Diabetes & Metabolism[JOURNAL]
Sun
200 papers
Ablation of microglial estrogen receptor alpha predisposes male mice to diet-induced obesity.
Velasco I, Frey JM, Baglaev V … +7 more , Jafari T, Huang T, Schwie S, Santiago OD, Fasnacht RD, Thaler JP, Dorfman MD
Metabolism · 2026 Jul · PMID 42392258 · Publisher ↗
Estrogen receptor alpha (ERα) signaling has metabolic and anti-inflammatory properties in addition to its impact on reproductive function. Compared to females, male mice generally exhibit greater inflammatory activation...
Estrogen receptor alpha (ERα) signaling has metabolic and anti-inflammatory properties in addition to its impact on reproductive function. Compared to females, male mice generally exhibit greater inflammatory activation of microglia and increased susceptibility to diet-induced obesity (DIO). Given the established metabolic protective effects of estrogen, these observations raise the possibility that sex differences in microglial estrogen signaling contribute to this sexual dimorphism. In this study, we assessed metabolic and CNS histopathological properties in a mouse model with inducible microglia-specific ablation of ERα (MG-ERαKO). Male MG-ERαKO mice developed increased weight gain and insulin resistance relative to controls during high-fat diet (HFD) feeding. Indirect calorimetry and food intake analysis revealed that reduced energy expenditure, coupled with an inadequate compensatory reduction in food intake, was the primary driver of the obese phenotype. In contrast, female MG-ERαKO mice fed HFD developed mild insulin resistance, with no change in body weight gain compared to controls, despite a similar reduction in energy expenditure. Immunohistochemical analyses of the microglial activation marker IBA1 in the mediobasal hypothalamus (MBH) revealed that female MG-ERαKO mice had an increased number of microglia without showing morphological signs of activation. In contrast, MBH microglial number was unchanged in MG-ERαKO male mice, but the cells adopted more activated morphological profiles. Finally, HFD-fed MG-ERαKO male mice had increased POMC neuron-microglia interactions but fewer overall hypothalamic POMC neurons, suggesting microglia may disrupt POMC neuron integrity to promote DIO. Together, these findings indicate that sex-specific actions of estrogen in microglia limit the metabolic complications of HFD feeding.
Pathophysiology-based subtypes of individuals at high-risk of type 2 diabetes: multi-omics profiles and lifestyle differences across subtypes.
Deng K, Hameete A, Schrauwen P … +8 more , Wagner R, van Hylckama Vlieg A, Rosendaal FR, Mook-Kanamori DO, le Cessie S, van Dijk KW, de Mutsert R, Li-Gao R
Metabolism · 2026 Jul · PMID 42385855 · Publisher ↗
BACKGROUND: Previous studies identified subtypes among individuals at elevated risk of type 2 diabetes mellitus (T2DM), yet the molecular signatures distinguishing these subtypes remain poorly characterized. We aimed to...
BACKGROUND: Previous studies identified subtypes among individuals at elevated risk of type 2 diabetes mellitus (T2DM), yet the molecular signatures distinguishing these subtypes remain poorly characterized. We aimed to identify and characterize T2DM risk subtypes using routine and non-routine clinical variable lists, and to compare their metabolomic, proteomic, and lifestyle profiles. METHODS: In the Netherlands Epidemiology of Obesity study (median age 56 years; median BMI 29 kg/m), we applied partitioning around medoids (PAM) clustering using two variable lists (routine, N = 5235; non-routine, N = 1510), both including variables derived from a liquid mixed meal challenge. Cox proportional hazards models estimated associations between subtypes and T2DM incidence. Random forest models identified discriminative metabolites and proteins across subtypes. RESULTS: Each variable list yielded four subtypes ranging from an insulin-sensitive and lean profile (subtype 1) to an obese profile with ectopic fat accumulation and insulin resistance (subtype 4), with a graded increase in T2DM risk (hazard ratios ranging from 1.9 [95% confidence interval (CI): 0.4-9.8] to 19.5 [95% CI: 9.1-41.6]). Both subtyping schemes captured metabolic heterogeneity beyond conventional weight-by-glycemia categories, e.g., redistributing overweight or obese but normoglycemic individuals across subtypes with divergent metabolic profiles and T2DM risks. While multi-omics profiling revealed shared metabolic and proteomic markers across higher-risk subtypes (e.g., glycoprotein acetyls, glucose, hepatocyte growth factor), subtype assignment was predominantly driven by fasting glucose and lipoprotein levels (e.g., very-low-density lipoprotein [VLDL]), with additional subtype-specific molecular signatures (e.g., branched-chain amino acids). Individuals in the higher-risk subtypes also exhibited less healthy lifestyle characteristics, including poorer dietary quality. CONCLUSIONS: Four metabolic subtypes with graded T2DM risk were identified in a predominantly overweight or obese, middle-aged population, revealing metabolic heterogeneity among individuals who appear homogeneous under conventional weight-by-glycemia categories. Although subtype differentiation was largely driven by fasting glucose and lipoproteins, multi-omics profiling uncovered additional molecular signatures, suggesting that data-driven subtyping may complement conventional risk markers and inform targeted prevention.
Endothelial NPR-C promotes insulin resistance via Caveolin-1-mediated insulin transcytosis.
Xu ZQ, Yu XY, Wei JQ … +8 more , Deng QW, Zhai WH, Rong WW, Li MY, Zhang QR, Gao PJ, Li XD, Wang JG
Metabolism · 2026 Jun · PMID 42379496 · Publisher ↗
Obesity-induced insulin resistance contributes to metabolic dysfunction and type 2 diabetes, yet the endothelial mechanisms involved remain incompletely understood. Here, we identify endothelial natriuretic peptide recep...
Obesity-induced insulin resistance contributes to metabolic dysfunction and type 2 diabetes, yet the endothelial mechanisms involved remain incompletely understood. Here, we identify endothelial natriuretic peptide receptor C (NPRC) as a key regulator of insulin transport and insulin sensitivity. NPR-C expression was increased in endothelial cells from adipose tissue and skeletal muscle of obese mice. Endothelial-specific deletion of NPR-C improved insulin sensitivity, whereas endothelial NPR-C overexpression aggravated insulin resistance, as demonstrated by glucose tolerance, insulin tolerance, and hyperinsulinemic-euglycemic clamp. Mechanistically, NPR-C impaired insulin uptake and transendothelial transport by reducing insulin receptor (IR) membrane localization and altering intracellular trafficking. NPR-C directly interacted with Caveolin-1 and promoted Tyr14 phosphorylation-dependent K48-linked ubiquitination and proteasomal degradation of Caveolin-1, disrupting caveolae function and impairing IR trafficking. Importantly, Cdh5 promoter-driven adeno-associated virus-mediated NPR-C knockdown improved insulin sensitivity in mice with established obesity. Together, these findings identify endothelial NPR-C as a regulator of Caveolin-1 stability and IR trafficking and suggest NPR-C as a potential therapeutic target for obesity-associated insulin resistance.
Ghrelin predicts food consumption up to three hours prior to eating: A randomised controlled trial.
Hulme OJ, Martinussen C, Andersen BV … +10 more , Svane MS, Holst JJ, Bojsen-Møller KN, Hartmann B, Rehfeld JF, Gregersen S, Hermansen K, Byrne DV, Siebner HR, Madsbad S
Metabolism · 2026 Jun · PMID 42331140 · Publisher ↗
Eating triggers a cascade of metabolic, neural, and subjective signals that unfold and interact over several hours, typically suppressing the motivation to eat until the next meal. Which of these signals predict next-mea...
Eating triggers a cascade of metabolic, neural, and subjective signals that unfold and interact over several hours, typically suppressing the motivation to eat until the next meal. Which of these signals predict next-meal intake is not well understood. In a cross-over, double-blinded, and repeated measures factorial design over four separate test days, we manipulated both the protein and caloric content of four preload meals to experimentally induce differences in satiety. We investigated how the neural, subjective, hormonal, and metabolite states unfolded after a meal and how much each of them predicted the next meal intake 3 h later. Bayesian analysis revealed an extreme level of evidence for the inclusion of the peptide hormone ghrelin as a predictor of next meal energy intake. This predictive effect was consistently found for all time points, including also the time point immediately preceding preload consumption. When measured immediately before the ad libitum test meal, the plasma level of the gut hormone Glucagon-like Peptide-1 (GLP-1) and the subjective report of estimated consumption also predicted next-meal intake. No other measure, including the protein and caloric content of the preload, adequately predicted next-meal intake. Our results link ghrelin levels with the regulation of food intake several hours later.
Dynamic regulation of circulating endotrophin by changes in fat mass in humans.
Fernández-Verdejo R, Bu D, Zhang N … +3 more , An Z, Ravussin E, Scherer PE
Metabolism · 2026 Jun · PMID 42320555 · Publisher ↗
BACKGROUND AND AIMS: During long-term weight gain, extracellular matrix remodeling in adipose tissue elevates local and systemic endotrophin, potentially contributing to metabolic dysfunction. Whether short-term increase...
BACKGROUND AND AIMS: During long-term weight gain, extracellular matrix remodeling in adipose tissue elevates local and systemic endotrophin, potentially contributing to metabolic dysfunction. Whether short-term increases or reductions in fat mass modulate circulating endotrophin concentrations in humans remains unclear. We aimed to determine the relationship between short-term changes in fat mass (kg and fat percentage points) and circulating endotrophin levels, and to explore whether endotrophin mediates the effects of adiposity on lipid profiles. METHODS: Secondary analysis of the pooled individual participant data from two clinical trials. One trial randomized 42 healthy adults (52.4% women, 26-49 years) to one of the following six-month interventions: (a) weight maintenance, (b) 25% caloric restriction, (c) 12.5% caloric restriction and 12.5% increased energy expenditure, or (d) very low-calorie diet. The other trial enrolled 31 healthy adults (19.4% women, 20-40 years) and exposed them to an eight-week 40% overfeeding. Fat mass, circulating endotrophin, and circulating lipid profile were measured before and after these interventions. RESULTS: Considering all participants, the changes in fat mass ranged from -11.0 to +7.0 kg or -9.6 to +5.7 percentage points. Changes in fat mass were positively associated with changes in circulating endotrophin (unstandardized B-coefficient [95% CI] = 0.76 [0.45, 1.07] ng/mL/kg and 0.89 [0.51, 1.28] ng/mL/percentage point, P < 0.001). Exploratory mediation analyses showed that endotrophin mediated 15% [4, 51] of the effect of fat mass on total cholesterol. CONCLUSION: Changes in fat mass, including loss and gain, are associated with corresponding changes in circulating endotrophin, which may partially mediate metabolic effects. Future studies should test whether endotrophin represents a therapeutic target for metabolic health in humans.
Rethinking hypercortisolism screening in obesity and diabetes: A systematic review and meta-analysis.
Ferrari D, Bonaventura I, Tenuta M … +6 more , Pofi R, Al Awadi F, Jamal HF, Pivonello R, Corona G, Isidori AM
Metabolism · 2026 Jun · PMID 42289244 · Publisher ↗
BACKGROUND AND AIM: The growing burden of obesity and diabetes underscores the need for innovative strategies to identify secondary causes. While hypercortisolism is traditionally considered rare, its broader spectrum -...
BACKGROUND AND AIM: The growing burden of obesity and diabetes underscores the need for innovative strategies to identify secondary causes. While hypercortisolism is traditionally considered rare, its broader spectrum - from mild autonomous cortisol secretion to overt Cushing's syndrome (CS) - may be under-recognized in these populations. METHODS: We systematically searched MEDLINE, Scopus and Web of Science for original studies assessing hypercortisolism in obesity or diabetes. We included first-line screening tests for hypercortisolism, particularly the dexamethasone suppression test (DST), and subsequent confirmed CS. Data were pooled using random-effects models and are presented as 95%CIs. Certainty of evidence was assessed with GRADE. RESULTS: Of 3038 articles, 39 (14,995 screened participants) were included. In a pooled cohort of 8705 individuals with obesity (19 studies), the prevalence of an abnormal DST was 4.6% (95%CI: 3.2-6.4), and CS confirmed in 0.8% [0.4-1.5]. Among 6638 patients with diabetes (22 studies), 14.3% (95%CI: 10.9-18.4) had an abnormal DST, increasing to 23.3% (95%CI: 22.2-24.5) after heterogeneity adjustment; 2.1% (95%CI: 1.3-3.3) had confirmed CS. Age, recent weight gain, and diabetes were significant predictors of CS. One in seven abnormal DST led to CS confirmation. Exploratory economic analyses supported broadening screening in selected cohorts. GRADE certainty ranged from low to moderate. CONCLUSIONS: In a clinically relevant subset of patients with obesity and diabetes, underlying hypercortisolism remains undiagnosed. The implications of abnormal DST without confirmed CS warrant further investigation. Screening strategies for secondary causes of obesity and type 2 diabetes might require reassessment, pending confirmation in unbiased cohorts.
SGLT2 inhibitors and GLP-1 receptor agonists in atrial fibrillation treatment: Clinical evidence and mechanistic insights.
Fan Y, Chen X, Cai X … +5 more , Dong Y, Liu C, Chen Y, Lip GYH, Zhu W
Metabolism · 2026 Jun · PMID 42289243 · Publisher ↗
Atrial fibrillation (AF) is the most common sustained arrhythmia globally. Despite certain progress in drug and interventional treatments, AF still presents high morbidity, high mortality, and unsatisfactory clinical out...
Atrial fibrillation (AF) is the most common sustained arrhythmia globally. Despite certain progress in drug and interventional treatments, AF still presents high morbidity, high mortality, and unsatisfactory clinical outcomes. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA), initially used to treat type 2 diabetes mellitus (T2DM), have demonstrated cardiorenal protective effects beyond glycemic control and have drawn broad attention for their potential in AF management. This narrative review comprehensively synthesizes clinical evidence and underlying mechanisms regarding the effects of SGLT2i and GLP-1 RA on new-onset AF and post-ablation AF recurrence across common comorbidities, including T2DM, heart failure (HF), chronic kidney disease (CKD) and obesity. Available evidence shows that SGLT2i may be associated with reduced new-onset AF risk in patients with T2DM, HF and CKD, and lower post-ablation AF recurrence in high-risk groups. GLP-1 RA show beneficial effects on AF in individuals with obesity or heart failure with preserved ejection fraction. Their protective effects are mainly mediated by upstream metabolic regulation and direct effects on atrial electrophysiology, as evidenced by cellular, animal, and clinical studies. Notably, most clinical evidence comes from post hoc analyses and observational studies, with AF rarely as a primary endpoint and without systematic measurement, leaving the evidence at a hypothesis-generating stage with limited clinical applicability. Overall, SGLT2i and GLP-1 RA serve as potential adjunctive therapies for AF patients with concomitant cardiometabolic comorbidities. Their AF-related outcomes represent exploratory secondary benefits instead of established therapeutic indications. Further specific randomized controlled trials with prespecified AF endpoint and standardized AF monitoring are needed to verify their clinical efficacy and application prospects.
Resistance training and diabetes mellitus type 2: An umbrella review of systematic reviews and meta-analyses on glycemic and cardiometabolic outcomes.
Trybulski R, Żebrowska A, Fostiak K … +2 more , Olaniszyn G, Wilk M
Metabolism · 2026 Jun · PMID 42248329 · Publisher ↗
OBJECTIVES: Resistance training (RT) is recommended for type 2 diabetes (T2D), but secondary evidence is voluminous and heterogeneous. We conducted an umbrella review to map, appraise, and grade the certainty of RT effec...
OBJECTIVES: Resistance training (RT) is recommended for type 2 diabetes (T2D), but secondary evidence is voluminous and heterogeneous. We conducted an umbrella review to map, appraise, and grade the certainty of RT effects on glycaemic and cardiometabolic outcomes in adults with T2D. METHODS: We searched PubMed, Scopus, and Web of Science for systematic reviews/meta-analyses of RT in adults with T2D. The studies were screened, extracted, mapped primary-study overlap (corrected covered area, CCA), and appraised review quality (AMSTAR-2). Certainty was judged at the overview level using a GRADE-style framework integrating review methods (AMSTAR-2). RESULTS: Forty-three reviews met inclusion. Overlap was moderate to very high across outcomes (e.g. , CCA: HbA1c 9.8%, fasting glucose 21.3%, blood pressure 33.4%, strength 35.3%, HRQoL 56.5%). RT versus non-exercise was associated with small-to-moderate improvements in HbA1c (~-0.3 to -0.6%-points), fasting glucose (~-0.5-1.4 mmol/L), and systolic blood pressure (~-4-7 mmHg); small reductions in triglycerides and LDL/total cholesterol; mixed HDL findings; and large gains in muscle strength, although the relevant evidence base showed substantial overlap across reviews. Effects on body weight/BMI were small or null; fat% and waist circumference tended to decrease modestly; physical HRQoL showed small benefits. Heterogeneity was substantial for several outcomes. AMSTAR-2 flagged frequent critical issues (e.g., use of quality scales instead of domain-based risk-of-bias; infrequent small-study bias assessment). GRADE certainty was moderate for HbA1c, LDL-C, triglycerides, and systolic BP; low-moderate for fasting glucose, diastolic blood pressure; and low for fasting insulin, HDLC, and mental/overall HRQoL. CONCLUSIONS: RT likely confers small-to-moderate metabolic and vascular benefits and large strength improvements in adults with T2D, but certainty is tempered by heterogeneity, trial overlap, and recurrent methodological shortcomings. Well-reported, prospectively registered syntheses and trials with standardized RT dose and domain-based bias assessment are needed.
Hepatic TGFβ1 signaling impairs insulin sensitivity via inducing insulin receptor substrate 1 degradation.
Ai W, Pan Q, Shen Z … +4 more , Yang W, Jiang W, Song J, Guo S
Metabolism · 2026 May · PMID 42214482 · Publisher ↗
AIMS/HYPOTHESIS: Obesity is associated with insulin resistance, a major risk factor for type 2 diabetes (T2D), yet the underlying mechanisms remain incompletely defined. We hypothesized that elevated transforming growth...
AIMS/HYPOTHESIS: Obesity is associated with insulin resistance, a major risk factor for type 2 diabetes (T2D), yet the underlying mechanisms remain incompletely defined. We hypothesized that elevated transforming growth factor beta 1 (TGFβ1) level is associated with impaired insulin sensitivity. METHODS: Using primary hepatocytes, and mouse models with hepatic TGFβ1 overexpression or hepatic TGFβ1 signaling disruption, we examined the impact of TGFβ1 signaling on hepatic insulin signaling and glucose metabolism. We performed bulk RNA sequencing of liver samples identify potential mediator of obesity-induced insulin resistance. Immunoprecipitation, in vitro kinase assay, and mass-spec assay were used to explore the mechanisms underlying TGFβ1-induced insulin receptor substrate (IRS1) degradation. We further evaluated the therapeutic potential of targeting TGFβ1 signaling to improve glycemic control using the TGFβ1 signaling inhibitor LY2157299. RESULTS: Prolonged TGFβ1 exposure markedly reduced IRS1 protein abundance and impaired insulin-stimulated Akt activation in hepatocytes. Hepatic TGFβ1 overexpression exacerbated insulin resistance, whereas hepatic TGFβ1 signaling disruption improved insulin sensitivity by increasing IRS1 protein abundance. Mechanistically, TGFβ1 signaling increased Cullin 7 (CUL7) expression and promoted IRS1 phosphorylation at serine 685, leading to ubiquitin-dependent IRS1 degradation. Pharmacological inhibition of TGFβ1 signaling by LY2157299 improved insulin sensitivity in both lean and diabetic db/db mice. CONCLUSIONS/INTERPRETATION: These findings identify TGFβ1 as a key driver of hepatic insulin resistance by promoting CUL7-dependent IRS1 degradation, establishing a mechanistic link between obesity-associated cytokine signaling and impaired insulin action and highlighting the TGFβ1-CUL7-IRS1 axis as a potential therapeutic target for T2D.
A multi-omics atlas of multisystem complications in type 2 diabetes reveals molecular signatures and improves risk prediction.
Zhang H, Yue T, Wang S … +9 more , Shi J, Geng M, Zhang H, Pan L, Gu Z, Sun L, Zhao M, Zheng X, Weng J
Metabolism · 2026 May · PMID 42167398 · Publisher ↗
BACKGROUND: Type 2 diabetes (T2D) causes multisystem complications, but an integrated multi-omics framework for cross-system, multi-outcome analysis is lacking. We aimed to comprehensively construct the proteomic and met...
BACKGROUND: Type 2 diabetes (T2D) causes multisystem complications, but an integrated multi-omics framework for cross-system, multi-outcome analysis is lacking. We aimed to comprehensively construct the proteomic and metabolomic atlas of major T2D outcomes and to identify predictive panels that balance performance and clinical feasibility. METHODS: Among UK Biobank participants with T2D, we established proteomic (n = 3104), metabolomic (n = 28,834), and multi-omics (n = 3059) subcohorts. Using cross-sectional and longitudinal analyses, we systematically evaluated the associations of plasma proteins and metabolites with 19 T2D-related outcomes. Predictive models were developed using machine learning-based molecular feature selection and were compared with the clinical risk model. RESULTS: The study identified molecular signals that consistently exhibited positive or negative associations across multiple T2D outcomes, revealing shared biological pathways. We also uncovered outcome-specific and heterogeneous molecular signatures. Furthermore, protein-based models substantially outperformed clinical models (median delta C-index = 0.108; range: 0.063-0.143), while combined models achieved the best performance (median delta C-index = 0.109; range: 0.080-0.150) with consistent improvements in reclassification metrics, whereas metabolites provided only modest incremental gains (median delta C-index = 0.027; range: 0.006-0.070). Evaluation across varying selection thresholds identified a simplified panel of 174 proteins that maintained robust predictive performance. CONCLUSION: This large-scale multi-omics study systematically constructs the molecular atlas of T2D complications, providing new insights into disease biology and potential therapeutic targets. It further defines the predictive value of proteomic and metabolomic profiles and proposes a clinically feasible and practical framework for risk prediction and precision intervention.
Reply to letter to the editor: Metabolomic signatures of type 2 diabetes and mortality: Methodological considerations and unresolved questions.
García-Gavilán JF, Paz-Graniel I, Salas-Salvadó J
Metabolism · 2026 Aug · PMID 42155850 · Publisher ↗
Abstract loading — click title to view on PubMed.
Islet inflammatory macrophages drive MSC loss and multiple interactions involved in β-cell adaptation during diabetes.
Liu J, Xu W, Yan W … +13 more , Qin Y, Wang X, Chen X, Meng Z, Pan Y, Zhang Y, Shen Y, Yang Y, Zhang F, Liu H, Zheng P, Yu J, Jin L
Metabolism · 2026 Aug · PMID 42144182 · Publisher ↗
While the functional adaptation of β-cells during type 2 diabetes progression is well-established, the role of non-β islet cells remains largely unexplored. Utilizing single-cell RNA sequencing, we identified a substanti...
While the functional adaptation of β-cells during type 2 diabetes progression is well-established, the role of non-β islet cells remains largely unexplored. Utilizing single-cell RNA sequencing, we identified a substantial expansion of the macrophage population and a concomitant reduction in the proportion of mesenchymal stem cells (MSCs) within the islets of diabetic mice transitioning from metabolic compensation to decompensation. Under conditions of metabolic stress, macrophages extensively infiltrated the islets and adopted a pronounced pro-inflammatory phenotype. This phenotypic shift impaired β-cell glucose-stimulated insulin secretion and induced β-cell apoptosis. Simultaneously, macrophage-derived inflammatory factors, notably TNF-α, suppressed MSC proliferation and downregulated Wntless (Wls), thereby reducing extracellular Wnt transport. The resultant loss of Wls diminished MSCs' capacity to provide trophic support to β-cells and hindered the transition of macrophages to an anti-inflammatory phenotype. This self-perpetuating cycle establishes a chronic pro-inflammatory environment within the islets, culminating in β-cell functional deterioration and the onset of diabetes. Experimental intervention involving macrophage elimination and MSC administration was shown to disrupt this detrimental cycle, restoring β-cell function and glycemic control. Collectively, our findings reveal that macrophages and MSCs jointly govern β-cell adaptation through intricate paracrine crosstalk. Modulating these macrophage-MSC interactions holds significant therapeutic implications for maintaining β-cell integrity and underscores the considerable potential of MSC-based therapies for type 2 diabetes treatment.
Structural determinants of beta-cell failure in type 2 diabetes: a multimodality imaging study.
Yamazaki H, Tokgöz S, Tauchi S … +14 more , Nakamura F, Dohke M, Hanawa N, Kodama Y, Katanuma A, Yamamoto Y, Fukuhara S, Prystupa K, Hummel J, Deden L, Boss M, Gotthardt M, Wagner R, Heni M
Metabolism · 2026 Aug · PMID 42134453 · Publisher ↗
BACKGROUND: Individuals with type 2 diabetes (T2D) tend to have a smaller pancreas and lower beta-cell mass; however, whether this is cause or consequence of T2D is unclear. We investigated the connection between pancrea...
BACKGROUND: Individuals with type 2 diabetes (T2D) tend to have a smaller pancreas and lower beta-cell mass; however, whether this is cause or consequence of T2D is unclear. We investigated the connection between pancreatic volume, beta-cell mass, beta-cell function, and T2D risk, and whether intrapancreatic fat deposition (IPFD) modifies these associations. METHODS: We conducted three complementary studies. In a PET/CT study (N = 52), beta-cell mass was estimated using [Ga]Ga-NODAGA-exendin-4 PET/CT imaging, and its correlations with CT-measured pancreatic volume, IPFD, and beta-cell function (HOMA2-%B) were evaluated. In a cross-sectional study using UK Biobank (N = 25,212), individuals were classified into four groups according to median pancreatic volume and IPFD on MRI, and the association with T2D prevalence was estimated. Finally, a case-cohort study with 6-year follow-up (N = 2168, subcohort of 658 and 146 incident T2D cases) used CT imaging to assess whether pancreatic volume and IPFD were associated with future T2D. RESULTS: In the PET/CT study, smaller pancreatic volume (r = 0.66 [95% CI: 0.47-0.80]) combined with higher IPFD (r = 0.29 [95% CI: 0.011-0.53]) was associated with reduced estimated beta-cell mass, which in turn was linked to lower insulin secretion (r = 0.48 [95% CI: 0.22-0.68]). In the UK Biobank, individuals with small pancreas that contained much fat (small/high-fat pancreas) had the highest T2D likelihood (adjusted-odds ratio: 1.71 [95% CI: 1.42-2.07]) compared to those with large/low-fat pancreas. Validation in the longitudinal study showed adjusted-hazard ratios for T2D of 3.12 (1.40-6.96) for small/high-fat, 0.99 (0.58-1.67) for large/high-fat, and 0.74 (0.26-2.14) for small/low-fat pancreas. CONCLUSION: The combination of a small pancreas and high IPFD is associated with increased T2D risk, supporting a structural phenotype linked to beta-cell failure.
Single-cell and spatial omics in liver identify cell-cell communication regulators in aging and insulin resistance.
Zhao W, Jiao X, Du K … +19 more , Sun Q, Duan J, Cao Y, Shen X, Said Z, Karri SS, Ellsworth P, Hu W, Sargsyan A, Astapova I, Kim SY, Gonzalez J, Higgins-Chen AT, Perry RJ, Seki E, Herman MA, Andersen B, Nie Q, Yang Q
Metabolism · 2026 Aug · PMID 42114673 · Publisher ↗
The liver is a major metabolic organ regulating systemic insulin sensitivity, which progressively declines with age. Due to the complexity of cellular components and spatial structures, how the liver regulates insulin re...
The liver is a major metabolic organ regulating systemic insulin sensitivity, which progressively declines with age. Due to the complexity of cellular components and spatial structures, how the liver regulates insulin resistance during aging remains to be elucidated. Using single-cell RNA-seq, ATAC-seq, and spatial transcriptomics, we studied liver cellular composition and zonation in young, insulin-sensitive mice and old mice with varying degrees of insulin resistance. Aging reduced pericentral zone 3 hepatocyte population but increased mid-zone 2 hepatocytes and hepatic stellate cells (HSCs). The interaction of aging and insulin resistance led to further zone 3 contraction and zone 2 expansion. Cell-cell communication and spatial proximity analysis revealed reduced hepatocyte growth factor (HGF) signaling activity from HSCs to zone 3 hepatocytes in aging and insulin resistance. In HGF activator (HGFAC)-knockout mice, a significant reduction in the zone 3 hepatocyte proportion was observed. Treating insulin-resistant aged mice with HGF reversed zone 3 contraction and improved insulin sensitivity. These findings highlight the significance of liver zonation dynamics in aging-associated insulin resistance.
Metabolomic signatures of type 2 diabetes and mortality: Methodological considerations and unresolved questions.
Han J
Metabolism · 2026 Aug · PMID 42106057 · Publisher ↗
Abstract loading — click title to view on PubMed.
Postprandial glucose profiles may reflect heterogeneity in insulin secretion and sensitivity in type 2 diabetes.
Giosuè A, Skantze V, Testa R … +8 more , D'Abbronzo G, Costabile G, Vitale M, Corrado A, Jirstrand M, Landberg R, Riccardi G, Bozzetto L
Metabolism · 2026 Aug · PMID 42082049 · Publisher ↗
BACKGROUND: Continuous glucose monitoring (CGM) reveals heterogeneity of postprandial glucose responses (PPGR), a key target for optimizing glycemic control in type 2 diabetes (T2D). We analyzed PPGR patterns to identify...
BACKGROUND: Continuous glucose monitoring (CGM) reveals heterogeneity of postprandial glucose responses (PPGR), a key target for optimizing glycemic control in type 2 diabetes (T2D). We analyzed PPGR patterns to identify subtypes reflecting pathophysiological differences. METHODS: Cross-sectional CGM data from 100 individuals with T2D were collected over 4 h following a standardized meal consumed twice. Dynamic PPGR features-glucose peak, incremental area under the curve (iAUC), rise and fall rates, final vs. fasting glucose-were used for K-Means clustering, with stability assessed using a Random Forest classifier trained on the first meal. In 50 participants, postprandial plasma glucose and insulin were measured, and clinical/metabolic parameters compared across clusters using one-way ANOVA. RESULTS: Three CGM-defined PPGR clusters were identified. Cluster 1 (n = 19) showed the highest peak and iAUC, with post-meal glucose remaining persistently above baseline. Cluster 2 (n = 56) and 3 (n = 25) had lower peaks and iAUCs, but Cluster 3 exhibited higher rise and fall rates than Cluster 2. Clusters did not differ in age, sex, BMI, or diabetes duration, but metformin use was lower in Cluster 3. Cluster 1 showed significantly lower insulin secretion (HOMA2-B%: 77.42 ± 25.64 vs. 104.96 ± 43.94) and higher insulin resistance (HOMA-IR: 7.94 ± 3.27 vs. 4.84 ± 2.78) than Cluster 3, with intermediate values for Cluster 2, confirmed by postprandial indices. Cluster 3 had a higher early insulin response than Cluster 1 and 2 (60-min insulinogenic index: 1.67 ± 1.07, 0.84 ± 0.31, 0.84 ± 0.58, respectively; p < 0.05). CONCLUSIONS: CGM-derived PPGR features could identify T2D subtypes with similar clinical profiles but distinct insulin secretion and sensitivity impairments, supporting targeted interventions.
Integrated plasma proteomics and metabolomics reveal immunometabolic pathways and predictive signatures for age-related eye diseases.
Cui X, Zhao Q, Yuan J … +1 more , Yu-Wai-Man P
Metabolism · 2026 Jul · PMID 42066985 · Publisher ↗
BACKGROUND AND AIMS: Age-related eye diseases (AREDs) share aging as a major risk factor, but the systemic molecular changes preceding disease onset remain incompletely understood. We aimed to define the shared and disea...
BACKGROUND AND AIMS: Age-related eye diseases (AREDs) share aging as a major risk factor, but the systemic molecular changes preceding disease onset remain incompletely understood. We aimed to define the shared and disease-specific immunometabolic architecture of major AREDs and to examine how circulating molecular features relate to retinal phenotypes, pre-diagnostic patterns, and disease risk. METHODS: We performed a large-scale prospective multi-omics study in the UK Biobank integrating baseline plasma proteomics, metabolomics, retinal imaging-derived phenotypes, and longitudinal follow-up across five major AREDs: age-related macular degeneration, cataract, diabetic retinopathy, glaucoma, and retinal vascular occlusion. Cox regression, functional enrichment, protein-metabolite correlation, mediation analysis, trajectory analysis, and machine-learning models were applied. RESULTS: Proteome-wide analyses identified both shared and disease-specific circulating signatures, mainly involving immune, extracellular matrix, vascular, and stress-response pathways. Reconstructed population-level molecular patterns diverged from controls up to 15 years before diagnosis, with marked heterogeneity across diseases. Integration with retinal imaging linked immune- and matrix-related proteins to retinal neurodegenerative and microvascular phenotypes. Metabolite clustering and mediation analyses highlighted recurrent lipoprotein-related pathways, particularly HDL-related structure and composition, as cross-layer features associated with systemic protein signals, metabolic states, and disease risk. Combined proteomic-metabolomic models improved prediction of incident disease compared with protein-only models. CONCLUSIONS: Major AREDs share a systemic immunometabolic aging architecture while retaining substantial disease-specific molecular features. Circulating molecular alterations are detectable years before clinical onset and may support future biological stratification and risk prediction.
Hepatocyte DDIT4 aggravates MASH progression through GPX4-mediated ferroptosis.
Wang H, Liu WY, Zhang F … +9 more , Chen W, Hu J, Cheng R, Chen Z, Wu D, Xie L, Tao Y, Zheng MH, Hu F
Metabolism · 2026 Jul · PMID 41997496 · Publisher ↗
BACKGROUND & AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease with limited therapeutic options, and the role of ferroptosis in its pathogenesis remains to be fully understood....
BACKGROUND & AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease with limited therapeutic options, and the role of ferroptosis in its pathogenesis remains to be fully understood. In this study, we aimed to investigate the action of DNA damage-inducible transcript 4 (DDIT4) in the ferroptosis and regulation of MASH progression. METHODS: The Gene Expression Omnibus database of MASH mice models and ferroptosis database were used to identify crucial ferroptosis related genes in MASH. Hepatic DDIT4 expression was detected in MASH patients, mouse models and hepatocytes. The functional role of DDIT4 was assessed in different diet-induced MASH mice models with hepatocyte-specific DDIT4 overexpression or knockout. RNA-sequencing and immunoprecipitation-mass spectrometry (IP-MS) were performed to determine DDIT4 interacting proteins. Molecular docking was used to explore the potential compound targeting DDIT4. RESULTS: We have discovered significantly elevated DDIT4 levels in mice and patients with MASH, which were positively correlated with MASH severity. Hepatocyte-specific over-expression of DDIT4 aggravated ferroptosis and MASH progression, while DDIT4 deletion alleviated ferroptosis and MASH progression. Mechanistically, DDIT4 decreased glutathione peroxidase 4 (GPX4) expression in an mTORC1 dependent manner. Additionally, DDIT4 interacted with cytosolic GPX4 and inhibited TOM22-mediated mitochondrial translocation, resulting in mitochondrial GPX4 reduction and ferroptosis activation. Importantly, through molecular docking and surface plasmon resonance (SPR), we have identified quercetagetin, a natural flavonoid, as a potential DDIT4-targeting compound. Administration of quercetagetin alleviated hepatic steatosis, inflammation, and fibrosis in MASH mice. CONCLUSIONS: Our study establishes the DDIT4-GPX4-ferroptosis axis as a new regulatory node in MASH progression and highlights DDIT4 as a potential therapeutic target for MASH.
6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3: A potential target in the development of diabetes and its complications.
Jiang M, An X
Metabolism · 2026 Jul · PMID 41990915 · Publisher ↗
6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) is a bifunctional enzyme involved in the production and breakdown of fructose-2,6-bisphosphate (F-2,6-BP) and serves as a key regulator of glucose metabolism...
6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) is a bifunctional enzyme involved in the production and breakdown of fructose-2,6-bisphosphate (F-2,6-BP) and serves as a key regulator of glucose metabolism. It is closely implicated in the progression of diabetes and its associated complications, including diabetic cardiomyopathy (DCM), diabetic kidney disease (DKD), and diabetic retinopathy (DR). PFKFB3 mediates diabetes-induced organ damage through its effects on immune-inflammatory responses, fibrosis, vascular dysfunction, as well as β-cells function and survival. In this review, we highlight the bidirectional regulatory role of PFKFB3 in diabetes and its complications and explore the therapeutic potential of PFKFB3 inhibitors for managing diabetes and its related complications.
When the proteome meets the metabolome observational and Mendelian randomization analyses.
Zheng R, Delgado-Velandia M, Ärnlöv J … +7 more , Sundström J, Engström G, Smith JG, Dekkers KF, Lundmark P, Fall T, Lind L
Metabolism · 2026 Jul · PMID 41962653 · Publisher ↗
OBJECTIVE: The basis for protein synthesis is the genetic code. Many of these proteins will affect intermediary metabolites by acting as enzymes, hormones, or by other actions. The aim of the present study was to assess...
OBJECTIVE: The basis for protein synthesis is the genetic code. Many of these proteins will affect intermediary metabolites by acting as enzymes, hormones, or by other actions. The aim of the present study was to assess the relationships of a large number of proteins with endogenous metabolites. METHODS: Plasma protein levels were measured by the proximity extension assay (PEA) and metabolites by mass spectrometry. Cross-sectional relationships of 242 proteins and 790 metabolites were evaluated in the EpiHealth and POEM studies using a discovery/validation approach. Genetic instruments identified in UK Biobank for protein levels (n = 1621) and genetics for metabolite levels (n = 777) in SCAPIS and EpiHealth were employed for Mendelian randomization (MR) analysis regarding putative causal associations. RESULTS: In the observational analyses, 20% of the evaluated pairwise protein-metabolite associations were found significant in both the discovery and validation samples. We could however only find support for causal effects in the MR analysis for <0.1% of the pairwise associations, representing 326 unique proteins. The R for the relationship between the MR and observational estimates was only 0.05. 37 protein-metabolite relationships that were significant in a congruent fashion in both the observational and MR analyses were identified. A searchable online protein vs metabolite atlas was created for the scientific community to use these results. We also give some examples where metabolites were used to enhance protein findings in cardiovascular epidemiological research. CONCLUSION: This study provides a comprehensive assessment of a large number of protein- metabolite relationships using both observational and MR analyses, highlighting how these results could be used to enhance clinical research.
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