhibition via siRNA knockdown, pharmacological inhibitors, or kidney tubule-targeted adeno-associated virus serotype carrying shRNA against NUAK1 delivery attenuated reactive oxygen species-tumor protein 53 (ROS/P53) axis-mediated renal tubular senescence, oxidative stress, inflammation, and fibrosis in vitro and in vivo. Mechanistically, chromatin immunoprecipitation quantitative PCR revealed that transcription factor ETS1 directly binds to the NUAK1 promoter, driving its transcriptional activation in DKD. Furthermore, molecular docking and dynamics simulations identified Asiatic acid (AA) as a potent NUAK1 inhibitor, with a stable binding affinity. AA suppressed NUAK1 expression and downstream pathological processes, ameliorating renal injury in DKD models. These findings elucidate the role and regulatory mechanisms of NUAK1 in modulating ROS/P53 axis-driven tubular senescence and oxidative stress, providing a theoretical basis for structure optimization in drug development targeting NUAK1.

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.

Gestational diabetes mellitus (GDM) is defined as hyperglycemia first identified during pregnancy and can lead to adverse maternal and neonatal outcomes. The molecular mechanisms leading to these outcomes are currently poorly understood. While transcriptomics of GDM placentas has been previously studied, the effect on precursor mRNA splicing remains largely unknown. This study explores the impact of GDM on placental splicing and identifies its regulatory mechanisms. Using RNA sequencing data from Norwegian and Chinese cohorts, we uncovered thousands of differential splicing events. Pathway enrichment analysis revealed significant associations with metabolic and diabetes-related pathways. Splicing factor motif and cross-linking and immunoprecipitation sequencing analyses highlighted serine/arginine-rich splicing factor 10 (SRSF10) as a key regulator in this process, with its binding enriched at misspliced exons. Silencing SRSF10 in placental cells mirrored GDM-associated missplicing in key genes. These findings underscore splicing dysregulation as a critical process in GDM pathogenesis, suggesting that targeting SRSF10 could be a potential therapeutic approach to mitigate the deleterious effects of GDM.

Preclinical studies show that dietary or central administration of monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) can reduce food intake, enhance energy expenditure, and attenuate hypothalamic inflammation (HI), whereas saturated fatty acids (SFAs) promote weight gain, HI, and neuronal injury. However, whether hypothalamic exposure to different fatty acids similarly influences HI and body weight in humans remains unclear. In this longitudinal study, we compared cerebrospinal fluid (CSF) free fatty acid (FFA) profiles between 19 normal-weight control participants and 44 individuals with obesity, both at baseline and 1 year after bariatric surgery (BS). We also examined associations between CSF FFA composition, MRI-based markers of HI (i.e., increased hypothalamic mean diffusivity [MD] and volume), and postoperative weight loss. At baseline, individuals with obesity had similar CSF concentrations of total FFA, SFA, and MUFA compared with control participants but significantly lower PUFA levels, mainly due to reduced docosahexaenoic acid (DHA) levels. BS did not substantially alter CSF FFA profiles. Lower baseline CSF DHA levels were associated with higher hypothalamic MD and independently predicted less weight loss at 1 year. Postoperative increases in CSF DHA levels correlated with reductions in hypothalamic MD. These findings suggest brain DHA level may influence hypothalamic microstructure and contribute to body weight regulation in human obesity.

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.

Type 1 diabetes (T1D) is an autoimmune disease characterized by β-cell destruction promoted by autoreactive T cells. Eukaryotic translation initiation factor 4E (eIF4E)–binding protein 1 (4E-BP1) and 4E-BP2 are translational repressors and downstream targets of mammalian target of rapamycin complex 1 (mTORC1). Activation of the 4E-BP2/eIF4E pathway by 4E-BP2 deletion promotes translation initiation, inducing β-cell expansion and proliferation and regulating adaptive immunity. However, the involvement of 4E-BP2 in T1D remains unexplored. This study aimed to determine the role of 4E-BP2/eIF4E signaling in T1D prevention. We used the NOD mouse model of T1D and generated mice with global 4E-BP2 deletion in the NOD background (Eif4ebp2−/−). We assessed T1D development, glucose homeostasis, pancreas morphometry, and immune responses in Eif4ebp2−/− and littermate control mice. We found that Eif4ebp2−/− male mice exhibited reduced diabetes incidence, which did not occur in female mice, as well as preserved β-cell mass, improved insulin secretion in vitro, and comparable insulitis. Characterization of T-cell compartments showed decreased splenic CD8+ cytotoxic T-cell proliferation and increased pancreatic regulatory T-cell infiltration in Eif4ebp2−/− mice, potentially resulting from increased proliferation and suppressive capacity. Adoptive transfer studies demonstrated that Eif4ebp2−/− male lymphocytes were less diabetogenic than those of controls. In conclusion, activation of 4E-BP2/eIF4E by 4E-BP2 deletion protected against T1D, supporting 4E-BP2 as a potential therapy target.

Obstructive sleep apnea (OSA) is a common condition strongly linked to increased cardiovascular risk and poor glycemic control. Little is known about OSA, cardiovascular risk, and glycemia in maturity-onset diabetes of the young (MODY), an inherited form of diabetes, which is different than both type 1 and type 2 diabetes. We assessed OSA, resting heart rate (RHR), an important prognostic marker of cardiovascular disease, and glycemic variability among the most common subtypes of MODY, glucokinase (GCK)-MODY, and transcription factor (TF)-related MODY (HNF1A, HNF4A, and HNF1B). Adults with GCK-MODY (n = 63) and TF-related MODY (n = 60) and control adults without diabetes (n = 65) were screened for OSA by home sleep test. Glycemic variability (continuous glucose monitoring) and RHR (wearable sleep-activity tracker) were concomitantly assessed for 2 weeks at home. Data from 188 individuals (2,853 recorded days) were analyzed. Individuals with TF-related MODY, compared with those with GCK-MODY or control individuals, had more OSA (48.3%, 27.0%, and 30.8%, respectively; P = 0.033), higher RHR (72.8 ± 10.8, 65.2 ± 7.9, and 67.3 ± 7.7 bpm, respectively; P < 0.001), and higher glycemic variability (coefficient of variation of glucose 31.6 ± 6.0%, 17.3 ± 4.5%, and 17.5 ± 4.0%, respectively; P < 0.001). Greater severity of OSA and higher RHR were associated with higher glycemic variability. These findings may have important clinical implications for cardiovascular risk assessment in MODY.

Type 1 diabetes is a progressive autoimmune disease characterized by the selective destruction of insulin-producing β-cells by CD8+ T cells. Although the mechanisms of antigen-specific β-cell killing are well established, the broader consequences of this targeted destruction on neighboring β-cells that escape direct T-cell receptor (TCR)-mediated attack remain poorly understood. Here, we developed a coculture model of HLA-A2-expressing human β-cells cultured as pseudoislets and CD8+ T cells specific for the INS15-24 epitope. Using this new in vitro model, we demonstrate that 1) β-cell death induced by CD8+ T cells strictly depends on TCR-HLA class I interactions and 2) neighboring β-cells that evade direct T-cell contact do not alter β-cell identity or glucose-stimulated insulin secretion. However, they exhibit increased expression of inflammatory markers, reduced insulin content, and impaired protein translation. The robust, versatile, and readily applicable model described here represents a strong basis to further address paracrine signaling that extend beyond direct cytotoxicity.

miRNAs are key regulators of metabolic homeostasis, yet their role in obesity-associated dysfunction remains incompletely understood. Here, we identify miR-432 as a driver of systemic metabolic dysregulation. Serum miRNA profiling revealed a positive correlation between miR-432 expression and obesity/type 2 diabetes mellitus. Functionally, adipose-specific miR-432 exacerbated high-fat diet-induced obesity and insulin resistance. Similarly, hepatic-specific miR-432 aggravated hepatic steatosis and systemic glucose dysregulation, while skeletal muscle-specific miR-432 disrupted glucose homeostasis without affecting body composition. Mechanistically, miR-432 disrupted insulin sensitivity by inhibiting the PIK3R3/AKT pathway and perturbed lipid homeostasis by suppressing the PIK3R3/PPAR-α axis. Notably, obesity-induced miR-432 upregulation was predominantly localized in adipocytes and driven by the CDK5/PPAR-γ axis. Furthermore, adipocyte-derived exosomal miR-432 was identified as a mediator of systemic metabolic dysfunction, facilitating intertissue cross talk in obesity. Collectively, our data demonstrate that miR-432 exacerbates obesity-induced dysregulation of glucose and lipid metabolism.

Diabetic cardiomyopathy (DbCM) is characterized by metabolic remodeling and energetic stress independent of coronary artery disease. Increased reliance on fatty acid and ketone body metabolism has been observed in DbCM, but the regulatory mechanisms linking altered substrate use to myocardial dysfunction remain poorly understood. In particular, lysine β-hydroxybutyrate (Kbhb), a ketone body-derived, posttranslational modification, has emerged as a potentially critical regulator but has not been fully investigated. We conducted a comprehensive multiomics study integrating metabolomics, transcriptomics, proteomics, and Kbhb-specific proteomics on myocardial tissues in a well-established mouse model of DbCM. Kbhb-modified proteins were systematically mapped and quantified, followed by motif, subcellular localization, and protein-protein interaction analyses. DbCM cardiac tissue exhibited coordinated upregulations of fatty acid β-oxidation, ketone metabolism, and tricarboxylic acid cycle activity at the transcriptomic, proteomic, and metabolomic levels. Kbhb profiling revealed extensive mitochondrial protein modification, with Atp5f1a-K239 identified as a key modification site strongly correlated with β-hydroxybutyrate and isocitric acid concentrations. This study identifies Kbhb as a potential metabolic-epigenetic modifier linking ketone body availability to the regulation of mitochondrial proteins in DbCM. Our findings provide novel insights into metabolic-epigenetic cross talk and identify potential therapeutic targets for interventions to restore mitochondrial function in alleviating diabetic heart disease.

Glucokinase (GK) catalyzes the key regulatory step in glucose-stimulated insulin secretion (GSIS). Correspondingly, hetero- and homozygous mutations in human GCK cause maturity-onset diabetes of the young (GCK-MODY) and permanent neonatal diabetes mellitus, respectively. To explore the possible utility of GK activators (GKAs) and of glucagon-like peptide 1 (GLP-1) receptor agonists in these diseases, we have developed a novel hypomorphic Gck allele in mice encoding an aberrantly spliced mRNA. In islets from homozygous knock-in (GckKI/KI) mice, GK immunoreactivity was reduced by >85%, and GSIS eliminated. Homozygous GckKI/KI mice displayed frank diabetes (fasting blood glucose >18 mmol/L; HbA1c ∼108 mmol/mol), ketosis, and nephropathy. Heterozygous GckKI/+ mice were glucose intolerant (HbA1c ∼37 mmol/mol). Abnormal glucose-stimulated Ca2+ dynamics in GckKI/+ islets were completely reversed by the GKA dorzagliatin, which was largely inactive in homozygous GckKI/KI mouse islets. The GLP-1 receptor agonist exendin-4 improved glucose tolerance in male GckKI/+ mice, an action potentiated by dorzagliatin. Sex-dependent additive effects of these agents were also observed on insulin secretion in vitro. Similar additive effects of the drugs were observed in obese hyperglycemic db/db mice. Combined treatment with GKA and incretin mimetics may thus be useful in GCK-MODY and in more common forms of type 2 diabetes.

Type 1 diabetes (T1D) is an autoimmune disease characterized by progressive stages culminating in T-cell-mediated destruction of the β-cells at the islets of Langerhans. The immune mechanisms that initiate T1D are not fully resolved but likely involve an interaction between proinflammatory antigen-presenting cells (APCs) and autoreactive T cells that initiate immune infiltration and activation. Previous studies have tested the use of tolerogenic APCs in adult female NOD mice to delay or prevent T1D with only slight to intermediate success. Moreover, immune infiltration begins as early as age 4 weeks; therefore, targeting autoreactive T cells with tolerogenic APCs in adult mice may not impact later stages of diabetes. Thus, we hypothesize that the transfer of tolerogenic APCs at the neonatal stage prior to priming and immune infiltration will result in effective protection from autoimmunity. Our studies demonstrate that immature APCs travel to the pancreatic draining lymph nodes, alter the cytokine milieu in young mice, divert autoreactive CD4+ T cells to anergy, and drastically decrease proliferation and function of cytotoxic lymphocytes in adult prediabetic mice, leading to a significant reduction in the incidence of T1D.

Activated neutrophils contribute to retinal endothelial cell (EC) death and capillary degeneration associated with early diabetic retinopathy (DR), a major vision-threatening complication of diabetes. However, the factors and mechanisms driving neutrophil activation and cytotoxicity in diabetes remain insufficiently understood. Here, we show that lysyl oxidase (LOX), a matrix cross-linking and stiffening enzyme that increases retinal EC susceptibility to activated neutrophils, simultaneously activates neutrophils in its soluble form. Specifically, treatment of diabetic mice with LOX inhibitor β-aminopropionitrile (BAPN) prevented the diabetes-induced increase in neutrophil activation (extracellular release of neutrophil elastase and superoxide) and cytotoxicity toward cocultured mouse retinal ECs. Mouse neutrophils and differentiated (neutrophil-like) human HL-60 cells treated with recombinant LOX alone exhibited significant activation and cytotoxicity. Mechanistically, this LOX-induced neutrophil activation was associated with biphasic F-actin remodeling, with the initial and rapid (∼10 min) F-actin depolymerization followed by a significant increase in F-actin polymerization and polarization. Preventing the initial F-actin depolymerization blocked LOX-induced neutrophil activation and cytotoxicity toward cocultured retinal ECs. Finally, this biphasic F-actin remodeling was found to be essential for LOX-induced membrane aggregation of azurophilic granule marker CD63 and NADPH organizer p47phox, which are associated with extracellular release of neutrophil elastase and superoxide, respectively. By revealing a previously unrecognized causal link between LOX and actin-dependent neutrophil activation in diabetes, these findings provide fresh mechanistic insights into the proinflammatory role of LOX in early DR that goes beyond its canonical matrix-stiffening effects.

Finding ways to increase β-cell mass is a key goal of diabetes research. During elevated insulin demand, β-cells turn on endoplasmic reticulum (ER) stress response pathways, and some β-cells enter the cell cycle. ER stress response protein activating transcription factor 6 (ATF6α) induces β-cell proliferation, but only in high glucose. The mechanism by which ATF6α increases proliferation, and the reasons for glucose dependence, remain unknown. Here we show that ATF6α activation in mouse and human islet cells increases expression of E2F1, a key cell cycle driver. E2F1 was required for ATF6α-induced proliferation in high glucose. However, E2F1 remained inactive in normal glucose, possibly because retinoblastoma (Rb), a direct E2F1 inhibitor, was in its dephosphorylated, active state. Indeed, inducing Rb phosphorylation by overexpressing cyclin-dependent kinase 4 (CDK4) allowed ATF6α to increase E2F1 activity and β-cell proliferation in normal glucose. E2F1 expression increased in an ATF6α-dependent manner during generalized ER stress by thapsigargin treatment. Importantly, in human β-cells, ATF6α failed to synergize with high glucose to induce proliferation, but the synergy was rescued by adding back CDK6. Taken together, this study establishes a new dual-input β-cell proliferation regulatory mechanism integrating ER load with current glycemic conditions via CDK4/6, in which Rb phosphorylation serves as a glucose sensor that permits ATF6α-driven proliferation.

Vascular dysfunction is considered a consequence of diabetes. However, in pancreatic islets, some hemodynamic changes occur before the onset of symptoms. The underlying mechanisms driving islet vascular abnormalities have not been fully characterized, but islet pericyte dysfunction seems to be an early event in the pathogenesis of type 1 diabetes in humans. It remains to be investigated, however, how abnormal pericyte physiology affects their ability to regulate islet blood flow and vascular permeability. To address this issue, we treated mice with multiple subdiabetogenic doses of the β-cell toxin streptozotocin (STZ; 50 mg/kg) and recorded islet vascular responses when animals developed glucose intolerance but were still not diabetic (average fed glycemia <200 mg/dL). At this stage, pericyte coverage of islet capillaries was abnormal, with capillaries either lacking pericytes or being covered by dysfunctional mural cells, which compromised islet vasomotor responses recorded ex vivo in living pancreas slices. These functional defects interfered with proper regulation of blood flow and compromised islet vascular integrity, because large fluorescent dextrans (500 kDa) could leak from peripheral islet vessels in the exteriorized pancreas of STZ-treated mice. Our study supports that the loss of functional pericyte coverage of islet capillaries is part of a pathogenic process occurring in islets before diabetes onset, associated with a loss of functional β-cell mass and inflammation.