Diabetes[JOURNAL]
Sun
200 papers
β-Cell Mass in Individuals With and Without Postbariatric Hypoglycemia After Roux-en-Y Gastric Bypass.
Tokgöz S, Deden LN, Hofboer A … +8 more , Hazebroek EJ, de Boer H, van Bon AC, Meijer RI, de Galan BE, Tack CJ, Boss M, Gotthardt M
Diabetes · 2025 Dec · PMID 41066755 · Full text
UNLABELLED: Postbariatric hypoglycemia (PBH) is a serious complication of Roux-en-Y gastric bypass (RYGB), characterized by severe hypoglycemia that may lead to loss of consciousness and seizures. The exact mechanism of...
UNLABELLED: Postbariatric hypoglycemia (PBH) is a serious complication of Roux-en-Y gastric bypass (RYGB), characterized by severe hypoglycemia that may lead to loss of consciousness and seizures. The exact mechanism of PBH is poorly understood. One potential mechanism is β-cell expansion. To this end, we investigated β-cell mass in individuals with and without PBH after RYGB using [68Ga]Ga-NODAGA-exendin-4 positron emission tomography/computed tomography imaging (PET/CT). Individuals with PBH (n = 10) and without PBH (n = 9) after RYGB were included. PET/CT imaging was performed after infusion with 102.2 ± 6.9 MBq of the [68Ga]Ga-NODAGA-exendin-4 tracer to quantify pancreatic β-cell mass. The two groups did not differ with respect to sex, age, BMI, and total body weight loss after RYGB. Time between RYGB and inclusion was longer for individuals with PBH compared with those without. β-Cell mass did not differ between the groups. Individuals with PBH had a smaller pancreas than those without. β-Cell mass correlated neither with body weight parameters nor with metabolic parameters. Our data indicating that β-cell mass does not differ between individuals with and without PBH after RYGB argue against expansion of β-cell mass to explain PBH. ARTICLE HIGHLIGHTS: The exact mechanism of postbariatric hypoglycemia (PBH) is unclear, but β-cell mass expansion is hypothesized to play a role. We used [68Ga]Ga-NODAGA-exendin-4 positron emission tomography/computed tomography (PET/CT) to determine β-cell mass in individuals with and without PBH after Roux-en-Y gastric bypass surgery. β-Cell mass did not differ between individuals with and without PBH. Pancreas volume was lower in individuals with PBH compared with those without PBH. Our data argue against β-cell mass expansion to explain PBH after Roux-en-Y gastric bypass. Further study is required to understand PBH.
Regulatory Roles of IGF2R in Insulin Secretion and Adaptive β-Cell Proliferation.
Shirakawa J, De Jesus DF, Tsuno T … +8 more , Basile G, Inoue R, Takatani T, Nishiyama A, Okawa ER, Tamura T, Terauchi Y, Kulkarni RN
Diabetes · 2025 Dec · PMID 41042627 · Full text
UNLABELLED: Insulin-like growth factor-2 receptor (IGF2R), also known as cation-independent mannose-6-phosphate receptor, is localized in cytosolic vesicles and is unique in its ability to transport enzymes to the lysoso...
UNLABELLED: Insulin-like growth factor-2 receptor (IGF2R), also known as cation-independent mannose-6-phosphate receptor, is localized in cytosolic vesicles and is unique in its ability to transport enzymes to the lysosome and to clear IGF2 from the cell surface by acting as a scavenger receptor. To evaluate the direct role of IGF2R in β-cell biology, we undertook complementary in vitro knockdown and in vivo knockout approaches. A β-cell line with a stable knockdown of IGF2R (IGF2RKD) exhibited decreased glucose-induced insulin secretion and enhanced cell proliferation. Tamoxifen-inducible β-cell-specific IGF2R knockout mice exhibited impaired glucose tolerance and blunted insulin secretion after high-fat-diet loading that was likely secondary to reduced β-cell mass due to attenuated proliferation. β-cells with IGF2RKD had fewer autophagosomes after starvation and reduced expression of p62, LC3B, and ULK1. Aged mice also had impaired autophagy in βIGF2R-deficient β-cells. Reduced IGF2R function and N6-methyladenosine (m6A) mRNA methylation were observed in islets from both mouse and human type 2 diabetes. Taken together, these data point to IGF2R as an important regulator of insulin secretion, cell proliferation, and autophagy in mammalian β-cells. ARTICLE HIGHLIGHTS: The significance of insulin-like growth factor-2 receptor (IGF2R) in β-cells remains unclear. To assess the physiological role of IGF2R in β-cells, the effects of IGF2R deficiency in vivo and in vitro were investigated. IGF2R modulates insulin secretion, cell proliferation, and autophagy in β-cells. IGF2R plays a role in the regulation of β-cell biology.
Trem2+ Macrophages Alleviate Renal Tubule Lipid Accumulation and Ferroptosis in Diabetic Nephropathy by Repressing IL-1β-Mediated CD36 Expression.
Wang X, Wan J, Wang C … +11 more , Tong Y, Chen Y, Wang X, Liu J, Li Q, Dong Z, Hong Q, Sun X, Cai G, Ouyang Q, Chen X
Diabetes · 2025 Dec · PMID 41042607 · Full text
UNLABELLED: The presence of macrophages surrounding lipotoxic tubular epithelial cells (TECs) is a hallmark of diabetic nephropathy (DN). Nevertheless, the mechanisms of communication between these cell types are not wel...
UNLABELLED: The presence of macrophages surrounding lipotoxic tubular epithelial cells (TECs) is a hallmark of diabetic nephropathy (DN). Nevertheless, the mechanisms of communication between these cell types are not well understood. Previous studies have revealed a unique subset of macrophages that express triggering receptor expressed on myeloid cells 2 (Trem2) in kidneys of human patients and mice with DN. Here, we explored the characteristics and the function of Trem2+ macrophages in the progress of DN. RNA-sequencing of macrophages in kidneys of Trem2 knockout (KO) mice fed a high-fat diet plus streptozotocin (HFD/STZ) revealed functional enrichment of metabolic processes, cytokine production, positive regulation of extracellular signal-regulated kinase (ERK) cascades, and the regulation of phagocytosis. In vivo studies demonstrated that Trem2+ macrophages reduced lipid accumulation and mitigated ferroptosis of TECs in diabetic mice. Mechanistically, Trem2-deficient macrophages amplified the production of interleukin-1β (IL-1β) through activating the ERK signaling pathway. Furthermore, IL-1β triggered CD36 expression via the transcription factor NF-κB. Bioinformatics and functional assays showed NF-κB binds the CD36 promoter, which directly bound to the promoters of CD36 to facilitate its transcription. Inhibition of NF-κB blocked IL-1β-induced CD36 production. This mechanism is exacerbated in Trem2-deficient macrophages, which release excess IL-1β to activate NF-κB in tubular cells, promoting CD36-dependent lipid uptake and ferroptosis. Additionally, we found Trem2 plays a role in enhancing the phagocytosis and clearance of ferroptotic cells by bone marrow-derived macrophages. Altogether, our results suggest Trem2+ macrophages maintain homeostasis of the renal microenvironment and exert a protective function in DN. ARTICLE HIGHLIGHTS: Levels of triggering receptor expressed on myeloid cells 2 (Trem2) in macrophages are increased in human patients and in mice with diabetic nephropathy. Trem2 suppresses the extracellular signal-regulated kinase signaling pathways, thereby inhibiting IL-1β production in macrophages. Macrophage Trem2 deficiency exacerbates tubular cell lipid deposition and ferroptosis by increasing CD36 expression in an IL-1β-dependent manner.
Novel Function of Osteoprotegerin in the Modulation of Glucose Metabolism in the Liver via mTORC1.
Qiu S, Wang X, Li K … +8 more , Zhang S, Lai Y, Mi Q, Yang M, Liu D, Li L, Wu Q, Yang M
Diabetes · 2025 Dec · PMID 41026625 · Publisher ↗
UNLABELLED: Osteoprotegerin (OPG) has emerged as a pivotal factor in metabolic disease pathology; however, its role in hepatic glucose metabolism remains poorly understood. We demonstrated a pronounced reduction in hepat...
UNLABELLED: Osteoprotegerin (OPG) has emerged as a pivotal factor in metabolic disease pathology; however, its role in hepatic glucose metabolism remains poorly understood. We demonstrated a pronounced reduction in hepatic OPG expression in obese mice, attributable to DNA hypermethylation mediated by DNMT3α. Opg overexpression in the liver reduced the basal metabolic rate and exacerbated glucose metabolism disorders in mice with high-fat diet-induced obesity, whereas Opg knockout yielded opposite effects. Furthermore, mammalian target of rapamycin complex 1 (mTORC1; Raptor)/S6K1/IRS1/AKT signaling was found to be required for the regulation of hepatic glucose metabolism. Mechanistic investigations revealed that OPG interacts with Raptor within the mTORC1 complex, facilitating its phosphorylation at Ser863 and Ser877, influencing the mTORC1 (Raptor)/S6K1/IRS1/AKT signaling pathway, and thereby affecting glucose metabolism and insulin sensitivity. These findings underscore the integral role of OPG in glucose homeostasis and suggest it as a novel therapeutic target in type 2 diabetes. ARTICLE HIGHLIGHTS: Methylation of the Opg promoter inhibits hepatic OPG expression in obese mice. Hepatic OPG regulates glucose metabolism and insulin sensitivity in obese mice. OPG regulates glucose metabolism through interaction with mammalian target of rapamycin complex 1 (Raptor). Opg deficiency in mice reduces age-related metabolic dysfunction.
Genotype-Phenotype Discrepancies in Family Members With a Novel Glucokinase Mutation: Insights Into GCK-MODY and Its Interplay With Insulin Resistance.
Ji S, Shu H, Zhao H … +16 more , Jiang H, Ye Y, Liu X, Chen S, Yang Y, Feng W, Qiao J, Zhen J, Yang X, Zhang Z, Fan Y, Huang Y, He Q, Wang M, Wang K, Liu M
Diabetes · 2025 Dec · PMID 40997347 · Publisher ↗
UNLABELLED: Heterozygous inactivating mutations in the glucokinase (GCK) gene cause maturity-onset diabetes of the young (GCK-MODY). We identified a novel variant of uncertain significance in the GCK gene (c.77A>T, p.Q26...
UNLABELLED: Heterozygous inactivating mutations in the glucokinase (GCK) gene cause maturity-onset diabetes of the young (GCK-MODY). We identified a novel variant of uncertain significance in the GCK gene (c.77A>T, p.Q26L) in two family members exhibiting contrasting diabetic phenotypes. To explore the diabetogenic potential of the GCK-Q26L mutation and investigate the mono- and polygenetic factors contributing to different phenotypes, whole-exome sequencing and polygenic risk score (PRS) assessments were conducted on three family members. We found that the proband inherited the GCK-Q26L mutation from her father (who had mild, stable hyperglycemia) but exhibited more severe diabetic symptoms, including polydipsia, polyuria, weight loss, ketosis, and significant dyslipidemia. Genetic analysis linked the proband's severe phenotypes to her high PRS for insulin resistance (IR) and type 2 diabetes. A global knock-in mouse model expressing GCK-Q26L presented mild hyperglycemia, impaired glucose tolerance, reduced serum insulin, and impaired glucose-stimulated insulin secretion. Both dorzagliatin and liraglutide improved glucose tolerance and insulin secretion in mutant mice. This study demonstrates that GCK-Q26L is a pathogenic GCK-MODY mutation, and its associated phenotypes are influenced by PRS for IR and type 2 diabetes. ARTICLE HIGHLIGHTS: This study was undertaken to investigate the diabetogenic potential of a novel GCK variant, c.77A>T, p.Q26L, found in two family members with marked differences in diabetic phenotypes. We aimed to understand the role of GCK-Q26L in glucose metabolism and to explore whether genetic backgrounds, including polygenic risk score for insulin resistance and type 2 diabetes, contribute to diabetes manifestations. We found that GCK-Q26L is a pathogenic mutation leading to GCK-MODY, with severity modulated by polygenic risk score for insulin resistance and type 2 diabetes. These findings not only expand the list of GCK-MODY causing mutations but also highlight the importance of polygenic backgrounds in the clinical presentation and management of monogenic diabetes.
Combined Weight Loss and Exercise Training Alters Skeletal Muscle Subcellular Lipid Localization and Intermuscular Adipose Tissue Cellular Composition.
Zemski Berry K, Garfield A, Whytock KL … +17 more , Macias E, Zarini S, Jambal P, Stepaniak T, Bowen S, Perreault L, Johnson C, Kahn D, Kerege A, Tamburini IJ, Nguyen CM, Viesi CH, Seldin M, Sun Y, Walsh M, Sparks LM, Bergman BC
Diabetes · 2025 Dec · PMID 40982756 · Full text
UNLABELLED: Subcellular lipid accumulation and intermuscular adipose tissue (IMAT) accumulation are associated with insulin resistance, but the impact of combined weight loss and exercise training on localization of lipi...
UNLABELLED: Subcellular lipid accumulation and intermuscular adipose tissue (IMAT) accumulation are associated with insulin resistance, but the impact of combined weight loss and exercise training on localization of lipids and IMAT cellular composition is not known. Twenty-one adults with obesity (18 female and 3 male; 46 ± 2 years; 35.0 ± 0.9 kg/m2) completed a 3-month supervised weight loss and exercise training intervention. Insulin sensitivity was measured using a hyperinsulinemic-euglycemic clamp, and basal and insulin-stimulated vastus lateralis biopsies were collected pre- and postintervention. After the intervention, body weight and body fat decreased (11 ± 1% and 9 ± 1%, respectively), while VO2 peak and insulin sensitivity increased (14 ± 3% and 68 ± 14%, respectively). Lipidomics revealed reduced sarcolemmal and nuclear triglycerides, with unchanged whole-muscle triglycerides. Whole-muscle diacylglycerols increased because of increased nuclear 1,2-diacylglycerols without PKCε, PKCθ, or PKCδ activation. Whole-muscle sphingolipid levels increased because of cytosolic accumulation. Single-nuclei RNA sequencing showed altered IMAT cellular composition, including increased fibro-adipogenic progenitors, vascular cells, and macrophages, and decreased preadipocytes. Bulk muscle RNA sequencing indicated upregulation of genes related to muscle remodeling and cellular respiration, and there were changes in the relationship between nuclear diacylglycerols and gene expression postintervention. These findings dissociate improvements in insulin sensitivity from total muscle diacylglycerol and sphingolipid levels and highlight roles for subcellular lipid redistribution and IMAT remodeling in insulin sensitization. ARTICLE HIGHLIGHTS: Evaluation of subcellular fractionated muscle revealed decreases in sarcolemmal and nuclear triglycerides and increases in nuclear diacylglycerols and cytosolic sphingolipids postintervention. Weight loss revealed alteration in the cellular composition of intermuscular adipose tissue and upregulation of genes related to muscle remodeling and cellular respiration. These findings dissociate improvements in insulin sensitivity from total muscle 1,2-diacylglycerol and sphingolipid levels and highlight roles of intermuscular adipose tissue remodeling for enhanced insulin sensitivity.
Predicting Sustained Benefit From Tirzepatide in SURPASS-4: Who Benefits and Why?
Varadinova M, Wagner R
Diabetes · 2025 Oct · PMID 40971612 · Publisher ↗
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Diabetes Spotlight: Rebecca Anne Haeusler, PhD-Investigating Metabolism Through Insulin Signaling.
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Diabetes · 2025 Oct · PMID 40971611 · Publisher ↗
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Genome-Wide Association Study of Hypoglycemia in Adults With Diabetes in the Million Veteran Program.
Raghavan S, Litkowski E, Jensen A … +15 more , Charest B, Wang Z, Hui Q, Chen HC, Rhee MK, Leong A, Meigs JB, Lange L, Lange E, Reaven P, Hung A, Zhou J, Sun YV, Phillips LS, Million Veteran Program*
Diabetes · 2025 Dec · PMID 40971195 · Full text
UNLABELLED: Hypoglycemia is a preventable adverse treatment effect in diabetes patients, but genetic markers to identify those with increased susceptibility are lacking. We performed a case/control genome-wide associatio...
UNLABELLED: Hypoglycemia is a preventable adverse treatment effect in diabetes patients, but genetic markers to identify those with increased susceptibility are lacking. We performed a case/control genome-wide association study (GWAS) of hypoglycemia in U.S. Million Veteran Program (MVP) participants with medication-treated diabetes. Case participants had an outpatient random serum/plasma glucose <70 mg/dL or an emergency department visit for hypoglycemia. GWAS was stratified by race/ethnicity, adjusted for age at MVP enrollment, sex, and top 10 population-specific principal components, followed by multipopulation meta-analysis. Secondary analyses examined genetic associations with hypoglycemia stratified by diabetes medication exposure as well as replication in UK Biobank and the Action to Control Cardiovascular Risk in Diabetes clinical trial. The study included 72,244 (22,045 case participants) non-Hispanic White participants, 24,162 (10,441 case participants) non-Hispanic Black participants, and 9,196 (2,800 case participants) Hispanic participants. Four loci had genome-wide significant associations with hypoglycemia in multipopulation meta-analysis: rs12712928 (chromosome 2, SIX2/SIX3 locus), rs1064173 (chromosome 6, HLA-DQB1/DQA2 locus), rs35198068 (chromosome 10, TCF7L2 locus), and rs113748381 (chromosome 17, SCL16A11 locus). All four loci replicated in at least one independent cohort, and the magnitude of associations with hypoglycemia varied by diabetes type. Genome-wide analyses may complement candidate pharmacogenetic studies to identify risk markers of adverse drug effects. ARTICLE HIGHLIGHTS: Genetic variants associated with hypoglycemia risk in individuals with medication-treated diabetes have not been evaluated genome-wide. The specific question we asked was whether common genetic variants are associated with hypoglycemia among individuals with diabetes treated with glucose-lowering medications. We found four genomic loci were associated with hypoglycemia in a genome-wide association study. One locus-on chromosome 6-was associated with hypoglycemia only in individuals with likely type 1 diabetes, and two loci-on chromosome 2 and chromosome 6-were associated with hypoglycemia only in the context of treatment with sulfonylureas (chromosome 2) or with insulin (chromosome 6). Genetic variants may help identify individuals with diabetes at increased hypoglycemia risk, but additional study is needed to address the clinical utility of genetic data to inform hypoglycemia risk.
Systems Biology and Functional Assessments of Human iPSC-Cardiomyocyte Models of Insulin Resistance Capture Key Hallmarks of Diabetic Cardiomyopathy.
Carter RD, Purnama U, Castro-Guarda M … +11 more , Montes-Aparicio CN, Chandran A, Mbasu R, Ruby M, Daly C, Brisk K, Christian HC, Miller JJJJ, Buffa FM, Heather LC, Carr CA
Diabetes · 2025 Nov · PMID 40956683 · Full text
UNLABELLED: Human-centric models of diabetic cardiomyopathy (DbCM) are needed to provide mechanistic insights and translationally relevant therapeutic targets for patients with diabetes. A systems biology approach using...
UNLABELLED: Human-centric models of diabetic cardiomyopathy (DbCM) are needed to provide mechanistic insights and translationally relevant therapeutic targets for patients with diabetes. A systems biology approach using insulin resistant (IR) two-dimensional (2D) human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and three-dimensional (3D) engineered heart tissue (EHT) provides a comprehensive evaluation of dysregulated pathways and determines suitability as a translationally relevant model of DbCM. Culturing hiPSC-CMs in 2D or 3D EHT in IR media induced insulin resistance and activated multiple pathways implicated in DbCM, including metabolic remodeling, mitochondrial dysfunction, extracellular matrix remodeling, endoplasmic reticulum stress, and blunted response to hypoxia, as assessed using transcriptomics and proteomics. Metabolic flux measurements in both IR 2D and 3D platforms demonstrated increased fatty acid oxidation and lipid storage, whereas glucose metabolism was downregulated. Modeling DbCM in 3D EHTs conferred additional metabolic and functional advantages over the 2D hiPSC-CM, demonstrating impaired contractility and muscle architecture. Metformin treatment improved both contractility and metabolic function, demonstrating the utility of IR EHT for drug assessment. In conclusion, IR 2D and 3D hiPSC-CM models effectively capture key DbCM features. However, 3D EHT provides additional insights into physiological and structural modifications. This highlights the potential of IR EHT for both mechanistic studies and drug screening in DbCM. ARTICLE HIGHLIGHTS: Human-centric cardiac models are needed that recapitulate mechanistic and functional changes in the type 2 diabetic myocardium for understanding disease pathogenesis and developing new therapies. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) in 2D and 3D as engineered heart tissue (EHT), we aimed to model diabetic cardiomyopathy in cellulo. Taking an unbiased systems biology approach, our cellular models recapitulated the dysregulated pathways and functional derangement of diabetic cardiomyopathy. Three-dimensional EHT models showed contractile dysfunction akin to that seen in patients, with mechanistic and functional changes reversed with metformin. It is possible to generate translationally relevant hiPSC-CM models that mimic diabetic cardiomyopathy.
Multiomics Integration of Epigenetics, Proteomics, and Metabolomics Identifies Putative Drug Targets and Improves Early Prediction for Diabetes.
Li W, Cheng Y, Cui A … +19 more , Huang M, Huang Q, Wang Q, Xia M, Qiu J, Peng Q, Li J, Li H, Wang Y, Zong G, Zheng Y, Wang J, Gao X, Ding C, Tang H, Jiang BH, Jin L, Li Y, Wang S
Diabetes · 2025 Dec · PMID 40938633 · Full text
UNLABELLED: Diabetes holds significant social importance due to its high incidence rate and multitude of associated complications. The identification of diabetes biomarkers and the understanding of the intricate biologic...
UNLABELLED: Diabetes holds significant social importance due to its high incidence rate and multitude of associated complications. The identification of diabetes biomarkers and the understanding of the intricate biological mechanisms underlying diabetes are crucial for the early diagnosis and treatment of diabetes. In this study, we conducted comprehensive omics profiling of CpGs, plasma proteins, and serum metabolites in an National Survey of Physical Traits (NSPT) cohort of 3,451 individuals, among whom 293 were patients with diabetes. Global association analysis identified 175 CpGs, 29 proteins, and 93 metabolites significantly linked to diabetes, among which 43 CpGs and 25 metabolites were validated in an independent cohort comprising 532 individuals. Mendelian randomization and mediation analysis identified 20 causal biomarkers and 190 signaling pathways linking biomarkers from different layers. By integrating the cross-omics evidence, we provide a list of putative causal biomarkers of diabetes to serve as a valuable resource for the diabetes community. Cross-omics integration prioritized biomarkers for therapeutic targeting, highlighting COLEC11 as an example of a potential target and whose function was further validated in vitro. The early-prediction model using the prioritized biomarkers improved the area under the receiver operating characteristic curve by 27.5% compared with the baseline model, using clinical features alone. Our findings provide a comprehensive list of prioritized multiomics biomarkers and elucidate specific signaling pathways in diabetes, contributing significantly to the selection of therapeutic target and the understanding of diabetes pathophysiology. ARTICLE HIGHLIGHTS: A total of 175 CpGs, 29 proteins, and 93 metabolites were identified as associated with diabetes, among which 43 CpGs and 25 metabolites were validated in an independent cohort. Causal and mediation analyses revealed 20 biomarkers and 190 signaling pathways involved in diabetes development. The integrative multiomics prioritization provides the community with an ordered list of diabetes biomarkers. We experimentally validated one of the prioritized proteins, COLEC11, and demonstrated its involvement in lipid metabolism. Our findings prioritize potential therapeutic targets and demonstrate that integrating multiomics biomarkers improves diabetes risk prediction beyond traditional clinical models.
β-Cell Neogenesis From the Pancreatic Ductal Epithelium Revealed Dynamically by Long-term Intravital Imaging.
Watts B, Altilio I, Alcázar Ó … +5 more , Álvarez-Cubela S, Berggren PO, Abdulreda MH, Pastori RL, Domínguez-Bendala J
Diabetes · 2025 Nov · PMID 40932308 · Full text
UNLABELLED: Pancreatic β-cells can self-renew in the adult pancreas through replication, but the contribution of ductal progenitors to endocrine regeneration has been the subject of debate for two decades. While these me...
UNLABELLED: Pancreatic β-cells can self-renew in the adult pancreas through replication, but the contribution of ductal progenitors to endocrine regeneration has been the subject of debate for two decades. While these mechanisms are not mutually exclusive, some lineage-tracing strategies suggest that intraductal endocrine cells cannot dynamically derive from ducts. Combining one such approach with a novel in vivo model in which live pancreatic slices are transplanted into the anterior chamber of the eye (ACE) of recipient mice, we show long-term growth of preexisting islets and real-time generation of neogenic insulin-expressing cells from ductal areas. Our results represent a departure from historical approaches to address these questions, which have been based on either static analyses of pancreatic tissue or "before and after" lineage-tracing designs. The slice-in-ACE model reveals the dynamic processes at play during regeneration and demonstrates the active formation of insulin-producing cells within the ductal network. ARTICLE HIGHLIGHTS: The adult pancreas' capacity to regenerate endocrine cells through ductal neogenesis has been disputed based on some pulse-chase lineage-tracing designs; however, no model described thus far has enabled the real-time study of regeneration in vivo. To facilitate long-term intravital imaging of pancreatic remodeling, we designed a novel system where pancreatic slices are transplanted into the anterior chamber of the eye of recipient mice. Using a transgenic mouse strain that enables the tracing of insulin-producing cells, we demonstrate that they arise dynamically from the ductal epithelium. Complementary work with human pancreatic slices suggests conservation of these mechanisms across species.
Serum Metabolomics Reveals Potential Differences in Gut Microbiota-Associated Metabolites in Twins Discordant for Type 1 Diabetes.
Flammer ER, Christopher MW, Powers ER … +5 more , Broncucia H, Steck AK, Gitelman SE, Garrett TJ, Ismail HM
Diabetes · 2025 Nov · PMID 40932298 · Full text
UNLABELLED: We investigated serum metabolites in monozygotic (MZ) and dizygotic (DZ) twins discordant for type 1 diabetes (T1D) to explore potential environmental factors, with a focus on differences in gut microbiota-as...
UNLABELLED: We investigated serum metabolites in monozygotic (MZ) and dizygotic (DZ) twins discordant for type 1 diabetes (T1D) to explore potential environmental factors, with a focus on differences in gut microbiota-associated metabolites that may influence T1D. Serum samples from 39 twins discordant for T1D were analyzed using a semi-targeted metabolomics approach via liquid chromatography-high-resolution tandem mass spectrometry. Statistical analyses identified significant metabolites (P < 0.1) within three groups: all twins (combined group [All]), MZ twins, and DZ twins. Thirteen metabolites exhibited significant differences between individuals with T1D and those without T1D. Across all groups, 3-indoxyl sulfate and 5-hydroxyindole were significantly reduced in individuals with T1D. Carnitine was reduced, and threonine, muramic acid, and 2-oxobutyric acid were significantly elevated in both All and MZ groups. Allantoin was significantly reduced and 3-methylhistidine was significantly elevated in All and DZ groups. These findings suggest metabolite dysregulation associated with gut dysbiosis was observed. However, further validation of our findings in a larger cohort is needed. ARTICLE HIGHLIGHTS: We believed this cohort of twins discordant for type 1 diabetes (T1D) would allow for control over genetic variability to examine environmental factors. We aimed to identify differences in microbial and microbiota-associated metabolites in twins discordant for T1D to examine the effect of the gut microbiome on T1D. Thirteen metabolites were identified as significantly different. Our results show dysregulation of several microbial metabolites in twin pairs, suggesting the role of the gut microbiome in T1D pathogenesis.
Mechanistic Insights Into Postprandial Insulin-Glucagon Interactions and Their Impact on Glucose Flux After Protein-Glucose Coingestion in Humans.
Dao GM, Shaw CS, Betik AC … +3 more , Kuriel V, Bruce CR, Kowalski GM
Diabetes · 2025 Nov · PMID 40928846 · Publisher ↗
UNLABELLED: Despite stimulating glucagon secretion, the mechanisms by which protein ingestion lowers glucose excursions remain unclear. We investigated this using the triple stable isotope glucose tracer technique to mea...
UNLABELLED: Despite stimulating glucagon secretion, the mechanisms by which protein ingestion lowers glucose excursions remain unclear. We investigated this using the triple stable isotope glucose tracer technique to measure postprandial glucose fluxes. Eleven healthy adults completed three trials, ingesting 25 g glucose (25G; 100 kcal), 50 g glucose (50G; 200 kcal), or 25 g glucose plus 25 g whey protein (25WG; 200 kcal). Glucose excursions were lowest for 25WG. Glucagon increased approximately threefold with 25WG but was suppressed with 25G and 50G. Insulin and glucose-dependent insulinotropic polypeptide (GIP) were higher for 25WG versus 25G, whereas glucagon-like peptide 1 (GLP-1) was similar. Compared with 50G, 25WG produced a greater GIP but similar GLP-1 response, with a trend toward higher early-phase insulin. Endogenous glucose production (EGP) was less suppressed with 25WG (∼50%) versus 25G (∼70%) or 50G (∼80%). Compared with 25G, 25WG did not enhance glucose disposal (Rd) but reduced early-phase (30-60 min) glucose absorption. These findings confirm that protein-glucose coingestion robustly stimulates glucagon while enhancing GIP and insulin, leading to lower postprandial glucose excursions. Despite greater insulin secretion, the net glycemic benefit seems to stem from reduced early glucose absorption rather than increased Rd. This provides novel insights into the mechanisms by which protein improves postprandial glucose handling despite interfering with EGP suppression. ARTICLE HIGHLIGHTS: Despite stimulating glucagon secretion, the addition of protein to carbohydrate typically lowers postprandial glucose excursions. The mechanisms underlying this phenomenon are incompletely understood. In healthy young adults, using the triple stable isotope glucose tracer technique, we investigated how whey protein and glucose coingestion modulates postprandial glucose fluxes. Despite stimulating glucagon secretion and impairing suppression of endogenous glucose production, whey protein-glucose coingestion significantly reduced glycemic excursions. Although whey protein-glucose coingestion strongly enhanced the insulin and glucose-dependent insulinotropic polypeptide (but not glucagon-like peptide 1) responses, whole-body glucose uptake was not enhanced; rather, the net glycemic benefit seemed to stem from reduced early-phase glucose absorption.
Heterogeneity in Phenotype and Early Metabolic Response to Lifestyle Interventions in Type 2 Diabetes in China Using a Tree-Like Representation.
Ding Y, Zhou Q, Jiang Y … +15 more , Cao Q, Wu X, Li X, Xu Y, Lu J, Xu M, Wang T, Zhao Z, Chen Y, Liu Y, Li J, Ning G, Wang W, Bi Y, Li M
Diabetes · 2025 Nov · PMID 40906542 · Publisher ↗
UNLABELLED: Deciphering the heterogeneity of type 2 diabetes in prognosis and treatment effect is essential. We used a novel dimensionality reduction approach to describe the type 2 diabetes phenotype continuum and visua...
UNLABELLED: Deciphering the heterogeneity of type 2 diabetes in prognosis and treatment effect is essential. We used a novel dimensionality reduction approach to describe the type 2 diabetes phenotype continuum and visualize the difference in lifestyle intervention efficacy in Chinese patients. Based on 17,816 participants with newly diagnosed type 2 diabetes (aged ≥40 years) from a nationwide cohort, 12 key phenotypes were residualized for age and sex to construct a two-dimensional tree structure. The tree demonstrated the continuous type 2 diabetes spectrum and region-specific characteristics, with a mixed phenotypic trunk and three extreme phenotypic branches. When mapping data from 325 participants with type 2 diabetes from a randomized controlled trial onto the original tree, lifestyle intervention induced a migration toward the left part of tree, indicating an overall metabolic improvement. Specifically, diet intervention was more effective for glycemic control in the upper part of the tree and featured moderate diabesity and elevated insulin, whereas exercise intervention was more effective for glycemic control in the left side of the tree and featured less adiposity and better overall metabolic status. In summary, this analysis depicted the tree structure representing the underlying pathophysiological features of patients with newly diagnosed type 2 diabetes and identified tree regions with different sensitivity to diet or exercise intervention. The results have the potential to aid lifestyle intervention selection. ARTICLE HIGHLIGHTS: Deciphering the heterogeneity of diabetes is essential for prognosis prediction and treatment guidance, but current classifications are flawed because they lose continuous phenotypic information. We wanted to determine if the novel data reduction method, the data dimensionality reduction tree (DDRTree), is applicable to visualizing the phenotypic continuum, comorbid conditions, and lifestyle intervention effects in Chinese patients with type 2 diabetes. The DDRTree structure demonstrated the region-specific characteristics of type 2 diabetes. Diet intervention was more effective for glycemic control in the upper part of the tree, featuring moderate diabesity, whereas exercise intervention was more effective in the left side of the tree, featuring less adiposity and better overall metabolic status. The Chinese type 2 diabetes tree structure indicates individualized pathophysiology and guides the selection of lifestyle intervention.
Proinflammatory Cytokines Mediate Pancreatic β-Cell-Specific Alterations to Golgi Integrity via iNOS-Dependent Mitochondrial Inhibition.
Blom SE, Narsian PR, Behan-Bush RM … +3 more , Ankrum JA, Yang L, Stephens SB
Diabetes · 2025 Nov · PMID 40906541 · Full text
UNLABELLED: Type 1 diabetes (T1D) is caused by the selective autoimmune ablation of pancreatic β-cells. Emerging evidence reveals β-cell secretory dysfunction arises early in T1D development and may contribute to disease...
UNLABELLED: Type 1 diabetes (T1D) is caused by the selective autoimmune ablation of pancreatic β-cells. Emerging evidence reveals β-cell secretory dysfunction arises early in T1D development and may contribute to diseases etiology; however, the underlying mechanisms are not well understood. Our data reveal that proinflammatory cytokines elicit a complex change in the β-cell's Golgi structure and function. The structural modifications include Golgi compaction and loss of the interconnecting ribbon resulting in Golgi fragmentation. We further show that Golgi structural alterations coincide with persistent altered cell surface glycoprotein composition. Our data demonstrate that inducible nitric oxide synthase (iNOS)-generated nitric oxide (NO) is necessary and sufficient for β-cell Golgi restructuring. Moreover, the unique sensitivity of the β-cell to NO-dependent mitochondrial inhibition results in β-cell-specific Golgi alterations that are absent in other cell types, including α-cells. Examination of human pancreas samples from autoantibody-positive and T1D donors with residual β-cells further revealed alterations in β-cell, but not α-cell, Golgi structure that correlate with T1D progression. Collectively, our studies provide critical clues as to how β-cell secretory functions are specifically impacted by cytokines and NO that may contribute to the development of β-cell autoantigens relevant to T1D. ARTICLE HIGHLIGHTS: Proinflammatory cytokines drive disruptions in Golgi structure and function in human, mouse, and rat β-cells. Golgi alterations result from inducible nitric oxide synthase (iNOS)- and nitric oxide (NO)-dependent inhibition of mitochondrial metabolism. α-Cell Golgi structure is insensitive to cytokine- and NO-mediated metabolic inhibition. Analysis of human donor tissue shows early Golgi alteration in β-cells from autoantibody-positive donors, which persists in residual β-cells from T1D donors.
Application of Dental Pulp Stem Cell-Derived Intracellular Vesicles for Diabetic Wound Healing.
Pang P, Liu Y, Song H … +9 more , Ye Z, Zhou H, Zhang R, Kumeria T, She W, Xu C, Mei PL, He Y, Ye Q
Diabetes · 2025 Nov · PMID 40906538 · Publisher ↗
UNLABELLED: Diabetic wounds represent a significant clinical and economic burden, affecting both patients and health care systems. While current therapeutic approaches, such as negative pressure wound therapy, offer bene...
UNLABELLED: Diabetic wounds represent a significant clinical and economic burden, affecting both patients and health care systems. While current therapeutic approaches, such as negative pressure wound therapy, offer benefits, their limitations necessitate alternative strategies. Newly discovered dental pulp stem cell-derived intracellular vesicles have emerged as a promising candidate in regenerative medicine due to their therapeutic potential. In vitro assessments using HUVECs, HaCaTs, and RAW264.7 cells revealed that intracellular vesicles enhance cell migration, angiogenesis, and proliferation while suppressing the cGAS-STING pathway. Additionally, intracellular vesicles promoted M2 macrophage polarization and maintained mitochondrial function. In a diabetic mouse wound model, both intracellular vesicles and negative pressure wound therapy individually improved wound healing, but their combination exhibited a synergistic effect, resulting in faster wound closure, enhanced angiogenesis, and reduced inflammation. The combined treatment also exhibited excellent biocompatibility. These findings highlight the therapeutic potential of intracellular vesicles as an adjunct to negative pressure wound therapy for diabetic wound treatment. ARTICLE HIGHLIGHTS: Chronic diabetic wounds are difficult to heal, and current treatments, such as negative pressure wound therapy, have limited effectiveness. The potential of intracellular vesicles derived from dental pulp stem cell lysate for diabetic wound healing is well worth exploring. Intracellular vesicles promoted angiogenesis, cell proliferation, and M2 macrophage polarization by inhibiting cGAS-STING signaling and restoring mitochondrial function. Combined with negative pressure wound therapy, intracellular vesicles accelerated wound healing in diabetic mice. Intracellular vesicles offer a promising cell-free strategy to enhance negative pressure wound therapy outcomes and improve diabetic wound treatment.
Cell Type-Specific Expression of Long Noncoding RNAs in Human Diabetic Kidneys Identifies TARID as a Key Regulator of Podocyte Function.
de Klerk JA, Slieker RC, Parker WC … +18 more , Wu H, Muto Y, Postma RJ, 't Hart LM, Peerlings JHD, Herrewijnen F, Song H, Spijker HS, Dumas SJ, Koning M, van der Pluijm LAK, Baelde HJ, Gerrits T, Rotmans JI, van Zonneveld AJ, van Solingen C, Humphreys BD, Bijkerk R
Diabetes · 2025 Nov · PMID 40902080 · Full text
UNLABELLED: Long noncoding RNAs (lncRNAs) play essential roles in cellular processes, often exhibiting cell type-specific expression and influencing kidney function. While single-cell RNA sequencing (scRNA-seq) has advan...
UNLABELLED: Long noncoding RNAs (lncRNAs) play essential roles in cellular processes, often exhibiting cell type-specific expression and influencing kidney function. While single-cell RNA sequencing (scRNA-seq) has advanced our understanding of cellular specificity, past studies focus solely on protein-coding genes. We hypothesize that lncRNAs, due to their cell-specific nature, have crucial functions within particular renal cells and thereby play essential roles in renal cell function and disease. Using single-nucleus RNA-seq (snRNA-seq) data from kidney samples of five healthy individuals and six patients with diabetic kidney disease (DKD), we explored the noncoding transcriptome. Cell type-specific lncRNAs were identified, and their differential expression in DKD was assessed. Integrative analyses included expression quantitative trait loci (eQTL), genome-wide association studies (GWAS) for estimated glomerular filtration rate (eGFR), and gene regulatory networks. Functional studies focused on TCF21 antisense RNA inducing promoter demethylation (TARID), a lncRNA with podocyte-specific expression, to elucidate its role in podocyte health. We identified 174 lncRNAs with cell type-specific expression across kidney cell types. Of these, 54 lncRNAs were differentially expressed in DKD. Integrative analyses, including eQTL data, GWAS results for eGFR, and gene regulatory networks, pinpointed TARID, a podocyte-specific lncRNA, as a key candidate upregulated in DKD. Functional studies confirmed TARID's podocyte-specific expression and revealed its central role in actin cytoskeleton reorganization. Our study provides a comprehensive resource of single-cell lncRNA expression in the human kidney and highlights the importance of cell type-specific lncRNAs in kidney function and disease. Specifically, we demonstrate the functional relevance of TARID in podocyte health. ARTICLE HIGHLIGHTS: This study provides a resource for kidney (cell type-specific) long noncoding (lnc)RNA expression and demonstrates the importance of lncRNAs in renal health. We identified 174 cell type-specific lncRNAs in the human kidney, with 54 showing altered expression in diabetic kidney disease. TCF21 antisense RNA inducing promoter demethylation (TARID), a podocyte-specific lncRNA upregulated in diabetic kidney disease, is crucial for actin cytoskeleton reorganization in podocytes.
Proteogenomic Discovery of Novel Open Reading Frames With HLA Immune Presentation on Human β-Cells.
Walters K, Castro-Gutierrez R, Sarkar S … +9 more , Baldwin A, Baker AS, Shilleh AH, Anderson AM, Nakayama M, Fugman T, Nakayasu ES, Mukherjee N, Russ HA
Diabetes · 2025 Dec · PMID 40896833 · Full text
UNLABELLED: Ribosome profiling (Ribo-seq) measures translational regulation and reveals novel or unannotated open reading frames (nuORFs) otherwise difficult to identify. Recent reports demonstrate that nuORFs regulate g...
UNLABELLED: Ribosome profiling (Ribo-seq) measures translational regulation and reveals novel or unannotated open reading frames (nuORFs) otherwise difficult to identify. Recent reports demonstrate that nuORFs regulate gene expression and immune recognition, highlighting their emerging biological roles. Pancreatic β-cells are critical for maintaining euglycemic conditions, and β-cell impairment contributes to diabetes development. Identification of nuORF and protein/peptide products in human β-cells could reveal novel mechanisms that regulate β-cell function during homeostatic and disease conditions. Here, we applied a proteogenomic approach to human β-cells to define previously unknown protein/peptide products. First, we applied cell type-specific Ribo-seq to map the translatome of human stem cell-derived β-cells (sBCs). Pathways crucial for β-cell function and antigen presentation were subject to translational regulation. We detected a recently described immunogenic neoantigen, INS-DRiP, presumably originating from a downstream start site in INS mRNA. Moreover, our analysis revealed 965 novel nuORFs in sBCs, with a majority showing protein-level support. Comparison with primary human islets further validated nuORF translation and highlighted β-cell specificity. We identified a novel, primate-specific regulatory upstream ORF within TYK2, which is crucial for β-cell function and interferon response and has many variants strongly associated with type 1 diabetes. Finally, we used immunopeptidomics, HLA-binding prediction models, and T-cell coculture assays to validate the presentation and immunogenicity of preproinsulin peptides and nuORFs. Our findings underscore the importance of translational regulation in β-cell function and provide an important resource to the diabetes research community. ARTICLE HIGHLIGHTS: We developed a cell type-specific proteogenomic approach to reveal novel or unannotated open reading frames (nuORFs) using transcriptomics, ribosomal profiling, and proteomic analysis of human pancreatic β-cells using stem cell-derived β-cells and/or cadaveric islets. Our analysis revealed translational regulation of β-cell-specific pathways during differentiation and identified 965 nuORFs, with a majority exhibiting protein support and substantial β-cell specificity. A primate-specific ORF located in the 5' untranslated region of the type 1 diabetes risk gene TYK2 may act as a translational activator. We provide HLA class I immunopeptidomic data from cytokine-stimulated human β-cells and demonstrate their utility in coculture assays with autoreactive T-cell transductants. Taken together, our results define the human β-cell translatome, an important resource to the research field.
Effects of Dorzagliatin, a Glucokinase Activator, on α- and β-Cell Function in Individuals With Impaired and Normal Glucose Tolerance.
Bai Z, Wang K, Yau T … +13 more , Lim CKP, Tsoi STF, Fan B, Tam CHT, Poon EWM, Luk AOY, Kong APS, Ma RCW, Ferrannini E, Mari A, Chen L, Chan JCN, Chow E
Diabetes · 2025 Nov · PMID 40896829 · Full text
UNLABELLED: Dorzagliatin is a dual-acting allosteric activator of glucokinase (GCK). Dorzagliatin improved second-phase insulin secretion in individuals with type 2 diabetes and heterozygous carriers of GCK mutations. We...
UNLABELLED: Dorzagliatin is a dual-acting allosteric activator of glucokinase (GCK). Dorzagliatin improved second-phase insulin secretion in individuals with type 2 diabetes and heterozygous carriers of GCK mutations. We investigated the effects of dorzagliatin on pancreatic insulin, glucagon, and glucagon-like-peptide 1 (GLP-1) secretion in individuals with impaired glucose tolerance (IGT) and normal glucose tolerance (NGT). In a double-blind, randomized, crossover, single-dose study, 9 participants with IGT and 10 with NGT underwent 2-h 12 mmol/L hyperglycemic clamp following a single dose of dorzagliatin 50 mg or matched placebo. Plasma insulin, C-peptide, glucagon, and total GLP-1 levels were measured at regular intervals. There were no differences in first-phase insulin after the dorzagliatin dose in either group. Dorzagliatin significantly increased second-phase insulin secretion rate and β-cell glucose sensitivity by 1.3-fold compared with placebo in IGT but remained similar in NGT. Dorzagliatin increased basal plasma insulin in the NGT group only. Glucagon (area under the curve0-120 min = 161 ± 58 vs. 234 ± 70 pmol*min/L [mean ± SD]; P = 0.01) was suppressed after dorzagliatin in the NGT group but not the IGT group. Plasma glucagon was positively correlated with total GLP-1 levels. Dorzagliatin did not affect insulin sensitivity in either group. Dorzagliatin has different actions on β- and α-cells depending on glucose tolerance, increasing second-phase insulin secretion in IGT while enhancing glucose-suppression of glucagon secretion in NGT. ARTICLE HIGHLIGHTS: Dorzagliatin is a dual-acting allosteric glucokinase (GCK) activator that increases β-cell glucose sensitivity and second-phase insulin in GCK monogenic diabetes of the young. Actions of dorzagliatin on α- and β-cell function in normal and impaired glucose tolerance are unknown. In this study, dorzagliatin increased second-phase insulin in individuals with impaired glucose tolerance while suppressing glucagon in participants with normal glucose tolerance during a hyperglycemic clamp. With increasing glucose, plasma glucagon and total GLP-1 levels declined progressively. A modest to moderate positive correlation between glucagon and total GLP-1 was observed under both dorzagliatin and placebo treatments.
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