Diabetes & Metabolism[JOURNAL]
Sun
200 papers
Metformin suppresses β-cell apoptosis under ER stress by inhibiting protein translation.
Inoue R, Tajima K, Okuyama T … +17 more , Sakai C, Kanno T, Zou M, Kyohara M, Matsunaga K, Tsuno T, Luo J, Ishida E, Horike SI, Hirano T, Arakawa N, Kin T, Shapiro AMJ, Terauchi Y, Obinata H, Hirano H, Shirakawa J
Metabolism · 2026 Jul · PMID 41962652 · Publisher ↗
Endoplasmic reticulum (ER) stress is a critical driver of pancreatic β-cell dysfunction and apoptosis. Although metformin, a drug used to treat type 2 diabetes, primarily decreases blood glucose levels by improving insul...
Endoplasmic reticulum (ER) stress is a critical driver of pancreatic β-cell dysfunction and apoptosis. Although metformin, a drug used to treat type 2 diabetes, primarily decreases blood glucose levels by improving insulin sensitivity, its direct effects on β-cell survival remain unclear. Here, we investigated the effect of metformin on β-cell stress responses under ER stress conditions. Thapsigargin (Tg)-induced ER stress increased β-cell apoptosis in mouse islets, which was prevented by metformin in a dose-dependent manner. Treatment with metformin for 24 h suppressed the Tg-induced upregulation of unfolded protein response (UPR)-related genes, as confirmed by transcriptomic and pathway analyses. Quantitative proteomics revealed that Tg inhibited eIF2 signaling and protein translation, both of which were partially restored by metformin. Enrichment analysis further indicated the attenuation of apoptotic pathways in metformin-treated islets. Polysome profiling and puromycin incorporation assays demonstrated that metformin reduced protein translation independently of ER stress. Metformin promoted the dephosphorylation of 4E-BP1, a key initiator of cap-dependent protein translation that is activated by phosphorylation, and the antiapoptotic effect of metformin was abolished by 4E-BP1 knockdown in MIN6 cells. Phosphoproteomic analysis indicated that the activation of mTOR signaling, a kinase of 4E-BP1, in Tg-treated islets was mitigated by metformin. Taken together, these findings reveal a cytoprotective mechanism of metformin in β-cells, in which metformin suppresses ER stress-induced apoptosis through 4E-BP1-mediated inhibition of mRNA translation and modulation of mTOR signaling. This study highlights a β-cell-intrinsic action of metformin that may contribute to its long-term therapeutic benefits in diabetes management.
Bone marrow rewired: Trained immunity and clonal hematopoiesis in metabolic disease.
Chronopoulos J, Hajishengallis G, Chavakis T
Metabolism · 2026 Jul · PMID 41932677 · Publisher ↗
Diseases associated with obesity and metabolic dysregulation, such as diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD) promote chronic low-grade inflammation, which in turn, may enhance the r...
Diseases associated with obesity and metabolic dysregulation, such as diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD) promote chronic low-grade inflammation, which in turn, may enhance the risk for cardiovascular disease. Emerging evidence in recent years suggests that chronicity of inflammation involves alterations in bone marrow homeostasis. Obesity-related inflammation and metabolic stress, including hyperglycemia or hyperlipidemia, may trigger rewiring of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow, driving production of myeloid cells with heightened inflammatory capacity that in turn fuel and sustain chronic inflammation. This process is akin to trained immunity and may promote an inflammatory memory that links metabolic disorders to their cardiovascular complications. Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by aging-related emergence of somatic mutations in hematopoietic cells that clonally expand and bear higher inflammatory potential. Importantly, a bidirectional link between CHIP and metabolic disorders as well as their cardiovascular sequelae emerges. Here, we review current concepts regarding the links between bone marrow biology and metabolic diseases and associated chronic inflammation.
Proteomics and metabolomics biomarkers for predicting the onset and progression of diabetic complications: A systematic review and bioinformatics integration.
Song W, Nie X, Zhu Z … +6 more , Wang Q, Zhao B, An Y, Maimaiti A, Liang X, Zhang Q
Metabolism · 2026 Jul · PMID 41895463 · Publisher ↗
Diabetic complications are major drivers of morbidity and mortality, leading to progressive cardiovascular, renal, retinal, and neurological damage. Early intervention is hindered by the lack of reliable biomarkers for p...
Diabetic complications are major drivers of morbidity and mortality, leading to progressive cardiovascular, renal, retinal, and neurological damage. Early intervention is hindered by the lack of reliable biomarkers for prediction and disease staging. Advances in proteomics and metabolomics provide powerful tools to elucidate molecular mechanisms and identify clinically actionable signatures. This systematic review included 67 cohort and 41 cross-sectional studies published between 2012 and August 2025, comprising 73,580 participants. Most studies involved type 2 diabetes (T2D) populations (n = 71), followed by type 1 diabetes (T1D) (n = 16), as well as mixed T1D and T2D cohorts (n = 8). Most investigations analyzed serum or plasma, with additional studies examining urine and other matrices. Proteomic profiling was primarily conducted using mass spectrometry (MS)-based platforms, alongside several affinity-based technologies. Metabolomic analyses were largely MS-based, with a minority employing nuclear magnetic resonance spectroscopy. Overall, 275 metabolites and 363 proteins demonstrated predictive relevance. Pathway enrichment implicated lipoprotein metabolism in macrovascular complications, complement/coagulation and inflammatory signaling in nephropathy, VEGFA-VEGFR2 signaling in retinopathy, and receptor-mediated endocytosis in neuropathy, while amino acid metabolism was consistently disrupted. These molecular signatures show promise for early detection and risk stratification but require standardized prospective validation before clinical translation. PROSPERO registration number: CRD420250656551 Name of the registration: Metabolomics and proteomics-based biomarkers for chronic complications of diabetes: A comprehensive systematic review and meta-analysis. URL: https://www.crd.york.ac.uk/PROSPERO/view/CRD420250656551.
Metabolomics profiles of type 2 diabetes and insulin resistance and their associations with total mortality.
García-Gavilán JF, Paz-Graniel I, Pérez-Acosta JA … +20 more , Ruiz-Canela M, Li J, Clish C, Razquin C, Yun H, Corella D, Estruch R, Ros E, Fitó M, Wang F, Fiol M, Lapetra J, Gómez-Gracia E, Liang L, Denis C, Babio N, Guasch-Ferré M, Martínez-González MÁ, Hu FB, Salas-Salvadó J
Metabolism · 2026 Jun · PMID 41881293 · Publisher ↗
OBJECTIVE: This study aimed to identify metabolomic profiles associated with type 2 diabetes and insulin resistance (HOMA-IR) and relate them to the risk of total mortality. METHODS: A longitudinal study was conducted in...
OBJECTIVE: This study aimed to identify metabolomic profiles associated with type 2 diabetes and insulin resistance (HOMA-IR) and relate them to the risk of total mortality. METHODS: A longitudinal study was conducted in a subset of participants from a diabetes case-cohort study (mean age, 66.5 years; 62% women; 176/699 with incident T2D) within the PREDIMED trial. Plasma metabolites were analyzed using LC-MS/MS methods at baseline (discovery sample) and 1-year follow-up (validation sample). Multi-metabolite profile scores for type 2 diabetes and HOMA-IR, respectively, were derived using elastic net regression. Cox proportional hazards were fitted to assess the association between metabolomic profiles and total mortality, adjusting for potential confounders. External validation was performed in the NHS/HPFS cohorts. RESULTS: A total of 31 metabolites were associated with type 2 diabetes and 105 with HOMA-IR. Both metabolomic profiles were significantly associated with a higher risk of total mortality (type 2 diabetes HR = 1.52, 95%CI: 1.04-2.25; HOMA-IR HR = 1.33, 95%CI: 1.00-1.75) in the PREDIMED cohort. Shared metabolites between both metabolomic signatures, including glycine, SDMA, DMGV, and phosphocreatine, were associated with mortality. These associations were replicated in a pooled analysis of three independent American cohorts (type 2 diabetes HR = 1.09, 95%CI: 1.05-1.13; HOMA-IR HR = 1.04, 95%CI: 1.00-1.09). CONCLUSIONS: In an older population at high cardiometabolic risk, metabolomic scores of type 2 diabetes and insulin resistance were associated with total mortality risk, potentially explaining some mechanisms behind the increased risk of mortality observed in epidemiological studies for individuals with glycemic dysregulations.
Mapping circulating microRNA signatures in type 1 diabetic microvascular disease: A systematic review and Bayesian multilevel meta-analysis with bioinformatic integration of molecular dysregulation.
Khadivi Y, Tavallaeinejad P, Hashemipour M … +2 more , Khachikian A, Hovsepian S
Metabolism · 2026 Jul · PMID 41833660 · Publisher ↗
BACKGROUND: To systematically evaluate microRNAs (miRNAs) associated with microvascular complications of type 1 diabetes mellitus (T1D), quantify differential expression using complementary frequentist and Bayesian meta-...
BACKGROUND: To systematically evaluate microRNAs (miRNAs) associated with microvascular complications of type 1 diabetes mellitus (T1D), quantify differential expression using complementary frequentist and Bayesian meta-analytic frameworks, and contextualize dysregulated signals through integrative multi-database pathway analysis. METHODS: A systematic search of Medline, Embase, Scopus, and Web of Science was conducted through February 2025 to identify observational studies reporting miRNA expression in diabetic nephropathy (DN) or diabetic retinopathy (DR). Effect sizes (Hedges' g) were pooled using random-effects models and Bayesian hierarchical meta-analysis to account for within-study dependence. Experimentally validated and predicted targets were retrieved via multiMiR and mapped to Gene Ontology, KEGG, and Reactome pathways to evaluate biological convergence. RESULTS: Nine studies comprising 34 contrasts and 19 unique miRNAs met inclusion criteria. miR-29a-3p (g = -0.99; 95% CI -1.33 to -0.65; I = 0.00) and miR-204-5p (g = -0.88; 95% CI -1.06 to -0.70; I = 0.00) were consistently downregulated in DN. Bayesian models corroborated frequentist estimates, demonstrated robust convergence, and showed minimal sensitivity to prior specification. No universal circulating miRNA signature emerged across complications, reflecting substantial biological and methodological heterogeneity. Enrichment analyses of validated targets indicated convergence on pathways related to autophagy, Wnt signaling, fibrosis, and apoptosis. CONCLUSION: Current evidence does not support a unified circulating miRNA signature for T1D microvascular complications. However, reproducible downregulation of miR-29a-3p and miR-204-5p highlights candidate signals warranting validation in adequately powered longitudinal and diagnostic-accuracy studies. By integrating quantitative synthesis with pathway-level interpretation, this study clarifies the present evidentiary landscape and provides a framework to guide future translational research in T1D microangiopathy.
Once-weekly insulin GZR4 versus once-daily insulin degludec in Chinese people with type 2 diabetes: A multicenter, open-label, randomized, phase 2 trial.
Chen L, Dong X, Zhang Q … +13 more , Wang H, Zhu H, Cheng Z, Deng X, Wang G, Zhang J, Liu X, Zhao J, Hao C, Xie T, He A, Li Y, Chen W
Metabolism · 2026 Jun · PMID 41833659 · Publisher ↗
BACKGROUND: Insulin GZR4 (GZR4) is a once-weekly insulin currently under development. This phase 2 trial assessed the efficacy and safety of once-weekly (QW) GZR4 versus once-daily (QD) insulin degludec (IDeg) in Chinese...
BACKGROUND: Insulin GZR4 (GZR4) is a once-weekly insulin currently under development. This phase 2 trial assessed the efficacy and safety of once-weekly (QW) GZR4 versus once-daily (QD) insulin degludec (IDeg) in Chinese people with type 2 diabetes (T2D). METHODS: This 16-week, randomized, open-label, multicenter, treat-to-target phase 2 trial consisted of 2 cohorts: Cohort A enrolled insulin-naïve people; Cohort B enrolled people previously treated with basal insulin. Participants were randomly assigned (1:1) to receive GZR4 or IDeg. The primary outcome was the change in HbA1c from baseline to week 16. RESULTS: Between August 22, and September 22, 2023, 179 participants were enrolled and allocated to Cohort A (n = 83) and Cohort B (n = 96). The estimated mean change in HbA1c from baseline to week 16 was -1.50 percentage points in the GZR4 group vs -1.48 percentage points in the IDeg group in Cohort A (estimated treatment difference [ETD] of -0.02 percentage points [95% CI -0.34 to 0.30], p = 0.902), -1.26 percentage points in the GZR4 group vs -0.87 percentage points in the IDeg group in Cohort B (ETD -0.38 percentage points [95% CI -0.66 to -0.11], p = 0.007). At week 16, GZR4 and IDeg group showed a similar proportion of participants achieving HbA1c targets. The treatment-emergent adverse events did not differ between two groups. The incidence of hypoglycemia (mostly level 1) was slightly higher in participants receiving GZR4 than IDeg, particularly in Cohort B. No severe hypoglycemia (level 3) was reported. CONCLUSIONS: In this phase 2 trial, once-weekly GZR4 demonstrated effective glycemic control over 16 weeks in both insulin-naïve patients and those previously treated with basal insulin. The incidence of hypoglycemia was slightly higher with GZR4, particularly in the basal insulin-treated group, though no severe hypoglycemic events were reported. These findings warrant further investigation in larger phase 3 trials, which will utilize an adjusted, more precise molar-dose potency of GZR4 to fully characterize its benefit-risk profile.
Metformin: Antidiabetic actions from cells to tissues.
Bailey CJ, Gwilt M, Brand KMG
Metabolism · 2026 Jun · PMID 41819225 · Publisher ↗
Metformin (dimethyl biguanide) is a primary pharmacotherapy to treat hyperglycemia in type 2 diabetes. It counters the effects of insulin resistance, improves glucose homeostasis, assists weight control and avoids overt...
Metformin (dimethyl biguanide) is a primary pharmacotherapy to treat hyperglycemia in type 2 diabetes. It counters the effects of insulin resistance, improves glucose homeostasis, assists weight control and avoids overt hypoglycemia via reduced hepatic gluconeogenesis, increased splanchnic glucose turnover and greater peripheral glucose utilization. The underlying cellular actions of metformin differ between tissues and drug exposures. High concentrations of metformin (e.g. millimolar in the intestine) can interrupt the mitochondrial respiratory chain at complex 1, increase cytosolic NADH (favouring pyruvate conversion to lactate), decrease ATP synthesis, raise cytosolic AMP and activate AMP-activated protein kinase (AMPK). Lesser concentrations of metformin in liver can interrupt the respiratory chain at complex 4, which inhibits mitochondrial glycerol-3-phosphate dehydrogenase and impedes the mitochondrial glycerophosphate shuttle. Low concentrations of metformin (e.g., ∼10 μM) can activate AMPK by a lysosomal pathway without interrupting oxidative metabolism. While AMPK implements many of the metabolic effects of metformin, other contributing mechanisms include separate effects on metabolic pathways (e.g. inhibiting fructose-1,6-bisphosphatase) and signalling intermediates (e.g. inhibiting phosphatases) to reinforce the actions of insulin. Thus, the antidiabetic effects of metformin reflect diverse concentration-dependent cellular actions on nutrient metabolism and energetics in different tissues. The breadth of cellular actions of metformin encourages investigation of potential opportunities to assist in the management of cardiovascular, inflammatory, neoplastic and neurodegenerative disorders.
Burden of metabolic diseases, 1990-2023, with forecasts to 2030 for the Asia-Pacific region.
Zhang H, Chen QF, Lip GYH … +14 more , Tilg H, Valenti L, Somers VK, Byrne CD, Targher G, Yang W, Mantzoros CS, Misra A, Lonardo A, Alswat K, Sung KC, Muthiah MD, Zhou XD, Zheng MH
Metabolism · 2026 Jun · PMID 41763388 · Publisher ↗
BACKGROUND: The latest data release from the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2023 has enabled us to conduct an updated analysis of the trends and burdens of common metabolic diseases/risk...
BACKGROUND: The latest data release from the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2023 has enabled us to conduct an updated analysis of the trends and burdens of common metabolic diseases/risk factors from 1990 to 2023 in the Asia-Pacific region. We aimed to highlight disparities across geographic regions, over time, and by sex, while incorporating a predictive assessment of future trends through 2030. METHODS: We analyzed estimates of disability-adjusted life years (DALYs) and mortality for five common metabolic diseases and risk factors in the Asia-Pacific region (type 2 diabetes mellitus [T2DM], high systolic blood pressure [SBP], high body mass index [BMI], high LDL cholesterol, and metabolic dysfunction-associated steatotic liver disease [MASLD]). We also used Bayesian age-period-cohort (BAPC) models to project disease burdens through 2030. RESULTS: In 2023, in Asia-Pacific region, high SBP accounted for the largest burden (~138 million DALYs; 6.27 million deaths), followed by high BMI (~55 million DALYs; 1.33 million deaths), high LDL cholesterol (~53 million DALYs; 2.02 million deaths), T2DM (~49 million DALYs; 1.13 million deaths), and MASLD (~1.26 million DALYs; 47 thousand deaths). From 1990 to 2023, total DALYs increased 1.7- to 3.7- fold, with absolute burdens highest in China, India, and Indonesia, and relative burdens concentrated in Pacific Islands. Projected trends through 2023 suggest that the burden of all metabolic diseases/risk factors, except MASLD, is likely to continue rising, with high SBP remaining the dominant contributor. CONCLUSION: Analysis of the GBD 2023 and 2030 projections show that metabolic diseases/risk factors will remain a persistent challenge for the Asia-Pacific region, with substantial increases in DALYs and mortality. These findings call for coordinated, intensified global actions to address interconnected metabolic conditions and can have positive implications for the United Nations' 2030 health-related goals.
Association of daytime circadian-aligned activity with glycemic control in type 2 diabetes: Insights from continuous glucose monitoring and wearable data.
Lee DY, Lee JB, Jung I … +5 more , Park SY, Yu JH, Seo JA, Lee HJ, Kim NH
Metabolism · 2026 Jun · PMID 41722851 · Publisher ↗
BACKGROUND: Prior research on circadian rhythms have primarily focused on the risk of diabetes, with limited evidence on their impact in glycemic control among individuals with type 2 diabetes. This study investigated th...
BACKGROUND: Prior research on circadian rhythms have primarily focused on the risk of diabetes, with limited evidence on their impact in glycemic control among individuals with type 2 diabetes. This study investigated the association between Fitbit-derived circadian rhythm parameters and continuous glucose monitoring (CGM) metrics. METHOD: Data were analyzed from 122 insulin-treated patients with type 2 diabetes who concurrently wore real-time CGM devices (Dexcom G6) and activity trackers (Fitbit Inspire 2) for 10 days. Cosinor analyses were used to derive circadian parameters from wearable-based heart rate data. Associations between time-of-day-specific activity metrics and CGM outcomes were evaluated using partial Spearman correlations and multivariable logistic regression. RESULTS: Stronger circadian rhythmicity-characterized by greater amplitude and higher goodness-of-fit (R2)-was significantly associated with improved glycemic outcomes and reduced glucose variability. Higher daytime step counts and lower sedentary time were associated with reduced hyperglycemia and variability. Longer sleep duration was inversely associated with hypoglycemia (TBR <70) and glucose variability indices. Notably, circadian robustness (R2) and afternoon step counts emerged as independent predictors of achieving comprehensive CGM-based targets after adjusting for key clinical and behavioral confounders. CONCLUSIONS: In this cross-sectional exploratory analysis, greater daytime physical activity and stronger circadian rhythmicity were associated with improved glycemic control and reduced glucose variability. These findings are hypothesis-generating and support the need for prospective trials testing circadian-aligned behavioral interventions.
Targeting Gβγ subunits in hypothalamic AgRP neurons to treat obesity.
Xuan Y, Xiong X, Wang X … +8 more , Wang Y, Shen Y, Zhang H, Zhang R, Chen L, Zhang P, Zhang Y, Hu C
Metabolism · 2026 Jun · PMID 41722850 · Publisher ↗
G protein-coupled receptors (GPCRs) in the central nervous system, particularly in the hypothalamus, are promising therapeutic targets for the treatment of obesity and related metabolic disorders. However, the developmen...
G protein-coupled receptors (GPCRs) in the central nervous system, particularly in the hypothalamus, are promising therapeutic targets for the treatment of obesity and related metabolic disorders. However, the development of anti-obesity drugs targeting GPCRs in hypothalamus has been significantly constrained by their propensity to induce a range of adverse effects. An alternative strategy is to directly target the G protein subunits downstream of GPCRs, potentially biasing GPCR signaling away from harmful pathways while preserving those essential for normal cellular functions. The G protein βγ (Gβγ) subunits have emerged as a potential therapeutic target, but its role in obesity is largely unknown. In this study, we found that gallein, a Gβγ inhibitor, can ameliorate diet-induced obesity (DIO) and related metabolic dysfunction by suppressing appetite. Given the critical role of hypothalamic orexigenic Agouti-related peptide (AgRP)-expressing neurons in maintaining whole-body energy balance, we further demonstrated that gallein suppressed appetite by inhibiting AgRP neuronal activity. More importantly, specific inhibition of Gβγ subunits in AgRP neurons can inhibit the activation of AgRP neurons, thereby reducing food intake and ameliorating DIO and related metabolic dysfunction. Conversely, overexpression of Gβγ in AgRP neurons promoted hyperphagia and obesity. Mechanistically, we discovered that Gβγ subunits increase AMPK activity to promote mitochondrial fatty acid oxidation and ATP production, ultimately increasing the activity of AgRP neurons and related peptide expression. In conclusion, our study demonstrates that Gβγ subunits regulate feeding and metabolism through multiple bioenergetic processes in AgRP neurons. Gallein, the small-molecule inhibitor of Gβγ subunits emerges as a promising therapeutic candidate for obesity and its associated comorbidities.
The early metabolic cardiac targets of empagliflozin during the development of heart failure, independent of SGLT2 inhibition.
Chen S, Hu X, Wang Q … +14 more , Bakker D, van der Made I, Tebbens AM, Guan Y, Lykidou M, van Goor FKJ, Hollmann MW, Weber NC, van Weeghel M, Schomakers BV, Pieper MP, Coronel R, Creemers EE, Zuurbier CJ
Metabolism · 2026 May · PMID 41707753 · Publisher ↗
BACKGROUND & PURPOSE: Cardiac metabolic changes are known early drivers of heart failure (HF). Recent preclinical research showed that protection against HF by sodium glucose transporter 2 inhibitors (SGLT2i) is independ...
BACKGROUND & PURPOSE: Cardiac metabolic changes are known early drivers of heart failure (HF). Recent preclinical research showed that protection against HF by sodium glucose transporter 2 inhibitors (SGLT2i) is independent of SGLT2 inhibition. Here, we unravel the SGLT2-independent metabolic effects of SGLT2i during early HF, to shed light on the early cardiac metabolic mechanisms through which SGLT2i may confer protection against HF. METHODS: Short-term HF was induced through transverse aortic constriction (TAC) and deoxycorticosterone (DOCA) administration in WT and SGLT2 KO mice, in the presence or absence of Empagliflozin (EMPA). Ten days post-surgery, following in vivo echocardiography, hearts were Langendorff-perfused. The SGLT2-independent metabolic effects of EMPA were determined by: 1) performing stable isotope tracer analysis for C-glucose to asses relative glucose contribution to metabolic pathways via fluxomics (C-glucose perfusion), 2) quantifying metabolic intermediates using metabolomics (LC/MS), 3) evaluating metabolic regulators through Western blot analysis, and 4) analyzing gene expression of metabolic pathways via RNA sequencing. RESULTS: Independent of SGLT2 (i.e., being present in both genotypes), TAC/DOCA resulted in in vivo HF (systolic and diastolic dysfunction) that was prevented by EMPA. The early SGLT2-independent cardiac metabolic properties showed: 1) HF hearts used relatively less glucose for energy production through glycolysis and TCA cycle, with more glucose being diverted toward synthesis of glutamine. In contrast, EMPA enhanced glucose labeling of the distal part of glycolysis without affecting relative glucose contribution to acetyl CoA or TCA intermediates, 2) HF led to increased metabolic intermediates (malate, aspartate, 2-hydroxyglutarate) that are known to drive pathology, whereas EMPA reduced pathology-causing metabolic intermediates (malate, glucose-6-P), together with increased lactate release and ATP content, 3) EMPA increased the metabolic regulator SIRT3 and the insulin-sensitive glucose transporter (GLUT4) without affecting AMPK, and 4) HF decreased fatty acid metabolism gene expression, whereas EMPA increased multiple mitochondrial metabolic pathways (TCA cycle, branched-chained amino acid, fatty acid, mitochondrial respiratory chain complexes), possibly through increased ERRα signaling. CONCLUSION: The early, SGLT2-independent, metabolic mechanism marking HF protection by SGLT2i entail 1) decreases in metabolic intermediates that drive hypertrophy (G6P, malate), 2) boosting glycolysis (GLUT4, distal part glycolysis, lactate release) without shifting glucose/fatty acid oxidation ratio, and 3) activating ERRα/SIRT3 pathway associated with increased gene expression of mitochondrial energy pathways and improved cardiac ATP levels.
Mini-review. Vitamin D for the prevention of type 2 diabetes: Evidence and implications.
Amrein K, Kim SH, Brath H … +2 more , Fasching P, Pittas AG
Metabolism · 2026 May · PMID 41707752 · Publisher ↗
Prediabetes is common worldwide and offers a critical opportunity for interventions to prevent type 2 diabetes. Vitamin D has biologically plausible effects on beta cell function, insulin sensitivity, and the immune syst...
Prediabetes is common worldwide and offers a critical opportunity for interventions to prevent type 2 diabetes. Vitamin D has biologically plausible effects on beta cell function, insulin sensitivity, and the immune system, and observational studies consistently associate higher 25-hydroxyvitamin D (25[OH]D) levels with a lower risk of developing diabetes. Three randomized, double-blind, placebo-controlled trials designed specifically for adults with prediabetes tested moderate-to-high doses of vitamin D (Tromsø, D2d) or an active analog (DPVD). Each study showed a modest reduction in progression to type 2 diabetes. An individual participant data meta-analysis of these trials (n = 4190) demonstrated a 15% relative risk reduction, with greater benefit among those with low baseline 25(OH)D levels or a body mass index less than 30 kg/m. Vitamin D supplementation also increased the likelihood of regression to normal glucose regulation. These findings are further supported by multiple aggregate-data meta-analyses showing a consistent benefit of vitamin D supplementation in adults with prediabetes. Compared with intensive lifestyle interventions, metformin, and incretin-based therapies, vitamin D is inexpensive, safe, accessible, and easy to implement, with an estimated number needed to treat of ∼30. The 2024 Endocrine Society Guideline now recommends vitamin D supplementation for adults with prediabetes at doses above the recommended dietary allowance without requiring routine 25(OH)D testing. Achieving and maintaining a blood 25(OH)D level above 40 ng/mL may confer additional benefit, but the hypothesis needs to be tested in clinical trials.
The multifaceted role of GLP-1 in metabolic disorders, chronic inflammation, and aging: Mechanisms and therapeutic potential.
Li M, Xu S, Cai H … +2 more , Xiao J, Qin Y
Metabolism · 2026 May · PMID 41672302 · Publisher ↗
Glucagon-like peptide-1 (GLP-1), an incretin secreted by intestinal L-cells in response to nutrients, regulates glucose homeostasis by enhancing insulin secretion, suppressing glucagon release, delaying gastric emptying,...
Glucagon-like peptide-1 (GLP-1), an incretin secreted by intestinal L-cells in response to nutrients, regulates glucose homeostasis by enhancing insulin secretion, suppressing glucagon release, delaying gastric emptying, and reducing appetite via hypothalamic signaling. Beyond these canonical actions, emerging evidence reveals GLP-1's pleiotropic functions across multiple systems, with relevance to metabolic disorders, chronic inflammation, and aging-related pathologies. This review summarizes molecular mechanisms underlying GLP-1's protective roles, highlighting its contributions to metabolic balance, inhibition of NF-κB-mediated inflammation, and attenuation of cellular aging through mitochondrial enhancement and autophagy promotion. GLP-1 also influences immune cell function and alleviates hallmarks of senescence, thereby offering therapeutic potential beyond diabetes. We further critically assess the translational potential of GLP-1 receptor agonists (GLP-1RAs), pharmacological agents with superior pharmacokinetics versus native GLP-1, in treating conditions linked to dysregulated metabolism, persistent inflammation, and accelerated aging. Despite demonstrated efficacy in preclinical models and clinical studies, important challenges persist, including inter-individual variability, off-target risks, and uncertainties regarding long-term safety. We conclude by emphasizing the necessity of integrated strategies to target the metabolic-inflammatory-aging axis and by advocating optimization of GLP-1RA formulations, identification of predictive biomarkers, and expansion of their utility for age-associated diseases.
Serum Response Factor (SRF) promotes actin cytoskeletal organization in adipocytes to support adaptive hypertrophic expansion and tissue remodeling during obesity in mice.
So J, Wann J, Kim K … +6 more , Taleb S, Kim HG, Kumari M, Banks AS, Dong XC, Roh HC
Metabolism · 2026 May · PMID 41655957 · Full text
BACKGROUND: Adipocyte hypertrophy, the unique capacity of adipocytes to enlarge in response to energy surplus, is a crucial determinant of metabolic health during obesity. Nonetheless, the molecular mechanisms governing...
BACKGROUND: Adipocyte hypertrophy, the unique capacity of adipocytes to enlarge in response to energy surplus, is a crucial determinant of metabolic health during obesity. Nonetheless, the molecular mechanisms governing this adaptive growth remain incompletely characterized. METHODS: Super-enhancer landscapes in adipocytes were mapped via H3K27ac chromatin immunoprecipitation sequencing analysis of adipocyte nuclei from mice fed either a standard chow diet or high-fat diet (HFD) to identify transcriptional regulators activated under obesogenic conditions. Functional validation was conducted through both in vitro and in vivo experiments, including adipocyte-specific gene deletion mouse models, followed by single-nucleus RNA sequencing. RESULTS: Super-enhancer profiling identified Serum Response Factor (SRF) as a critical driver of actin cytoskeletal remodeling in adipocytes during obesity. SRF was shown to be both necessary and sufficient for regulation of actin cytoskeletal gene expression in 3T3-L1 adipocytes. Adipocyte-specific SRF ablation in mice led to reduced expression of actin cytoskeletal genes, disruption of actin filament organization, and impaired adipocyte enlargement under HFD feeding. Despite comparable body weight, SRF-deficient mice developed exacerbated insulin resistance and ectopic lipid accumulation in the liver and brown adipose tissue, indicative of compromised lipid storage within adipocytes. Single-nucleus RNA-seq further revealed that cell-intrinsic actin cytoskeletal defects in adipocytes propagated to tissue-level dysfunction, impairing vascularization and increasing inflammation. CONCLUSION: These findings establish SRF as a central regulator of actin cytoskeletal organization that promotes healthy adipocyte hypertrophy and adipose tissue remodeling. Enhancing SRF-dependent cytoskeletal remodeling in adipocytes may offer a therapeutic strategy to preserve metabolic health in obesity.
PFKFB3 nuclear translocation improves diabetic retinopathy by attenuating endothelial cell senescence through inhibition of USP7-p53 axis.
Liu P, Shen N, Zhou Y … +12 more , Wu J, Hao M, Zhang S, Wang Y, Wang X, Li H, You Z, Fan H, Xu X, Wang N, Sun D, Wei F
Metabolism · 2026 May · PMID 41655956 · Publisher ↗
BACKGROUND: Endothelial cell (EC) senescence is a key contributor to retinal vascular dysfunction in diabetic retinopathy (DR), yet its molecular mechanisms remain incompletely understood. While PFKFB3 is well recognized...
BACKGROUND: Endothelial cell (EC) senescence is a key contributor to retinal vascular dysfunction in diabetic retinopathy (DR), yet its molecular mechanisms remain incompletely understood. While PFKFB3 is well recognized for its critical function in modulating EC glycolysis and angiogenesis, its contribution to endothelial senescence in DR has not been elucidated. METHODS: Single-cell RNA sequencing was used to profile EC senescence signatures and barrier/tight-junction programs in diabetic retinas. PFKFB3/USP7 abundance and senescence in vivo and in vitro were assessed by Western blotting, SA-β-gal staining, immunofluorescence, and cell-cycle flow cytometry. PFKFB3-USP7 interaction was examined by co-immunoprecipitation, mass spectrometry, and nuclear colocalization. Retinal vascular dysfunction was quantified by Evans blue leakage and PAS-stained retinal trypsin digests. RESULTS: Single-cell analysis identified EC subclusters enriched for senescence transcripts and simultaneously depleted for barrier/tight-junction pathways in diabetic retinas. Hyperglycemia reduced PFKFB3 and impaired its nuclear entry, leading to prominent cellular senescence in vitro and in vivo, and restoration of PFKFB3 effectively reversed this phenotype. By establishing stable endothelial cell lines expressing PFKFB3 only in the nucleus (NLS mutant) or cytoplasm (K472Q mutant), we revealed that anti-senescent activity required PFKFB3 nuclear localization. Nuclear-localized PFKFB3 interacted with USP7, a critical modulator of the p53 pathway, and regulated the USP7-p53 axis by constraining their coupling, thereby promoting proteasomal degradation of p53. As a downstream effector of PFKFB3, USP7 abrogated the protective effect of PFKFB3, whereas its inhibition attenuated hyperglycemia-induced senescence and mitigated retinal vascular dysfunction. CONCLUSIONS: Our findings highlighted the essential role of nuclear PFKFB3 dysfunction and USP7-p53 axis dysregulation in mediating EC senescence under diabetic stress, suggesting that targeting PFKFB3 nuclear translocation may be a novel therapeutic strategy for the prevention of diabetic retinopathy.
A biological-systems-based analysis using proteomic and metabolic network inference reveals mechanistic insights into hepatic steatosis.
Atabaki NN, Coral DE, Pomares-Millan H … +60 more , Smith K, Behjat HH, Koivula RW, Tura A, Miller H, Pinnick KE, Agudelo LZ, Allin KH, Brown AA, Chabanova E, Chmura PJ, Jacobsen UP, Dawed AY, Elders PJM, Fernandez-Tajes JJ, Forgie IM, Haid M, Hansen TH, Jones AG, Kokkola T, Kalamajski S, Mahajan A, McDonald TJ, McEvoy D, Muilwijk M, Tsirigos KD, Vangipurapu J, van Oort S, Vestergaard H, Adamski J, Beulens JW, Brunak S, Dermitzakis ET, Giordano GN, Gupta R, Hansen T, 't Hart LM, Hattersley AT, Hodson L, Laakso M, Loos RJF, Merino J, Ohlsson M, Pedersen O, Ridderstråle M, Ruetten H, Rutters F, Schwenk JM, Tomlinson J, Walker M, Yaghootkar H, Karpe F, McCarthy MI, Thomas EL, Bell JD, Mari A, Pavo I, Pearson ER, Viñuela A, Franks PW
Metabolism · 2026 May · PMID 41655955 · Publisher ↗
OBJECTIVE: To delineate organ-specific and systemic drivers of metabolic dysfunction-associated steatotic liver disease (MASLD), we applied integrative causal inference across clinical, imaging, and proteomic domains in...
OBJECTIVE: To delineate organ-specific and systemic drivers of metabolic dysfunction-associated steatotic liver disease (MASLD), we applied integrative causal inference across clinical, imaging, and proteomic domains in individuals with and without type 2 diabetes (T2D). METHODS: Bayesian network analyses and complementary two-sample Mendelian randomization were used to quantify causal pathways linking adipose distribution, glycemia, and insulin dynamics with liver fat in the IMI-DIRECT prospective cohort study. Data included frequently sampled metabolic challenge tests, MRI-derived abdominal and hepatic fat content, serological biomarkers, and Olink plasma proteomics from 331 adults with new-onset T2D and 964 adults without diabetes, with harmonized protocols enabling replication. RESULTS: High basal insulin secretion rate (BasalISR), estimated via C-peptide deconvolution, emerged as the primary potential causal driver of liver fat accumulation in both cohorts. BasalISR, a clearance-independent measure of β-cell insulin output distinct from peripheral insulin levels, was independently linked to hepatic steatosis. Visceral adipose tissue exhibited bidirectional associations with liver fat, suggesting a self-reinforcing metabolic loop. Of 446 analyzed proteins, 34 mapped to these metabolic networks (27 in the non-diabetes network, 18 in the T2D network, and 11 shared). Key proteins directly associated with liver fat included GUSB, ALDH1A1, LPL, IGFBP1/2, CTSD, HMOX1, FGF21, AGRP, and ACE2. Sex-stratified analyses identified GUSB in females and LEP in males as the strongest protein predictors of liver fat. CONCLUSIONS: BasalISR may better capture early β-cell-driven disturbances contributing to MASLD. These findings outline a multifactorial, sex- and disease stage-specific proteo-metabolic architecture of hepatic steatosis and identify potential biomarkers or therapeutic targets.
Enduring improvements in hepatic insulin sensitivity predict sustained remission of prediabetes during a 3-year lifestyle intervention: results from the PREVIEW multinational diabetes prevention trial.
Zhu R, Guo J, Huttunen-Lenz M … +13 more , Stratton G, Swindell N, Macdonald IA, Handjieva-Darlenska T, Handjiev S, Navas-Carretero S, Poppitt SD, Silvestre M, Schlicht W, Fogelholm M, Martinez JA, Raben A, Brand-Miller J
Metabolism · 2026 May · PMID 41654010 · Publisher ↗
BACKGROUND: Recent investigation advocates the use of prediabetes remission as a goal of diabetes prevention. We aimed to compare changes in metabolic markers in participants with and without sustained remission of predi...
BACKGROUND: Recent investigation advocates the use of prediabetes remission as a goal of diabetes prevention. We aimed to compare changes in metabolic markers in participants with and without sustained remission of prediabetes during a 3-year lifestyle intervention. METHODS: This post-hoc analysis used data from the PREVIEW trial, a 3-year, multinational, multicenter, randomized controlled trial aiming to examine the effects of lifestyle interventions on prevention of type 2 diabetes among high-risk adults. Adult participants with prediabetes and overweight/obesity underwent 8-weeks of rapid weight loss followed by a 148-week lifestyle intervention for weight loss maintenance. Participants who completed the full protocol and had available data (n = 846) were included in the current analysis. Participants were classified into prediabetes maintainers, relapsers, and non-responders according to blood glucose levels at 1 and 3 years. Changes in metabolic markers over 3 years were compared in those who achieved sustained remission (maintainers, n = 102) vs those who failed (non-responders, n = 618), as well as those who were successful at 1 year but then relapsed (relapsers, n = 126). RESULTS: Only 12% participants experienced sustained remission at 3 years. After adjusting for baseline covariates, compared with non-responders, maintainers achieved greater weight loss (mean difference -4.0 kg; 95% CI -5.8, -2.2 kg) and fat mass loss at 3 years. Maintainers also made further improvements in markers of hepatic insulin sensitivity, regardless of weight change. Compared with relapsers, maintainers had greater decreases in weight and fat mass, but changes in visceral adiposity index were similar. Relapsers gradually reverted to an insulin resistant state at 2 and 3 years compared with maintainers, independent of weight change. CONCLUSIONS: In a long-term lifestyle intervention, sustained remission of prediabetes was associated with enduring improvements in hepatic insulin sensitivity, regardless of weight change. In addition to weight loss, targeting hepatic insulin sensitivity per se may help prevent relapse in prediabetes.
Rising burden of MASLD and CKM syndrome in Asia: A decade of trends and future projections.
Duo T, Wen Y, Bian Y … +7 more , Wang Y, Zhang X, Ju J, Lu Y, Wang Z, Wang J, Yang B
Metabolism · 2026 May · PMID 41643809 · Publisher ↗
OBJECTIVE: To analyze epidemiological trends and project the future burden of metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular-kidney-metabolic (CKM) syndrome in Asia using data from th...
OBJECTIVE: To analyze epidemiological trends and project the future burden of metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular-kidney-metabolic (CKM) syndrome in Asia using data from the Global Burden of Disease (GBD) Study. This analysis quantifies the substantial co-occurrence of MASLD and CKM syndrome, which together accounted for 50.9% of the total disease prevalence in Asia in 2021, by evaluating incidence, prevalence, deaths, and disability-adjusted life years (DALYs) from 2010 to 2021. METHODS: Data from the GBD 2021 database were used to assess the burden of MASLD and CKM syndrome in Asia. The study analyzed incidence, prevalence, deaths and DALYs for nine metabolic diseases or related conditions: MASLD, atrial fibrillation and flutter (AF/AFL), ischemic heart disease (IHD), hypertension heart disease (HHD), lower extremity peripheral arterial disease (PAD), type 2 diabetes mellitus (T2DM), stroke, and chronic kidney disease (CKD) due to hypertension (HTN) and T2DM. Age-standardized rates (ASRs) and estimated annual percentage changes (EAPCs) were calculated. The autoregressive integrated moving average (ARIMA) model was applied to forecast the trend of MASLD over the next 20 years. This model, widely used in time-series forecasting, identifies trends, cyclical variations, and random fluctuations to provide scientifically grounded projections. RESULTS: In 2021, the collective burden of the nine CKM-related conditions analyzed (including MASLD) accounted for 50.9% of total disease prevalence and 34.4% of all deaths in Asia, with 12.68 million deaths and 306.82 million DALYs. Among the nine metabolic diseases analyzed, MASLD had the highest incidence and prevalence, with MASLD-related liver cirrhosis (MASLD-LC) and MASLD-related steatohepatitis (MASLD-SH) affecting approximately 786.69 million and 786.65 million individuals, respectively. IHD and stroke were the leading causes of death and DALYs. Between 2010 and 2021, the incidence (MASLD-LC/MASLD-SH: +25.4%) and prevalence (MASLD-LC/MASLD-SH: +38.0%) of MASLD increased substantially. T2DM showed the greatest rise in age-standardized incidence rate (EAPC: +1.7%) and age-standardized prevalence rate (EAPC: +2.0%). Geographically, MASLD represented the predominant metabolic burden in most Asian countries, with the exception of Central and South Asia, where IHD prevailed. ARIMA projections suggest that the MASLD burden will continue to grow, with a projected increase in incidence of approximately 34% compared to 1990 levels (MASLD-LC: +34.01%; MASLD-SH: +34.04%), underscoring the need for timely and proactive interventions. CONCLUSION: MASLD and CKM syndrome constitute a major and growing health challenge in Asia. These findings underscore the need for early diagnosis, targeted interventions, and comprehensive public health strategies. Future research should aim to elucidate the mechanisms of disease interactions, enhance diagnostic criteria, and improve data collection to support more accurate burden estimation and inform evidence-based policymaking.
Efficacy and safety of sepiapterin versus sapropterin in patients with phenylketonuria: Results from the Phase 3, randomized, crossover, open-label, active-controlled AMPLIPHY trial.
Giżewska M, Inwood A, Tyčová R … +20 more , Vijay S, Fjellbirkeland O, van Spronsen F, Venegas-Moreno EM, Guilder L, Burlina A, Peters H, Potter M, Grošelj U, Chakrapani A, Bélanger-Quintana A, Maillot F, Rutsch F, Arnoux JB, Tchan M, Ingalls K, Zhao Z, Hughes C, Smith N, Muntau AC
Metabolism · 2026 May · PMID 41616812 · Publisher ↗
AIM: AMPLIPHY is the first Phase 3 study comparing sepiapterin versus sapropterin in children and adults with phenylketonuria (PKU). METHODS: AMPLIPHY was an international, Phase 3, two-part, open-label study in particip...
AIM: AMPLIPHY is the first Phase 3 study comparing sepiapterin versus sapropterin in children and adults with phenylketonuria (PKU). METHODS: AMPLIPHY was an international, Phase 3, two-part, open-label study in participants with PKU aged ≥2 years. Participants responsive to sepiapterin (60 mg/kg/day) in Part 1 (≥20% reduction in blood phenylalanine [Phe]) entered Part 2, a crossover treatment period, and were randomized 1:1 to alternative treatment sequences of sepiapterin (60 mg/kg/day, licensed dosage) and sapropterin (20 mg/kg/day, maximum licensed dosage) for 4 weeks each, with a 14-day washout between treatments. The primary endpoint was mean change in blood Phe from baseline to Weeks 3-4 of each treatment period (Part 2). RESULTS: Of 82 participants enrolled, 67 (81.7%) and 62 (75.6%) had reductions in blood Phe ≥20% and ≥30%, respectively, in Part 1. Sixty-two participants were randomized in Part 2 (mean [SD] age, 15.8 [10.8] years). In the primary analysis set (≥30% reduction in blood Phe in Part 1, n = 58), mean (SD) baseline blood Phe before sepiapterin and sapropterin treatment was 725.8 (302.1) and 790.4 (370.0) μmol/L, respectively. Least-squares mean (SE) reduction in blood Phe from baseline was -437.0 (28.0) and -256.6 (28.2) μmol/L, respectively, representing a least-squares mean difference of -180.4 μmol/L (95% CI: -229.5, -131.4; p < 0.0001) and a relative 70% greater reduction with sepiapterin versus sapropterin. Both treatments were well tolerated, with safety profiles consistent with previous reports. CONCLUSIONS: Sepiapterin was superior to the highest approved dose of sapropterin in lowering blood Phe. No new safety signals were observed. The trial was registered in the UK Clinical Study Registry, ISRCTN, on January 29, 2024 (ID number, ISRCTN79102999; https://www.isrctn.com/ISRCTN79102999).
HMGCS2 desuccinylation modulates acetoacetate to drive tubule-macrophage inflammatory crosstalk in diabetic kidney disease.
Lin Z, Lv D, Zha H … +7 more , Liu H, Peng R, Yang J, Li W, Liao X, Sun Y, Zhang Z
Metabolism · 2026 Apr · PMID 41580118 · Publisher ↗
Mitochondrial dysfunction in renal tubular epithelial cells (TECs) is a hallmark of diabetic kidney disease (DKD), accompanied by macrophage infiltration, yet how metabolic perturbations in TECs-macrophage driven inflamm...
Mitochondrial dysfunction in renal tubular epithelial cells (TECs) is a hallmark of diabetic kidney disease (DKD), accompanied by macrophage infiltration, yet how metabolic perturbations in TECs-macrophage driven inflammation remains unclear. Here, we identify 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), the rate-limiting enzyme of ketogenesis, as a critical mediator linking tubular mitochondrial stress to macrophage M1 polarization in DKD. In mice subjected to DKD, conditional knockout HMGCS2 in TECs decreases mitochondrial fission of TECs, M1 macrophage infiltration and tubular inflammatory injury. Combining LC-MS/MS and ketone flux detection reveals that desuccinylated HMGCS2 produced more acetoacetate (AcAc) than beta-hydroxybutyrate (β-HB) in TECs of DKD. Mechanistically, Signal Transducer and Activator of Transcription 3 (STAT3) promotes Hmgcs2 transcription and sirtuin 5 (SIRT5) activates HMGCS2 through lysine desuccinylation at K367, which promotes AcAc overload shuttling from TECs to macrophages. AcAc acts as a signaling metabolite to activate the MIF/ERK pathway, driving M1 polarization and amplifying a pro-inflammatory feedback loop of tubular injury. In addition, AAV9-mediated Hmgcs2 silencing therapy improves tubular inflammatory injury and attenuates DKD progression. Taken together, this study unveils a tubule-macrophage metabolic crosstalk axis mediated by HMGCS2-driven AcAc accumulation, which couples mitochondrial stress to immune response in DKD.
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