Search Medical Journals & Research Articles

Impact of an Additional Pregnancy on the Natural History of Insulin Sensitivity, β-Cell Function, and Glycemia in Parous Women

OBJECTIVEIt has been postulated that pregnancies may contribute to the lifetime risk of type 2 diabetes mellitus (T2DM) in women, although direct evidence is lacking. In this context, we hypothesized that pregnancy may impact the long-term natural history of the pathophysiologic determinants of T2DM: insulin sensitivity and β-cell function. We sought to evaluate 10-year trajectories of these features in parous women with and without an additional pregnancy.RESEARCH DESIGN AND METHODSMetabolic characterization was done in 303 women at 1 year postpartum and on three or more occasions over the decade thereafter. Each assessment included an oral glucose tolerance test, enabling serial evaluation of insulin sensitivity/resistance (Matsuda index; HOMA-insulin resistance [IR]), β-cell function (Insulin Secretion-Sensitivity Index-2; insulinogenic index/HOMA-IR), and glycemia. Linear mixed-effect models adjusted for diabetes risk factors were constructed to evaluate the natural time trend of these measures over 10 years in those with (n = 78) and without (n = 225) an additional pregnancy.RESULTSAt baseline, women who subsequently had an additional pregnancy were younger (P < 0.001) and more likely to be primiparous (P < 0.001) than their peers. Notably, they had higher covariate-adjusted insulin sensitivity (Matsuda index) at baseline (estimated adjusted average difference 1.64; 95% CI 0.22–2.86) and at 1.5 years’ follow-up (1.28; −0.15 to 2.50), but this difference disappeared by 3.5 years and 5.5 years. The 10-year trajectory of the Matsuda index differed between the groups (time-group interaction P = 0.02), with no differences in trajectories of β-cell function and glycemia.CONCLUSIONSPregnancy is associated with worsening of the long-term trajectory of insulin sensitivity, revealing both a pathophysiologic basis for enhanced diabetes risk and a target for risk modification.

Effects of Sodium–Glucose Cotransporter 2 Inhibitor Use on Mortality, Amputation, and Healing in Patients With Diabetic Foot Ulcer

OBJECTIVEDiabetic foot ulcer (DFU) is the leading cause of nontraumatic lower-limb amputation (LLA). The impact of sodium–glucose cotransporter 2 inhibitor (SGLT2i) use on LLA is still debated in studies in which the proportion of patients with DFU is unknown. The aim of our study was to determine, specifically in patients with DFU, if the use of an SGLT2i could influence amputation and wound healing.RESEARCH DESIGN AND METHODSThis retrospective, monocentric study was conducted in a French specialized diabetic foot center. All patients treated for a new DFU between January 2022 and May 2024 and who had 1 year of follow-up were included. The primary end point was 1-year amputation rate.RESULTSOf the 452 patients included in this study, 94 were treated with an SGLT2i and 358 were not. The mean ± SD age of the study population was 70.2 ± 11.6 years and 77% of patients were men. In the adjusted statistical model, there was no significant association between the 1-year amputation rate and SGLT2i use (P = 0.688). The 6-month healing rate was not significantly different between patients treated or not treated with SGLT2is (54.4% vs. 44.5%; P = 0.091). Healing time was significantly less in patients treated with SGLT2is, with a mean ± SD difference of 44 days (136.5 ± 97.8 vs. 181.2 ± 159.8; P = 0.04). The 1-year mortality rate was significantly lower in the SGLT2i group (1.1% vs. 9.2%; P = 0.009).CONCLUSIONSThe use of SGLT2is does not negatively impact the 1-year amputation rate or healing rate of DFU. One-year mortality was lower in patients treated with an SGLT2i.

Persistent Burden of Severe Hypoglycemia and Impaired Awareness of Hypoglycemia Among People With Type 1 Diabetes Despite Technology Use: A Follow-up Survey

OBJECTIVETo assess longitudinal trends in glycemic metrics, prevalence of severe hypoglycemic events (SHEs), impaired awareness of hypoglycemia (IAH), and technology use (continuous glucose monitoring [CGM], automated insulin delivery [AID]) in a real-world U.S. cohort of adults with type 1 diabetes.RESEARCH DESIGN AND METHODSThis was a cross-sectional study of adults with type 1 diabetes conducted ∼2 years after participants enrolled in the original retrospective observational study. Participants self-reported technology use, insulin delivery method, glycated hemoglobin (HbA1c), IAH, and SHEs. Change was assessed among these variables from the initial and follow-up study.RESULTSApproximately 2 years after the original survey, 1,056 adults responded to the follow-up survey and were eligible for analysis (53% response rate; mean [SD] age: 46 [16] years; mean [SD] type 1 diabetes duration: 29 [16] years; 71% female; 97% White). Most reported using CGM in the original study (91.8%) and at follow-up (94.4%), while the use of AID increased 17.7%. In the original study, 61.7% reported HbA1c <7% vs. 67.4% at follow-up. Proportions of individuals with IAH and SHEs remained high at ∼30% and ∼20%, respectively, in both studies.CONCLUSIONSAlthough most participants used CGM and the use of AID increased, approximately one-third of respondents did not achieve HbA1c targets, ∼20% continued to have SHEs in the last year, and ∼30% had IAH. This highlights that while CGM and AID systems are a significant advancement, their use alone has not mitigated the risk of severe hypoglycemia, and glucose management still remains suboptimal.

Investigating the Spectrum of Normoglycemia: Time in Glycemic Ranges and Their Association With Metabolic Outcomes in Individuals Without Diabetes

OBJECTIVETo characterize the distribution of time in tight and broader glycemic ranges in adults without diabetes and to examine cross-sectional and longitudinal associations with metabolic health.RESEARCH DESIGN AND METHODSWe analyzed continuous glucose monitoring data from 8,687 adults (40–70 years, 54% women) in the Human Phenotype Project, each contributing 1,149 ± 279 glucose readings from FreeStyle Libre Pro sensors. Age- and sex-adjusted correlations linked time-in-range metrics with 45 clinical phenotypes encompassing adiposity, vascular, and liver markers, sleep indices, and nutrition. Cox models tested associations of time above glycemic thresholds with incident metabolic disease over 2.6 ± 1.3 years.RESULTSParticipants spent a median 93.0% (interquartile range [IQR] 91.8–98.2) of continuous glucose monitor time within 70–140 mg/dL and 95.2% (IQR 95.1–99.8) within 70–180 mg/dL. Time below 140 mg/dL and 180 mg/dL was 97.7% (IQR 97.6–97.8) and 99.9% (IQR 99.9–99.9), respectively. Less time at <140 mg/dL correlated with higher waist circumference, visceral fat, triglycerides, blood pressure, serum ALT, and liver attenuation, and with lower HDL cholesterol and mean nocturnal oxygen saturation. Associations weakened using the <180 mg/dL threshold. Less time at <180 mg/dL and <140 mg/dL was associated with higher risk of incident metabolic disease (hazard ratio 1.21 [95% CI 1.15–1.26] and 1.34 [95% CI 1.26–1.42], respectively).CONCLUSIONSWe provide population references for time spent in different glycemic ranges by adults without diabetes. Although our study is observational and not designed to establish causality, our findings suggest that even within normoglycemic ranges, less time at <140 mg/dL is associated with unfavorable health parameters and higher incident metabolic disease risk.

Redefining Diabetes and Creating Solutions—The Hong Kong Diabetes Register: Kelly West Award Lecture 2025

Variations of disease patterns among populations, geographies, and time periods underpin the use of descriptive and analytical cohort analysis to define causal relationships between exposures and outcomes. This epidemiological knowledge forms the basis for designing clinical experiments to inform practice and policies. In the 1990s, rapid environmental and lifestyle changes among Chinese living in Hong Kong led to a rising prevalence of diabetes. The benefits of structured care in a clinical trial setting motivated the establishment of the Hong Kong Diabetes Register (HKDR) in 1995 as a data-driven quality improvement program accompanied by a biobank. Systematic data collection and analysis revealed the Asian diabetes phenotype characterized by young age at diagnosis, moderately increased BMI, visceral fat excess, and propensity for chronic kidney disease. In 2000, the HKDR protocol was incorporated into the territory-wide electronic medical record (EMR) system with setup of diabetes centers/teams for implementation. This 2-yearly Risk Assessment and Management Programme for Diabetes Mellitus (RAMP-DM) contributed to marked decline in diabetes-related complication and death rates. In 2007, the HKDR and its equations were digitalized to become the first web-based Joint Asia Diabetes Evaluation (JADE) platform for risk stratification and personalized reporting with decision support aimed at closing care gaps in Asia. The HKDR with its multidimensional data provides the fulcrum for building capacity to transform care and discover knowledge, including on the vulnerability, multiple hits, and reduced capacity of β-cells underlying young-onset diabetes. Using well-designed registers and biobanks to redefine diabetes can lead to innovative diabetes prediction, prevention, classification, and treatment with value, quality, and precision.

Optimizing Single-Cell Long-Read Sequencing for Enhanced Isoform Detection in Pancreatic Islets

Alternative splicing is an essential mechanism for generating protein diversity by producing distinct isoforms from a single gene. Dysregulation of splicing that affects pancreatic function and immune tolerance has been linked to both types 1 and 2 diabetes. Next-generation sequencing technologies, with their short read lengths, are limited in their ability to accurately detect splice variants. Long-read sequencing technologies offer the potential to overcome these limitations by providing full-length transcript information; however, their application in single-cell RNA sequencing has been hindered by technical challenges, including insufficient read lengths and higher error rates. Furthermore, cell types that produce high levels of a single transcript, such as islet endocrine cells, can obscure identification of lower-abundance transcripts. In this study, we optimized a protocol for single-cell long-read sequencing in pancreatic islets to improve read length and transcript detection. Our findings demonstrate that 5′ library preparation protocols outperform 3′ protocols, resulting in better transcript identification. Furthermore, we show that targeted depletion of insulin transcripts enhances the detection of informative reads, highlighting the utility of transcript-depletion strategies. This optimized protocol enables isoform-specific gene expression analysis and reveals differential transcript usage across the various cell types in pancreatic islets. By leveraging this approach, we gain deeper insights into the transcriptomic complexity and cellular heterogeneity within pancreatic islets.Article HighlightsThis study addresses the limitations of current single-cell long-read RNA sequencing technologies in detecting full-length transcripts and isoform diversity, particularly in pancreatic islets.We demonstrate that optimizing single-cell library preparation protocols reproducibly enhances read length and transcript identification in pancreatic islets.Combined with targeted insulin depletion and extended reverse transcription, 5′ capture methods significantly improved read length and isoform detection compared with standard protocols, while maximizing the number of informative reads.These improvements yield longer reads in single-cell experiments, substantially enhancing transcript identification and enabling more accurate analysis of isoform diversity.

Diabetic Corneal Neuropathy Precedes and Is Associated With Diabetic Retinopathy

Diabetic corneal neuropathy (DCN) and diabetic retinopathy (DR) are microvascular complications and share common pathophysiological mechanisms. However, the relationship between them remains poorly defined. In this cross-sectional study, we aimed to investigate the association among DCN, DR, and tear mediators in 1,654 eyes from 822 participants, comprising 634 patients with type 2 diabetes and 188 healthy participants. Our data demonstrated that compared with control participants, all patients with diabetes had significantly impaired corneal nerve metrics, increased dendritic cell length and density, and larger corneal microneuromas, even in the absence of DR. Patients with nonproliferative DR (NPDR) and proliferative DR (PDR) showed significantly reduced corneal nerve parameters compared with those with no DR. Furthermore, patients with PDR presented significantly worse ocular surface clinical manifestations than patients with no DR, patients with NPDR, and control participants. Cumulative link mixed models demonstrated that corneal sensitivity and corneal nerve parameters were significantly associated with the severity of DR. Tear substance P concentrations were significantly lower across all stages of DR compared with control participants. Tear MMP-9, substance P, and IGFBP-3 levels were significantly associated with corneal nerve and ocular surface parameters. This study demonstrates that DCN precedes the onset of DR and worsens with the severity of DR. Corneal nerve status could be an early indicator and predictor of DR.Article HighlightsBoth diabetic corneal neuropathy (DCN) and diabetic retinopathy (DR) are microvascular complications and share common pathophysiological mechanisms. The links between them are poorly understood.We investigated the relationship between DCN and DR by studying imaging features, clinical manifestations, and tear biomarkers.Our study demonstrated that DCN precedes the onset of DR, and DCN worsens with the severity of DR stage. Corneal sensitivity and corneal nerve parameters are significantly associated with DR severity. Tear MMP-9, substance P, and IGFBP-3 were significantly altered in DR.Corneal nerve status could be an early indicator and predictor of DR.

Endogenous Glucagon-Like Peptide 1 Enhanced by Vildagliptin Reduces Triglyceride Appearance During Intraduodenal Fat Infusion in Type 2 Diabetes

Glucagon-like peptide 1 (GLP-1) receptor agonists improve dyslipidemia and reduce cardiovascular risk in type 2 diabetes (T2D), but the role of endogenous GLP-1 in lipid metabolism remains unclear. We evaluated the effect of dipeptidyl peptidase 4 (DPP-4) inhibition on the response of plasma triglycerides (TGs) to intraduodenal lipid and a mixed meal, and the impact of GLP-1 receptor blockade with exendin(9-39) in T2D. Fifteen participants with T2D, managed by diet and/or metformin, were studied on three occasions in a double-blind, randomized, crossover design. Vildagliptin (50 mg) or placebo was administered orally (t = −60 min), followed by intravenous exendin(9-39) from t = −60 to 150 min on one of the two vildagliptin days or 0.9% saline on two other days. A lipid emulsion was infused intraduodenally (2 kcal/min, t = 0–120 min), followed by a mixed meal (t = 120–150 min). Plasma TG levels, quantified by liquid chromatography–tandem mass spectrometry, increased after lipid and meal, with most individual TGs corresponding to those in the lipid emulsion. Vildagliptin reduced TG(54:4) and TG(54:5) concentrations (each P < 0.01), without affecting total TGs. Blocking endogenous GLP-1 during vildagliptin treatment increased plasma total TGs (P < 0.001), associated with elevations of 10 individual TG species (P < 0.05 each). These outcomes suggest that endogenous GLP-1 contributes to the physiological modulation of postprandial TG appearance in T2D.Article HighlightsThe contribution of endogenous glucagon-like peptide 1 (GLP-1) to postprandial lipid metabolism in type 2 diabetes (T2D) is poorly defined.The specific questions we wanted to answer were what is the effect of dipeptidyl peptidase 4 (DPP-4) inhibition on plasma triglyceride (TG) profiles during an intraduodenal lipid infusion and following a mixed meal in T2D, and how does blockage of endogenous GLP-1 signaling affect these responses?We found that plasma TGs increased after intraduodenal lipid infusion and the meal, with most species reflecting the infused lipid emulsion. Vildagliptin selectively reduced TG(54:4) and TG(54:5) species, whereas exendin(9-39) increased total TGs and 10 individual TG species.The implications of our finding are that endogenous GLP-1 plays a physiological role in the regulation of postprandial lipid handling in T2D.

Distinct Enterovirus Antigen Landscape in Children With Islet Autoimmunity

Enteroviruses (EVs) have long been implicated in the development of islet autoimmunity (IA) and type 1 diabetes. However, given the ubiquity of EV infections in children, disease susceptibility is likely driven by host-specific immune responses rather than viral exposure alone. To investigate the host antibody response to EVs, we used virome-wide serological profiling (VirScan) to compare the EV antigen landscapes in IA-positive case children versus IA-negative control children across two independent pediatric cohorts separated by 12 years, using samples collected at the time point of seroconversion. We identified a reproducible and distinct EV-specific antibody signature in IA-positive case samples, with an enriched immunogenic hotspot localized within a highly conserved region in the 3D RNA-dependent RNA polymerase. Additionally, IA-positive male children exhibited significantly heightened antibody responses against a motif in the VP1 capsid protein compared with IA-negative male children (risk ratio 1.24; 95% CI 1.02, 1.52; P = 0.03). Our findings provide paradigm-shifting evidence that differential antiviral humoral responses, rather than the specific types of EV infection, play a central role in IA development, highlighting the need for an updated framework to study host-virus interactions in autoimmune pathogenesis.Article HighlightsChildren positive for islet autoimmunity (IA) in two different Australian cohorts showed a distinct enterovirus (EV) antibody signature against specific regions of the EV genome polyprotein.A specific motif in the 3D region of the EV polyprotein was consistently enriched across cohorts and sexes, making it a potential marker for IA onset.Anti-VP1 motif antibody levels varied by sex, with significantly elevated levels in male children linked to early IA onset, highlighting possible sex-specific antiviral immunity.Findings support that host immune responses against EVs drive IA development, calling for a new framework to study host-virus interactions in IA.

Exofacial Epitope–Specific Antibodies Detect GLUT4 Translocation in Adult Human, Rat, and Mouse Skeletal Muscle

Skeletal muscle glucose transporter 4 (GLUT4) translocation to the plasma membrane determines glucose uptake in response to insulin and exercise and is disrupted in insulin resistance, making its experimental measurement critical. Confocal light microscopy is widely used for this purpose because of its ability to provide quantitative, high-resolution spatial information from small tissue amounts. However, conventional immunofluorescence colocalization microscopy lacks sensitivity and specificity in the detection of GLUT4 translocation. We validated the use of exofacial epitope–specific GLUT4 antibodies to quantify sarcolemmal GLUT4 translocation in fixed, nonpermeabilized adult human and rodent muscle fibers. Across human, mouse, and rat muscles, these antibodies sensitively detected stimulus-induced GLUT4 translocation, and labeling was abolished in muscle-specific GLUT4-knockout muscle, confirming specificity. Importantly, this study includes the first unambiguous visualization of endogenous GLUT4 translocation in intact human skeletal muscle fibers after insulin stimulation and exercise. In TBC1D4-knockout rats, insulin-stimulated GLUT4 translocation was absent despite wild-type–level GLUT4 expression, confirming an essential role for TBC1D4 in this process. Thus, exofacial GLUT4 antibodies provide a straightforward, sensitive, and specific approach to quantify endogenous GLUT4 translocation in fixed adult skeletal muscle.Article HighlightsReliable quantification of glucose transporter 4 (GLUT4) translocation in intact skeletal muscle is essential for understanding insulin and exercise responses but remains technically challenging.We aimed to test whether exofacial GLUT4 antibodies can specifically detect sarcolemmal GLUT4 translocation in fixed, nonpermeabilized muscle fibers from humans and rodents.GLUT4 translocation in response to insulin, AMPK activation, and exercise was detectable in human and rodent muscles. Insulin-stimulated translocation correlated with 2-deoxyglucose uptake and was abolished in TBC1D4-knockout muscle.Exofacial GLUT4 antibodies enable straightforward, specific quantification of endogenous GLUT4 translocation in rodent and human muscles in healthy and insulin-resistant states.

Staying Functional Through Connection and Adaptation: When Islets Inspire Islet Biologists

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.

ISL1 Restricts Progenitor Programs and Promotes β-Cell Maturation, Revealing Sex Differences in Diabetes Progression

Pancreatic islet cells differentiate from a common progenitor pool through tightly regulated transcriptional and epigenetic programs. ISL1, a LIM homeodomain transcription factor, is essential for islet development, but its molecular functions remain poorly defined. Here, we demonstrate that ISL1 is critical for maintaining endocrine cell identity and enabling terminal differentiation, particularly of α- and β-cells. Using conditional Isl1 deletion in endocrine precursors, combined with single-cell RNA sequencing and chromatin profiling (H3K27ac and H3K27me3), we reveal disruption of the transcriptional and epigenetic landscape in Isl1-deficient islets. Loss of Isl1 results in the failure to establish α-cell identity, loss of δ- and γ-cell lineages, and the persistence of immature β-cells with impaired functional profiles in Isl1CKO mice. Longitudinal single-cell analysis shows that Isl1CKO endocrine cells exhibit sustained progenitor-like states and defective β-cell maturation. These defects are accompanied by activation of stress and diabetes-associated transcriptional programs, along with sex-specific responses that may influence disease onset and progression. Mechanistically, ISL1 represses intermediate progenitor programs and facilitates chromatin remodeling necessary for endocrine lineage commitment and terminal maturation. Our findings highlight a previously underappreciated role for ISL1 in preserving endocrine cell fate and function and offer insight into how its dysregulation may contribute to diabetes.Article HighlightsISL1 is a known maturity-onset diabetes of the young candidate and type 2 diabetes susceptibility gene, yet its molecular role in pancreatic endocrine maturation has remained unresolved.Deletion of Isl1 in endocrine progenitors results in islets composed of dysfunctional α-cells lacking glucagon production and immature β-cells with impaired basal insulin secretion, ultimately accelerating diabetes progression.ISL1 functions as a transcriptional repressor guiding chromatin remodeling and transcriptional transitions toward hormone-producing endocrine cells.The metabolic phenotype resulting from Isl1 deletion is associated with sustained progenitor-like states and activation of diabetes- and stress-associated pathways, with distinct sex-specific responses observed between male and female mice.

GDF5 Exacerbates Tubulointerstitial Injury by Inducing Partial Epithelial–Mesenchymal Transition of Tubular Epithelial Cells in Diabetic Kidney Disease

Adipokines serve crucial functions in diabetic kidney disease (DKD) pathogenesis. Growth differentiation factor 5 (GDF5) is highly expressed in adipose tissue, but its specific role in DKD is unknown. In this study, we observed elevated GDF5 expression in both patients with DKD and db/db mice, suggesting a potential association between GDF5 and DKD progression. Elevated plasma GDF5 levels are associated with an increased risk of incident chronic kidney disease in patients with type 2 diabetes. In animal studies, adipose-specific overexpression of GDF5 increased circulating GDF5 and exacerbated renal injury in db/db mice, characterized by increased tubulointerstitial injury and inflammation infiltration. Conversely, adipose-specific knockdown reduced circulating GDF5 and alleviated renal injury. In vitro studies demonstrated that GDF5 induces partial epithelial–mesenchymal transition in renal tubular epithelial cells via activation of the SMAD1/5/8 signaling pathway, as evidenced by reduced E-cadherin expression and increased Snail1 levels. Notably, the supernatant from GDF5-treated injured HK-2 cells was found to enhance the secretion of proinflammatory cytokines by macrophages. These findings suggest that adipose-derived GDF5 acts as a novel mediator contributing to tubulointerstitial injury in DKD.Article HighlightsElevated growth differentiation factor 5 (GDF5) expression is correlated with disease progression in both patients with diabetic kidney disease and db/db mice.Adipose-specific GDF5 overexpression exacerbates, whereas its knockdown alleviates, renal tubulointerstitial injury in vivo.GDF5 directly induces partial epithelial–mesenchymal transition in tubular cells by activating the SMAD1/5/8 signaling pathway.Tubular cells exposed to GDF5 release factors that promote proinflammatory cytokine secretion in macrophages.

Activation of the Pancreatic “Metabolic Synapse” Aggravates Type 2 Diabetes Mellitus by Inducing PANoptosis in β-Cells

Pancreatic β-cells play a central role in type 2 diabetes mellitus (T2DM), yet the interactions between β-cells and stromal components within the islet microenvironment remain poorly defined. We investigated the contribution of pancreatic fibroblasts to β-cell dysfunction and T2DM progression. We used single-cell sequencing technology and in vitro experiments to investigate the mechanisms by which bariatric surgery ameliorates T2DM. We introduce the novel concept of a “metabolic synapse” to describe the interaction between pancreatic fibroblasts and β-cells. Our findings reveal that pancreatic fibroblasts secrete excessive glutamate in the early stages of T2DM. Elevated glutamate concentrations within the islet microenvironment subsequently activate N-methyl-d-aspartic acid receptors (NMDARs), triggering PANoptosis in pancreatic β-cells and accelerating T2DM progression. Consistent with this, significant changes in NMDAR expression were observed in human pancreatic samples from patients with T2DM. These findings uncover a previously unrecognized fibroblast–β-cell communication pathway in the islet niche, provide mechanistic insights into T2DM pathogenesis, and highlight the glutamate–NMDAR axis as a potential therapeutic target for nonsurgical intervention.Article HighlightsWe identify a fibroblast–β-cell “metabolic synapse” in type 2 diabetes that couples stromal glutamate overflow to–β-cell N-methyl-d-aspartic acid receptor (NMDAR) activation.Single-cell maps and coculture assays show diabetogenic stress drives fibroblasts to hypersecrete glutamate, whereas β-cells upregulate NMDARs, triggering PANoptosis.In rodents, pharmacologic NMDAR blockade attenuates β-cell PANoptosis, preserves islet function, and improves glycemic control.Human pancreatic samples cohorts reveal fibrosis regression and stage-wise NMDAR upregulation, highlighting the glutamate–NMDAR axis as a therapeutic target.

Adipose Tissue Resistance to the Antilipolytic Effect of Insulin and Niacin in Humans With Obesity

Adipose tissue (AT) lipolysis insulin resistance results in excess free fatty acid (FFA) release. We tested the hypothesis that the ability of insulin to suppress AT lipolysis is unrelated to the ability of niacin to suppress lipolysis, because niacin acts through a different proximal signaling pathway. Ten volunteers (5 women and 5 men) with upper-body obesity and/or type 2 diabetes mellitus (T2DM) underwent two study visits with overnight intravenous infusions of niacin (1.4 mg/min) or saline, followed by a hyperinsulinemic-euglycemic clamp. FFA-palmitate Ra was measured using [U-13C] and [2H9]palmitate infusions; abdominal AT biopsies were performed before and during the insulin clamp. The suppression of FFA-palmitate Ra by insulin on the saline control day and by niacin after an overnight infusion were highly correlated (r = −0.93, P < 0.001). Fasting AT Akt (pAktS473/474-to-panAkt ratio, P = 0.01) and perilipin 1 (PLN1) (pPLN1S552-to-panPLN1 ratio, P = 0.02) phosphorylation were less during niacin treatment than in the saline control study. Because the suppression of lipolysis by insulin and niacin are highly correlated within individuals and because niacin and insulin act through different proximal signaling pathways, we propose dysregulated AT lipolysis in obesity/T2DM is due to dysfunction(s) in distal lipolysis proteins rather than isolated “insulin resistance.”Article HighlightsWe undertook this study to compare adipose tissue lipolysis responses to insulin and niacin in humans.We tested the hypothesis that adipose tissue insulin resistance would be unrelated to adipose tissue niacin resistance.The suppression of lipolysis by insulin and niacin were highly correlated.Dysregulated adipose tissue lipolysis in obesity/type 2 diabetes is due to dysfunction(s) in distal lipolysis proteins rather than isolated “insulin resistance.”