Diabetes[JOURNAL]
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200 papers
Protection Against Periodontitis by Improving Mitochondrial Function in Diabetes.
Onizuka S, Shinjo T, Ishikado A … +11 more , Wu IH, Ohsugi Y, Jangolla SVT, Li Q, Park K, Fu J, Yu MG, Li Q, Hasturk H, Van Dyke TE, King GL
Diabetes · 2026 Jul · PMID 42138738 · Full text
UNLABELLED: Diabetes is a major risk factor for severe periodontitis. This is partly due to impaired wound healing associated with concomitant failure to resolve inflammation and chronic infection. Studies from the Josli...
UNLABELLED: Diabetes is a major risk factor for severe periodontitis. This is partly due to impaired wound healing associated with concomitant failure to resolve inflammation and chronic infection. Studies from the Joslin Medalist Cohort, people with >50 years of type 1 diabetes, have reported that protective factors exist to delay the onset of severe retinopathy, nephropathy, and periodontitis, even with persistent hyperglycemia. Proteomic analysis of healthy gingival tissues from individuals with hyperglycemia versus those with periodontitis and good glycemic control showed substantial upregulation of oxidative phosphorylation, particularly mitochondrial complex I and II, as validated by immunoblot analysis. Diabetes reduced mitochondrial enzyme expression and function, measured by oxygen consumption rate in the gingiva, compared with nondiabetic mice, in parallel, with exacerbation of ligature-induced periodontal bone loss, elevation of inflammatory cytokines (Il-1b, Il-6, and Il-17a) and activation of osteoclasts. However, activation of pyruvate kinase M2 reversed diabetes and ligature-induced mitochondrial dysfunction, reduced levels of inflammatory cytokines, and mitigated periodontal bone loss, without affecting glycolytic function. These results suggested that enhancing mitochondrial protein expression and function can decrease periodontal inflammation and osteoclast activation in diabetes, thereby protecting against the onset of periodontitis and bone loss, suggesting a potential therapy for chronic wounds, even with persistent hyperglycemia. ARTICLE HIGHLIGHTS: Characterization of protective factors against periodontal inflammation with long durations of diabetes. Proteomic analysis of gingival tissue from people with type 1 diabetes >50 years and poor glycemic control without periodontitis showed elevated mitochondrial enzymes and functions. These mitochondrial dysfunctions, as well as inflammatory and osteoclast activation, were validated in diabetic mouse models of periodontitis. Elevation of mitochondrial functions by pyruvate kinase 2 activation reversed diabetes-induced gingival inflammation, osteoclast activation, and periodontitis, even in the presence of hyperglycemia. Mitochondrial activation could be a potential therapy for periodontitis and, perhaps, chronic wound healing in diabetes.
Nicotinic Acetylcholine Receptor Signaling Activates Beige Adipocytes and Mediates Systemic Metabolism.
Liu S, Zhu K, Zhang W … +12 more , Pan T, O'Brien M, Abe I, Dale L, Piejak J, Houssein N, Zhang B, Fein M, Kajimura S, Yung R, Xu XZS, Wu J
Diabetes · 2026 May · PMID 42127320 · Publisher ↗
Beige-adipocyte activity, mediated by CHRNA2, significantly influences adipose function and systemic metabolism. The CHRNB2 subunit forms a functional receptor with CHRNA2 and is essential for the response to nicotinic a...
Beige-adipocyte activity, mediated by CHRNA2, significantly influences adipose function and systemic metabolism. The CHRNB2 subunit forms a functional receptor with CHRNA2 and is essential for the response to nicotinic acetylcholine receptor agonists in beige adipocytes. Deletion of Chrnb2 in mice compromises the adaptive response to cold in subcutaneous adipose tissue and renders exacerbated metabolic dysfunction due to diet-induced obesity. This cholinergic signaling within subcutaneous adipose tissue declines with aging. CHRNB2 partial agonists, a family of drugs clinically used for smoking cessation, activate both murine and human beige adipocytes.
Glycemic Improvement and Active Charcot Neuroarthropathy: Osteocalcin as a Candidate Biomarker of Transient Skeletal Vulnerability.
Dardari D
Diabetes · 2026 Jul · PMID 42118606 · Publisher ↗
UNLABELLED: Active Charcot neuroarthropathy (CN) remains difficult to predict. This hypothesis-generating article proposes a deliberately restricted, testable model in which a clinically meaningful fall in HbA1c may temp...
UNLABELLED: Active Charcot neuroarthropathy (CN) remains difficult to predict. This hypothesis-generating article proposes a deliberately restricted, testable model in which a clinically meaningful fall in HbA1c may temporally coincide with active CN in a subset of people with diabetes, established neuropathy, and a vulnerable foot. The signal is based on a sequence of observations-an initial case report, a 44-case retrospective series, and the EPiChar study-and therefore is supportive of association and biological plausibility, but not causation. Within this framework, osteocalcin should presently be regarded mainly as a candidate biomarker of a transient skeletal activation state rather than a proven pathogenic mediator. This article should therefore be read as a suggestion for prospective testing and not as confirmation of an osteocalcin-mediated pathway. We propose that this systemic signal may intersect with established local drivers-neuropathy, repetitive microtrauma, inflammation, and RANKL/OPG imbalance-and can be tested prospectively with serial bone turnover markers, neuropathy phenotyping, kidney function, and modifiable exposure data during treatment intensification. ARTICLE HIGHLIGHTS: Active Charcot neuroarthropathy remains difficult to predict, and its timing is not fully explained by neuropathy and mechanical stress alone. We asked whether a clinically meaningful HbA1c fall may temporally coincide with active Charcot neuroarthropathy and whether osteocalcin could mark transient skeletal vulnerability. Available observations support association and biological plausibility, not causation, and do not prove that osteocalcin is a pathogenic mediator. Prospective monitoring studies are warranted, but current evidence does not justify delaying evidence-based glycemic optimization.
Distinct Interplay Between β-Cell Function and Insulin Resistance in Latent Autoimmune Diabetes in Adults Versus Type 2 Diabetes.
Amendolara R, De Vita F, Abedi V … +7 more , Luverà D, Risi R, D'Onofrio L, Zerunian M, Caruso D, Buzzetti R, Maddaloni E
Diabetes · 2026 Jul · PMID 42113684 · Full text
UNLABELLED: We conducted a cross-sectional study to explore the interplay between β-cell function and peripheral insulin resistance in latent autoimmune diabetes in adults (LADA) compared with type 2 diabetes. Thirty-one...
UNLABELLED: We conducted a cross-sectional study to explore the interplay between β-cell function and peripheral insulin resistance in latent autoimmune diabetes in adults (LADA) compared with type 2 diabetes. Thirty-one people with LADA were matched for sex, BMI, and disease duration with 31 people with type 2 diabetes. Insulin resistance was estimated using established surrogate indexes, and serum C-peptide levels were measured by ELISA. Despite the similar BMI, the LADA group exhibited lower mean values of estimated insulin resistance compared with the type 2 diabetes group. Among individuals with similar insulin resistance, the LADA group consistently showed lower C-peptide values compared with the type 2 diabetes group. C-peptide levels showed a direct relationship with the majority of insulin resistance indexes exclusively in type 2 diabetes, but not in LADA. Our findings show that people with LADA exhibit a blunted insulin secretory capacity compared with people with type 2 diabetes, even at similar levels of insulin resistance, being unable to mount a meaningful compensatory response to insulin resistance. This discrepancy may explain the worse glycemic control often observed in people with LADA, placing these people at higher risk of suboptimal glycemic control and highlighting the importance of early and accurate classification of adult-onset diabetes and tailored therapeutic strategies. ARTICLE HIGHLIGHTS: The identification of differences in the relationship between insulin secretion and resistance among different diabetes types will help inform clinical decisions. The interplay between insulin secretion and resistance may distinguish latent autoimmune diabetes in adults (LADA) from type 2 diabetes. Individuals with LADA are less capable of mounting a sustained compensatory insulin secretion compared with those with type 2 diabetes, even at similar insulin resistance levels. Distinct pathophysiology characterizes LADA and type 2 diabetes. The defect in insulin secretion for similar levels of insulin resistance might contribute to the higher risk of poor glycemic control often observed in LADA, arguing for accurate diagnosis of adult-onset diabetes types.
HMGA1 Lactylation-Mediated Regulation of the SP1/VEGFA Axis in Pathological Angiogenesis Under Diabetic Retinopathy.
Hou J, Liu S, Zhou Y … +6 more , Fan J, Xiao D, Wang C, Lin S, Tao L, Jiang Z
Diabetes · 2026 Jul · PMID 42102382 · Full text
UNLABELLED: Diabetic retinopathy (DR), a major complication of diabetes that causes blindness, is characterized by hyperglycemia-induced vascular dysfunction of incompletely defined mechanisms. Our study demonstrated gly...
UNLABELLED: Diabetic retinopathy (DR), a major complication of diabetes that causes blindness, is characterized by hyperglycemia-induced vascular dysfunction of incompletely defined mechanisms. Our study demonstrated glycolytic pathway activation in a DR rat model, which led to lactate accumulation and elevated pan lysine lactylation. Reduced lactate levels ameliorate vascular dysfunction. Global lactylome analysis of rat retinal tissues revealed 49 proteins with upregulated lactylation at 55 sites. The findings revealed that HMGA1 at lysine 74 (K74) directly promotes the transcriptional upregulation of specificity protein 1, enhancing vascular endothelial growth factor A expression and aggravating vascular dysfunction. Crucially, a K74 mutation in HMGA1 mitigated these pathological changes. This study is the first to identify HMGA1 lactylation as a critical molecular mechanism driving vascular dysfunction in DR, revealing a promising interventional target for the development of novel diagnostic markers and therapeutic strategies aimed at this specific posttranslational modification. ARTICLE HIGHLIGHTS: Diabetic retinopathy (DR) is a major complication of diabetes that results in blindness. The underlying mechanisms of the hyperglycemia-induced vascular dysfunction that characterizes DR are not fully elucidated. Glycolytic pathway activation in DR rats causes lactate accumulation; reduced lactate levels ameliorate vascular dysfunction in DR; HMGA1 at lysine 74 (K74) lactylation promotes specificity protein 1 upregulation, enhancing vascular endothelial growth factor A expression; and K74 mutation in HMGA1 mitigates pathological changes in DR. HMGA1 lactylation is a critical molecular mechanism driving DR vascular dysfunction.
Estrogen Mediates Capacity for Hyperplastic Adipose Expansion and Preserves Adipose Progenitor Cell Availability in Subcutaneous Depots of Female Mice.
Scheidl TB, Wager JL, Yonan SZ … +3 more , Yoon JS, Wellberg EA, Thompson JA
Diabetes · 2026 Jul · PMID 42096595 · Publisher ↗
UNLABELLED: Female protection against cardiometabolic disease wanes after menopause, concomitant with a transition toward the male-like pattern of visceral adiposity. Since recruitment of adipose progenitor cells (APCs)...
UNLABELLED: Female protection against cardiometabolic disease wanes after menopause, concomitant with a transition toward the male-like pattern of visceral adiposity. Since recruitment of adipose progenitor cells (APCs) to support adipose expansion is depot-specific and thought to maintain metabolic homeostasis, sex differences in the capacity for APC differentiation were explored as a mechanism underlying female cardiometabolic protection. Female APCs from subcutaneous depots were more proliferative and responsive to adipogenic stimuli and were enriched in pathways regulating cell cycle compared with male APCs. The female bias toward a higher number of committed preadipocytes in subcutaneous depots was reversed by ovariectomy (ovx) and restored in ovx females with 17β-estradiol (E2) replacement. In response to pharmacological stimulation of adipogenesis by rosiglitazone, intact females gained more fat mass and were protected against the diminished abundance of subcutaneous APCs that was observed in males. Ovx eliminated fat accumulation in response to rosiglitazone, but amplified diet-induced obesity and abolished female protection against metabolic dysfunction. E2 replacement restored female protection against obesity-associated adipose inflammation and metabolic dysfunction. Thus, we conclude that E2 mediates hyperplastic expansion in subcutaneous depots and preserves adipose function in premenopausal women. ARTICLE HIGHLIGHTS: We undertook this study to elucidate the role of adipose progenitor cells (APCs) in governing sex differences in metabolic disease susceptibility and the heightened risk for metabolic disease in women after menopause. How do sex and estrogen influence APC differentiation capacity in subcutaneous adipose depots, and how does this relate to metabolic function in obesity? Estrogen mediates the recruitment of APCs for hyperplastic expansion of subcutaneous depots, which may contribute to female-specific protection against obesity-induced metabolic disease. Our findings highlight an underrecognized contributor to sex differences in the risk for obesity-associated metabolic disease throughout the life course and implore a revision of the adipose tissue expandability hypothesis in consideration of the influence of sex.
The Glucagonotropic Effect of GIP Is Negated During Insulin-Induced Hypoglycemia in Type 1 Diabetes: A Randomized, Placebo-Controlled, Crossover Study.
Sørum NE, Warnøe J, Holst JJ … +9 more , Hartmann B, Gasbjerg LS, Størling J, Bergmann ML, Dejgaard TF, Christensen MB, Campbell JE, Knop FK, Lund AB
Diabetes · 2026 Jul · PMID 42085567 · Publisher ↗
UNLABELLED: Glucose-dependent insulinotropic polypeptide (GIP[1-42]) increases glucagon levels in the presence of normal-to-low plasma glucose concentrations in individuals with type 1 diabetes (T1D), suggesting its pote...
UNLABELLED: Glucose-dependent insulinotropic polypeptide (GIP[1-42]) increases glucagon levels in the presence of normal-to-low plasma glucose concentrations in individuals with type 1 diabetes (T1D), suggesting its potential use as a safeguard against hypoglycemia. We investigated the dose-dependent effects of exogenous full-length GIP[1-42] and its truncated variant GIP[1-30]NH2 on glucagon concentrations during insulin-induced hypoglycemia in individuals with T1D. In a randomized, double-blind, placebo-controlled, crossover study, 10 men with C-peptide-negative T1D participated in five experimental visits. On each visit, participants received a 135-min intravenous infusion of GIP[1-42] or GIP[1-30]NH2 (both at 4 or 8 pmol/kg/min), or placebo. The infusion period included a 30-min euglycemic period, a 60-min insulin-induced hypoglycemic clamp (target glucose 2.5 mmol/L), and a 45-min recovery phase. During the euglycemic period, glucagon concentrations were higher with all GIP infusions compared with placebo, reaching statistical significance only for GIP[1-30]NH2 (P < 0.05 for both high-dose [8 pmol/kg/min] and low-dose [4 pmol/kg/min]). However, the insulin infusion suppressed glucagon to similarly low levels for all interventions. Both GIP variants increased norepinephrine levels, and high-dose GIP[1-42] slightly reduced the amount of glucose required to recover from hypoglycemia. These findings demonstrate that although GIP acutely increases glucagon concentrations during euglycemia in T1D, insulin infusion overrides this effect, indicating that elevated GIP levels alone cannot effectively restore the glucagon response to insulin-induced hypoglycemia in T1D. ARTICLE HIGHLIGHTS: The glucose-dependent glucagonotropic effects of glucose-dependent insulinotropic polypeptide (GIP) variants in type 1 diabetes (T1D) are incompletely understood. We investigated whether native full-length GIP[1-42] and its truncated variant GIP[1-30]NH2 increase glucagon concentrations during insulin-induced hypoglycemia in individuals with T1D. During euglycemia, both GIP variants increased glucagon [statistically significantly for GIP(1-30)NH2 only] and norepinephrine, but insulin suppressed glucagon levels similarly across interventions. High-dose GIP[1-42] was associated with slightly reduced glucose requirements during recovery from hypoglycemia, suggestive of increased hepatic glucose production through either glucagon or norepinephrine action.
CHD4 and NKX2.2 Cooperate to Regulate β-Cell Function by Repressing Non-β-Cell Gene Programs.
Sarbaugh D, Oliveira TG, Guney MA … +7 more , Casey MR, Hoelscher VM, Hill CJ, Michel CR, Wells KL, Benninger RKP, Sussel L
Diabetes · 2026 Jul · PMID 42080624 · Full text
UNLABELLED: NKX2.2 is a transcription factor that regulates pancreatic islet β-cell identity and function; however, cofactor proteins that modulate the functional activity of NKX2.2 in β-cells are relatively unexplored....
UNLABELLED: NKX2.2 is a transcription factor that regulates pancreatic islet β-cell identity and function; however, cofactor proteins that modulate the functional activity of NKX2.2 in β-cells are relatively unexplored. An unbiased proteomics screen identified chromodomain helicase DNA-binding protein 4 (CHD4) as an NKX2.2 interacting partner. CHD4 is a nucleosome remodeler that directs the appropriate differentiation, maturation and function of many cell types. To characterize the roles of CHD4 in β-cells, we generated Chd4 β-knockout (βKO) mice. Deletion of Chd4 substantially impaired the function of β-cells. The Chd4 βKO mice became diabetic due to the disruption of islet integrity, calcium signaling, and downregulation of essential β-cell regulatory genes. We also discovered CHD4 is required to bind at and repress non-β-cell genes, including Kcnj5, the gene that encodes the G protein-activated inward rectifier potassium channel 4 (GIRK4) in β-cells. Aberrant upregulation of GIRK4 causes impaired glucose-stimulated insulin secretion. These studies demonstrate that CHD4 is an essential transcriptional cofactor of NKX2.2 that is required for the proper maturation and function of pancreatic β-cells. ARTICLE HIGHLIGHTS: NKX2.2 interacts with the nucleosome remodeling and deacetylase complex through its interaction with chromodomain helicase DNA-binding protein 4 (CHD4). Deletion of CHD4 from developing pancreatic β-cells in mice causes diabetes due to a loss of islet integrity, disrupted calcium signaling, and impaired insulin secretion. β-Cells lacking CHD4 inappropriately upregulate the G protein-activated inward rectifier potassium channel 4 (GIRK4) potassium channel; inhibition of GIRK4 rescues the insulin secretion defect.
Neuroligin-3: A Novel Exercise-Induced Secreted Factor Enhancing Insulin Sensitivity in Obese Insulin-Resistant Mice.
Sinha A, Patra D, Mishra S … +9 more , Vashisth A, Sharma S, Dey U, Ramprasad P, Roy S, Kumar A, Tikoo K, Pal D, Dasgupta S
Diabetes · 2026 Jul · PMID 42065629 · Publisher ↗
UNLABELLED: The salutary effects of physical exercise in mitigating metabolic disorders, particularly type 2 diabetes, are well recognized. Several studies have demonstrated that endurance training boosts the production...
UNLABELLED: The salutary effects of physical exercise in mitigating metabolic disorders, particularly type 2 diabetes, are well recognized. Several studies have demonstrated that endurance training boosts the production of exercise-induced myokines, which are pivotal for interorgan communication enhancing insulin sensitivity. However, several challenges, including an incomplete understanding of underlying molecular mechanisms, hinder their therapeutic application. Here, we have identified a potential exercise-induced mediator, neuroligin-3 (NLGN3), that enhances insulin sensitivity and abrogates inflammation. Mechanistic studies in white adipocytes revealed that NLGN3 interacts with neurexin-3 (NRXN3) to modulate their function and insulin sensitivity, while in macrophages, NLGN3 engages with NRXN1 to attenuate inflammation and promote an anti-inflammatory phenotype. Administration of NLGN3 in high-fat diet (HFD)-fed mice significantly ameliorated obesity-induced visceral adipose tissue dysfunction and insulin insensitivity; however, these attributes are markedly abolished in NRXN1/3-deficient mice. In addition, elevated serum NLGN3 levels following swimming exercise training correlated with improved metabolic outcomes in HFD-fed obese diabetic mice. These findings suggest that NLGN3 may serve as a key mediator of exercise-induced metabolic benefits and highlight the NLGN3-NRXN1/3 pathway as a promising target for managing obesity-induced insulin resistance. ARTICLE HIGHLIGHTS: This study aimed to identify novel exercise-induced myokines and their role in improving insulin sensitivity and reducing inflammation. We identified neuroligin-3 (NLGN3) as an exercise-induced mediator that enhances insulin sensitivity and alleviates inflammation. Exercise-induced NLGN3 upregulation or recombinant NLGN3 administration improved metabolic function in high-fat diet-fed mice via neurexin-1 and -3 (NRXN1/3), but these benefits were lost upon NRXN1/3 ablation. NLGN3 emerges as a key mediator of exercise-driven metabolic benefits and a promising therapeutic target for obesity-associated insulin resistance.
Gut-Derived GLP-1 Released by Rare Sugar d-Allulose Cooperates With Insulin to Activate Left-Sided Vagal Afferents and Enhance Insulin Sensitivity.
Ohbayashi K, Tanida M, Abe C … +6 more , Ishihara H, Omi W, Kubota N, Drucker DJ, Yada T, Iwasaki Y
Diabetes · 2026 Jul · PMID 42062836 · Publisher ↗
UNLABELLED: Glucagon-like peptide 1 receptor agonists (GLP-1RAs) ameliorate hyperglycemia by directly stimulating insulin secretion from the pancreas. In contrast, the physiological role of short-lived endogenous GLP-1 r...
UNLABELLED: Glucagon-like peptide 1 receptor agonists (GLP-1RAs) ameliorate hyperglycemia by directly stimulating insulin secretion from the pancreas. In contrast, the physiological role of short-lived endogenous GLP-1 remains unclear largely because of its limited access to pancreatic β-cells. Here, we used d-allulose, a nonmetabolizable noncaloric rare sugar, as a GLP-1 secretagogue. We show that d-allulose-induced intestinal GLP-1 secretion (AIGS) cooperates with insulin to reduce blood glucose levels by enhancing insulin action, rather than insulin secretion, in male mice. This cooperation and remote signaling require left-sided vagal afferents forming the common hepatic branch, but not right-sided afferents. AIGS-enhanced insulin action required both GLP-1Rs and insulin receptor substrate 2 in these neurons. Remarkably, in db/db mice exhibiting severe insulin resistance, AIGS improved insulin resistance and hyperglycemia more rapidly and potently than the GLP-1RA exendin-4. These findings reveal that a subclass of vagal afferent neurons synergistically activated by endogenous intestinal GLP-1 and insulin does not stimulate insulin secretion but augments insulin action to improve glucose tolerance. This novel extrapancreatic GLP-1 action mediated by vagal afferents provides a promising basis for innovative type 2 diabetes therapies. ARTICLE HIGHLIGHTS: Compared with glucagon-like peptide 1 (GLP-1) receptor agonists, the physiological roles and mechanisms of endogenous, short-lived GLP-1 in glucose metabolism remain poorly understood. We used the rare sugar d-allulose, a noncaloric GLP-1 secretagogue, as a tool to elucidate the physiological actions of endogenous GLP-1. d-Allulose-induced intestinal GLP-1 release cooperates with insulin to activate left-side vagal afferents, enhancing insulin action rather than insulin secretion and thereby regulating glycemic control. Because this acute mechanism improved hyperglycemia in type 2 diabetes to an extent comparable to that observed with GLP-1 receptor agonists, targeting GLP-1/insulin-vagal signaling may inform novel therapies and dietary or nutritional interventions for type 2 diabetes.
MicroRNAs in Islet Biology and Diabetes: Progress, Gaps, and Opportunities.
Rodriguez-Calvo T, Martinez-Sanchez A
Diabetes · 2026 Jul · PMID 42060523 · Publisher ↗
UNLABELLED: MicroRNAs (miRNAs) are small RNAs that posttranscriptionally repress gene expression of their target mRNAs. miRNA discovery dates to 1993, when Ambros and Ruvkun identified them in nematodes. More than two de...
UNLABELLED: MicroRNAs (miRNAs) are small RNAs that posttranscriptionally repress gene expression of their target mRNAs. miRNA discovery dates to 1993, when Ambros and Ruvkun identified them in nematodes. More than two decades later, their pioneering research was recognized with the Nobel Prize in Medicine, a fitting acknowledgment of the profound impact these tiny molecules exert on nearly every biological process and disease studied to date. The regulation of pancreatic islet function, critical for glucose homeostasis and diabetes development, is no exception. The identification of miR-375 as a key regulator of insulin secretion in 2004 provided the first connection between miRNAs and islets, followed by studies showing that miRNAs are essential for endocrine development. Research in this field has since expanded rapidly, yielding insights into how miRNAs influence nutrient sensing, glucose metabolism, and diabetes pathogenesis while also highlighting their potential as biomarkers and therapeutic targets. Despite this progress, the field still faces major challenges. The mechanisms controlling miRNA expression, their precise roles in islet function and diabetes progression, and strategies for their therapeutic modulation remain poorly defined. In this perspective, we summarize key findings in islet miRNA biology and diabetes and critically discuss knowledge gaps, technical challenges, and translational opportunities that define this rapidly evolving field. ARTICLE HIGHLIGHTS: This perspective marks the commemoration of the 2024 Nobel Prize in Medicine for miRNA discovery and reflects on more than two decades of research linking MicroRNAs (miRNAs) to islet biology and diabetes. We very briefly summarize key roles of islet miRNAs in β-cell development, function, and immune interactions and identify major gaps in current knowledge. We discuss emerging concepts in miRNA regulation, cellular heterogeneity, and therapeutic targeting, alongside ongoing challenges in biomarker validation. Our view underscores that integrating mechanistic, single-cell, and translational approaches will be essential to advance miRNA-based therapies.
Lysosomal Ion Channel TRPML1 Contributes to Neuropathic Pain Associated With Diabetic Peripheral Neuropathy in Mice.
Yang Y, Teng S, Zhang Y … +3 more , Ji YH, Wang H, Tan ZY
Diabetes · 2026 Jul · PMID 42059777 · Full text
UNLABELLED: Neuropathic pain associated with diabetic peripheral neuropathy (DPN) is a common and hard-to-treat complication of diabetes. Ion channels of plasma membrane are major mechanisms and targets for DPN pain. Thi...
UNLABELLED: Neuropathic pain associated with diabetic peripheral neuropathy (DPN) is a common and hard-to-treat complication of diabetes. Ion channels of plasma membrane are major mechanisms and targets for DPN pain. This study explores the role of a major lysosomal ion channel, TRPML1, in DPN pain. Mouse models of DPN pain and TRPML1 knockout were combined with pharmacological inhibition and detection of molecular expression and function. Major findings included 1) BKS db/db increased expression and function of TRPML1 in dorsal root ganglion (DRG); 2) lysosomes of DRG neurons expressed functional TRPML1 currents; 3) global knockout (gKO) or conditional knockout (cKO) in DRG neurons of TRPML1 prevented mechanical allodynia in male mice fed a high-fat diet; 4) a TRPML1 inhibitor significantly reversed mechanical allodynia in BKS db/db mice through intraperitoneal injection and in streptozotocin (STZ) mice through intrathecal injection; and 5) gKO or astrocyte cKO of TRPML1 prevented STZ-induced mechanical allodynia in male and female mice. The results suggest that TRPML1 in DRG neurons and astrocytes contributes to type 2 and type 1 DPN pain, respectively (type 1 and type 2 DPN pain refer to neuropathic pain associated with type 1 diabetes and type 2 diabetes or pre-diabetes). This study may serve as a proof of concept to explore the role of lysosomal ion channels in painful DPN, painless DPN, and chronic pain. ARTICLE HIGHLIGHTS: A lysosomal ion channel, TRPML1, contributes to neuropathic pain associated with diabetic peripheral neuropathy (DPN). TRPML1 of dorsal root ganglion neurons contributes to type 2 DPN pain. Astrocyte TRPML1 contributes to type 1 DPN pain. Lysosomal ion channels may be novel mechanisms and targets for DPN pain.
Islet Autotransplant Recipients Have Elevated Proinsulin-to-C-Peptide Ratios Supporting Metabolic Stress as a Cause of Islet Attrition.
Ali E, Eaton A, Rickels MR … +7 more , Evans-Molina C, Ramanathan K, Martin D, Trikudanathan G, Downs E, Beilman GJ, Bellin MD
Diabetes · 2026 Jul · PMID 42048053 · Full text
UNLABELLED: Attrition of islet function is observed over time following total pancreatectomy with islet autotransplantation (TPIAT). Metabolic stress on a suboptimal islet mass is a suspected, but unconfirmed, contributo...
UNLABELLED: Attrition of islet function is observed over time following total pancreatectomy with islet autotransplantation (TPIAT). Metabolic stress on a suboptimal islet mass is a suspected, but unconfirmed, contributor. We measured proinsulin-to-C-peptide (PI:C) ratios as an indicator of β-cell stress in TPIAT recipients >5 years post-TPIAT. Individuals ≥16 years old with TPIAT 5-20 years prior underwent 4-h mixed-meal tolerance testing (MMTT) and assessment of ambulatory glycemia by continuous glucose monitoring (CGM). Insulin use and HbA1c were obtained. PI:C was measured from fasting and +90 min MMTT samples. PI:C ratios were compared with healthy control individuals (n = 24) and were associated with MMTT and CGM measures. PI:C ratios from 132 TPIAT (median age 48 [interquartile range 33, 55] years, 33% male, 9.4 [6.7, 11.8] years post-TPIAT, islet mass transplanted 4,022 [2,777, 5,390]) were high compared with healthy control individuals (P < 0.0001; mean PI:C two- to threefold higher). Within the TPIAT recipients, higher PI:C ratios were associated with lower islet equivalents per kilogram transplanted, partial or failed islet function, higher HbA1c, higher BMI, reduced time in range on CGM, and more time in hyperglycemia by MMTT. Overweight/obesity and low islet mass associations with PI:C ratios were only partially mediated by hyperglycemia. PI:C ratios were elevated at a median of 10 years after TPIAT. These findings support the concept that metabolic stress is a cause of islet attrition in TPIAT and that having fewer islets, poor glycemic control, or unhealthy body weight may contribute to islet function decline. ARTICLE HIGHLIGHTS: β-Cell stress after total pancreatectomy with islet autotransplantation has been proposed an important cause of islet loss. We measured circulating proinsulin-to-C-peptide ratios, measured to determine whether total pancreatectomy with islet autotransplantation recipients exhibit β-cell stress, and whether this is associated with hyperglycemia and other clinical factors. Proinsulin-to-C-peptide ratio levels were elevated twofold or more compared with healthy control volunteers and were higher with hyperglycemia, high BMI, and low islet mass. These results support the hypothesis that metabolic stress is a cause of long-term islet attrition and suggest potential opportunity to reduce β-cell stress through maintaining healthy body weight and avoiding significant time in hyperglycemia.
Whey Protein Ingestion Stimulates Glucagon Secretion and Raises Blood Glucose Levels in Adults With Type 1 Diabetes.
Dao GM, Zhao S, Schofield C … +8 more , Vogrin S, Hennessy DT, Smart CE, Zaharieva DP, O'Neal DN, Bruce CR, Kowalski GM, Morrison DJ
Diabetes · 2026 Jul · PMID 42030105 · Publisher ↗
UNLABELLED: This study characterized the dose effect of whey protein isolate (WPI) ingestion on glucagon secretion, glycemia, and the underlying mechanisms in adults with type 1 diabetes. Twelve insulin pump-treated adul...
UNLABELLED: This study characterized the dose effect of whey protein isolate (WPI) ingestion on glucagon secretion, glycemia, and the underlying mechanisms in adults with type 1 diabetes. Twelve insulin pump-treated adults with type 1 diabetes (mean ± SD age 47.3 ± 16.4 years; BMI 26.1 ± 3.8 kg/m2) and six adults without diabetes (age 36.2 ± 20.9 years; BMI 27.3 ± 5.8 kg/m2) received 1) control (water), 2) low-dose WPI (0.25 g/kg), and/or 3) high-dose WPI (0.5 g/kg). Those with diabetes replaced subcutaneous insulin with fixed-rate i.v. insulin. [6,6-2H]glucose infusion was used to measure glucose flux. In participants with type 1 diabetes, low- and high-dose WPI raised plasma glucagon by approximately fivefold and approximately ninefold, respectively. Endogenous glucose production increased by ∼50% (peak) for both WPI doses, with the high dose producing more sustained stimulation. Plasma glucose decreased by a median (interquartile range) of ∼1.7 (2.0, 1.0) mmol/L for control but increased by 1.3 (1, 1.7) and 3.1 (2.5, 3.3) mmol/L for the low and high doses, respectively. Participants with and without diabetes had similar increases in amino acids, glucagon, glucagon-like peptide 1, and glucose-dependent insulinotropic polypeptide. This study highlights the substantial glucagon-stimulating and glycemic effects of WPI, which could be clinically useful for hypoglycemia management in type 1 diabetes. ARTICLE HIGHLIGHTS: The effect of protein ingestion on glucagon and glycemic responses in individuals with type 1 diabetes is not well characterized. This study examined how ingestion of varying amounts of fast-absorbing whey protein (in the absence of other macronutrients) affected glucagon secretion, glucose levels, and associated metabolic hormone levels in adults with type 1 diabetes. Whey protein ingestion stimulated glucagon secretion and endogenous glucose production and increased blood glucose in adults with type 1 diabetes. Our findings highlight the potential of whey protein as a tool to support glycemic management and mitigate hypoglycemia in type 1 diabetes.
IDH3A Deficiency Compromises Adaptive Thermogenesis and Exacerbates Obesity-Induced Metabolic Dysfunction via Impaired BCKDHA-Dependent BCAA Catabolism.
Lu X, Bai N, Lyu J … +10 more , Sun J, Su Y, Ye Y, Hu T, Liu T, Li W, Li X, Ma X, Yang Y, Bao Y
Diabetes · 2026 May · PMID 42008693 · Full text
UNLABELLED: Adaptive thermogenesis in beige adipocytes is essential for maintaining energy homeostasis and preventing obesity. Emerging evidence suggests that human visceral adipose tissue harbors adipocytes with beige-l...
UNLABELLED: Adaptive thermogenesis in beige adipocytes is essential for maintaining energy homeostasis and preventing obesity. Emerging evidence suggests that human visceral adipose tissue harbors adipocytes with beige-like thermogenic features, enabling analysis of thermogenic gene regulation in humans. Isocitrate dehydrogenase 3A (IDH3A) is a rate-limiting enzyme of the tricarboxylic acid cycle, yet its function in adipocytes remains poorly defined. In this study, we examined IDH3A expression in human visceral adipose tissue and generated adipocyte-specific IDH3A knockout mice to investigate its role in beige adipocyte thermogenesis and metabolic regulation. IDH3A expression in human visceral fat was inversely associated with adiposity and adverse metabolic traits. Moreover, IDH3A expression was induced in human and mouse adipocytes following thermogenic stimulation. Adipocyte-specific IDH3A deletion in mice impaired beige fat thermogenic capacity, led to cold intolerance, and exacerbated diet-induced metabolic dysfunction. Mechanistically, IDH3A deficiency increased DNA methylation at the Bckdha promoter, resulting in the repression of this key branched-chain amino acid (BCAA) catabolic gene and impaired BCAA catabolism. Notably, restoring BCKDHA in IDH3A-deficient adipocytes rescued respiration and thermogenic function. Together, in addition to its canonical enzymatic role, our findings identify IDH3A as a critical regulator of BCAA catabolism that facilitates adaptive thermogenesis under metabolic stress conditions. ARTICLE HIGHLIGHTS: IDH3A expression in human visceral fat exhibits a negative correlation with metabolic dysfunction indicators. IDH3A is induced during thermogenic activation, yet its role in adipose tissue is not well characterized. Adipocyte-specific deletion of IDH3A impairs adaptive thermogenesis and metabolic homeostasis by disrupting BCKDHA-mediated BCAA catabolism. Overexpression of BCKDHA restores the thermogenic program in IDH3A-deficient beige adipocytes.
Tomosyn-2 Regulates Postnatal β-Cell Expansion and Insulin Secretion to Maintain Glucose Homeostasis.
Perez KC, Alexander J, Rahman MM … +6 more , Alsharif H, Liu Y, Kim JA, Hunter CS, Nguyen T, Bhatnagar S
Diabetes · 2026 May · PMID 42008692 · Full text
UNLABELLED: The transition from a proliferative to a functionally mature state is a critical phase in postnatal pancreatic β-cell development, yet the molecular mechanisms coordinating this shift remain poorly understood...
UNLABELLED: The transition from a proliferative to a functionally mature state is a critical phase in postnatal pancreatic β-cell development, yet the molecular mechanisms coordinating this shift remain poorly understood. Here, we identify tomosyn-2 as a key regulator that restrains β-cell maturation and insulin secretory capacity. Tomosyn-2 expression progressively declines in mouse islets with age, coinciding with enhanced biphasic glucose-stimulated insulin secretion and reduced β-cell proliferation. Mice lacking tomosyn-2 exhibit improved glucose clearance, elevated plasma insulin levels, and enhanced insulin secretion from isolated islets without changes in insulin action. Mechanistically, tomosyn-2 interacts with syntaxin-1A to inhibit insulin granule exocytosis by limiting SNARE complex assembly. Transcriptomic and network analyses reveal that loss of tomosyn-2 is associated with coordinated changes in insulin secretion and cell-cycle regulation, reducing β-cell proliferation and mass expansion by downregulating Akt1 signaling and cell-cycle mediators, while promoting β-cell identity and functional maturation accompanied by altered islet cytoarchitecture. These findings identify tomosyn-2 as a molecular brake that balances proliferation and insulin secretion to achieve a threshold of functionally mature β-cell mass during postnatal development. Targeting tomosyn-2 or its downstream pathways may enhance β-cell functional competence and offer new strategies to restore insulin secretion in diabetes. ARTICLE HIGHLIGHTS: The mechanisms governing the postnatal transition of pancreatic β-cells from a proliferative, immature state to a functionally mature, glucose-responsive state remain poorly understood. We investigate the role of tomosyn-2 in modulating β-cell proliferation and insulin secretion during postnatal maturation. Tomosyn-2 inhibits SNARE complex formation and insulin secretion, and its loss is associated with enhanced β-cell maturation, increased biphasic insulin secretion, reduced β-cell proliferation, and suppressed Akt1-cyclinD1 signaling. Tomosyn-2 functions as a physiological brake on insulin secretion, coordinating the balance between β-cell maturation and proliferation, with implications for diabetes pathogenesis and β-cell regenerative strategies.
Associations of Combined Genetic and Lifestyle Risks With Incident Type 2 Diabetes in the UK Biobank.
Zhao C, Hatzikotoulas K, Balasubramanian R … +18 more , Bertone-Johnson E, Cai N, Huang L, Huerta-Chagoya A, Janiczek M, Ma C, Mandla R, Paluch A, Rayner NW, Southam L, Sturgeon SR, Suzuki K, Taylor HJ, Vankim N, Yin X, Lee CH, Collins F, Spracklen CN
Diabetes · 2026 May · PMID 42008691 · Full text
UNLABELLED: Type 2 diabetes (T2D) results from the interplay of genetic susceptibility and an unhealthy lifestyle, but their combined effects are not well studied. We examined whether unhealthy modifiable behaviors were...
UNLABELLED: Type 2 diabetes (T2D) results from the interplay of genetic susceptibility and an unhealthy lifestyle, but their combined effects are not well studied. We examined whether unhealthy modifiable behaviors were associated with similar increases in the risk of incident T2D in individuals with different levels of genetic risk. Among 332,251 UK Biobank participants without diabetes, we constructed a multiancestry genetic risk score (GRS) based on 783 T2D-associated variants, categorized into tertiles. Lifestyle was classified as healthy, intermediate, or unhealthy based on baseline self-reported smoking status, BMI, physical activity level, and diet quality. Cox proportional hazards regression models were used to generate adjusted hazard ratios (HRs) for T2D and associated 95% CIs. During follow-up (median 13.6 years), 13,128 (4.0%) participants developed T2D. GRS (P < 0.001) and lifestyle classification (P < 0.001) were independently associated with increased risk of T2D. Compared with a healthy lifestyle, an unhealthy lifestyle was associated with increased risk in all genetic risk strata, with adjusted HRs ranging from 7.11 to 16.33. High genetic risk and an unhealthy lifestyle were the most significant contributors to T2D development. Individuals at all levels of genetic risk can substantially mitigate their T2D risk through lifestyle modifications. ARTICLE HIGHLIGHTS: Both genetic susceptibility and an unhealthy lifestyle are known to be associated with elevated type 2 diabetes (T2D) risk. However, their combined effects on T2D risk are not well studied. In this large prospective cohort study of more than 332,000 individuals, unhealthy lifestyle factors were associated with risk of incident T2D within and across different levels of genetic risk. These findings suggest individuals at all levels of genetic risk can greatly mitigate their risk of T2D by adhering to a healthy lifestyle.
Diabetes Spotlight: Jennifer Estall, PhD-Identifying Signals Between the Pancreas and Liver.
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Diabetes · 2026 May · PMID 42008690 · Publisher ↗
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Co-occurrence of Loss-of-Function GCK and ABCC8 Variants in a Pedigree With a Spectrum of Dysglycemia.
Saint-Martin C, ElSheikh A, Jacqueminet S … +4 more , Arnoux JB, Ciangura C, Bellanné-Chantelot C, Shyng SL
Diabetes · 2026 Jul · PMID 41996282 · Full text
UNLABELLED: Glucokinase and ATP-sensitive potassium (KATP) channels in pancreatic β-cells control insulin secretion in response to glucose stimulation to maintain glucose homeostasis. It is well established that loss-of-...
UNLABELLED: Glucokinase and ATP-sensitive potassium (KATP) channels in pancreatic β-cells control insulin secretion in response to glucose stimulation to maintain glucose homeostasis. It is well established that loss-of-function (LOF) variants in GCK, which encodes glucokinase, are diabetogenic, whereas LOF variants in KATP channel genes lead to congenital hyperinsulinism (HI) and hypoglycemia. However, how the co-occurrence of GCK and KATP channel variants manifests in glycemic phenotypes is unknown. This study presents a multiplex pedigree with a heterozygous GCK deletion along with a heterozygous ABCC8 variant that results in the E1209K missense variant in the regulatory subunit of the KATP channel sulfonylurea receptor 1 (SUR1). The three-generation pedigree exhibits a complex spectrum of dysglycemia depending on genotype and age at referral. Individuals harboring the heterozygous GCK deletion alone present with maturity-onset diabetes; those harboring the heterozygous ABCC8 E1209K variant alone exhibit HI resulting from the LOF of KATP channels, with some developing diabetes later in life; and those harboring both GCK and ABCC8 variants escape HI but not diabetes. This unique pedigree offers insights into the complex interplay between LOF genetic variants of glucokinase and KATP channels in age-dependent dysglycemia. ARTICLE HIGHLIGHTS: Genetic variants causing loss of function (LOF) of glucokinase or ATP-sensitive potassium (KATP) channels underlie diabetes or congenital hyperinsulinism, respectively, but how the co-occurrence of such variants affects glucose control is unknown. This study presents genotypes and clinical phenotypes in a pedigree with LOF variants in both GCK and the pancreatic KATP channel. Heterozygous glucokinase deletion masked infantile hyperinsulinemia and hypoglycemia caused by a heterozygous LOF KATP channel variant. Carriers of the LOF KATP variant exhibited a shift from hypoglycemia to diabetes, as has been reported previously in some carriers of KATP LOF variants.
Activating Transcription Factor 6α Governs Stress-Adaptive Pancreatic β-Cell Mass Expansion by Coordinating Proliferation and Survival.
Otani D, Murakami T, Fauzi M … +10 more , Botagarova A, Sekito S, Tatsuoka H, Tokumoto S, Usui R, Ogura M, Toyoda T, Murakawa Y, Yabe D, Inagaki N
Diabetes · 2026 Jul · PMID 41996190 · Full text
UNLABELLED: Progressive loss of pancreatic β-cell mass (BCM) is a hallmark of type 2 diabetes, yet strategies to preserve or restore BCM remain elusive due to incomplete understanding of the molecular mechanisms governin...
UNLABELLED: Progressive loss of pancreatic β-cell mass (BCM) is a hallmark of type 2 diabetes, yet strategies to preserve or restore BCM remain elusive due to incomplete understanding of the molecular mechanisms governing β-cell proliferation in adults. The unfolded protein response (UPR) maintains endoplasmic reticulum (ER) proteostasis, but the in vivo role of activating transcription factor 6α (ATF6α), the most recently evolved UPR branch, in β-cell proliferation and survival is unclear. Here, we investigated the role of ATF6α in β-cell adaptation under chronic metabolic and physiological stress. We demonstrated that β-cell-specific ATF6α knockout mice exhibited impaired BCM expansion accompanied by reduced β-cell proliferation and increased apoptosis during high-fat diet feeding and pregnancy, but not under basal conditions. In vitro, ATF6α knockdown suppressed proliferation and enhanced apoptosis in chronically stressed MIN6Akita cells, but not in MIN6 cells, whereas ATF6α overexpression promoted β-cell proliferation. Single-cell transcriptomic analysis further revealed that ATF6α directs proliferative transcriptional states in β-cells under metabolic stress, while its absence diverts cells toward nonproliferative states. Together, these findings establish ATF6α as a coordinating regulator of adaptive β-cell proliferation and survival that supports BCM expansion under sustained stress. ARTICLE HIGHLIGHTS: The role of activating transcription factor 6α (ATF6α) in the stress-adaptive regulation of pancreatic β-cell mass (BCM) in vivo remains incompletely defined. We investigated the role of ATF6α in the regulation of BCM, β-cell proliferation, and survival under sustained stress using in vivo and in vitro models. Loss of ATF6α consistently impaired BCM expansion through reduced β-cell proliferation and increased apoptosis across models. Our findings establish ATF6α as an important regulator of stress-adaptive BCM expansion through coordinating β-cell survival and proliferation under sustained stress.
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