Diabetes & Metabolism[JOURNAL]
Sun
200 papers
Emerging incretin- and multi-agonist-based treatments - the continued refinement and continuous expansion of a potent therapeutic armamentarium for cardio-kidney-liver-metabolic diseases and beyond.
Muzurović E, Katsiki N, Volčanšek Š … +3 more , Plescia F, Rizzo M, Mantzoros CS
Metabolism · 2026 Apr · PMID 41564595 · Publisher ↗
While the use of glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) has achieved a central position in our therapeutic armamentarium, new and innovative incretin- and multi-agonist-based treatment strategies hold fu...
While the use of glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) has achieved a central position in our therapeutic armamentarium, new and innovative incretin- and multi-agonist-based treatment strategies hold further promise as potential game-changers for obesity and cardio-kidney-liver-metabolic diseases. Molecular pathways of GLP-1, glucose-dependent insulinotropic polypeptide (GIP), amylin, glucagon and peptide YY have been consistently involved in improved outcomes associated with obesity and related disorders. Single, dual, and even triple drug combinations are being researched throughout all phases of clinical trials. The similarities in GLP-1, GIP, and glucagon peptide sequences enable the development of unimolecular multi-receptor activating agonists and/or antagonists. Furthermore, subcutaneously administered peptides are being supplemented with oral analogs currently in development. Both well-designed clinical trials and real-world evidence are fuelling the development of incretin and multi-agonist-based therapies, thereby holding the promise to deliver an increasing double-digit percent weight loss in addition to addressing many obesity-related comorbidities and complications. It is increasingly evident that early initiation of incretin-based therapy across a broad spectrum of cardio-kidney-metabolic disorders improves body weight, dysglycemia, and cardiovascular risk factor management and consequently is expected to reduce cardio-kidney-liver-metabolic and vascular morbidity and mortality and soon most probably those from obesity-related malignancies, Alzheimer's, and other neurocognitive diseases. This review explores new incretin- and multi-agonist-based therapies undergoing clinical trials for chronic weight management, type 2 diabetes mellitus with its complications, chronic kidney disease, metabolic dysfunction-associated steatotic liver disease and obstructive sleep apnea; it also highlights areas of uncertainty regarding the potency, safety, tolerability, and sustainability of incretin-based approaches for obesity and cardio-kidney-liver-metabolic disorders and finally, we discuss future directions.
Personalizing bariatric metabolic surgery: Predictors of weight-loss success and risk of weight recurrence.
Panunzi S, Russo S, Pompa M … +17 more , De Gaetano A, Verrastro O, Tuccinardi D, Guidone C, Gissey LC, Casella G, Casella Mariolo JR, Angelini G, Pattou F, Sabatini S, Gastaldelli A, Franks PW, Al Ozairi E, Sparso T, Bornstein S, Le Roux CW, Mingrone G
Metabolism · 2026 Apr · PMID 41539472 · Publisher ↗
BACKGROUND: Bariatric metabolic surgery (Roux-en-Y gastric bypass [RYGB] and sleeve gastrectomy [SG]) effectively treats obesity and type 2 diabetes; however, weight loss varies, necessitating predictive factors. METHODS...
BACKGROUND: Bariatric metabolic surgery (Roux-en-Y gastric bypass [RYGB] and sleeve gastrectomy [SG]) effectively treats obesity and type 2 diabetes; however, weight loss varies, necessitating predictive factors. METHODS: We analysed 12- and 24-month weight loss data from 811 patients (RYGB or SG). Factor Analysis of Mixed Data and neural network (NN) modelling identified distinct patient phenotypes and predicted weight-loss patterns. A comparative analysis evaluated weight loss and recurrence between the two procedures. FINDINGS: RYGB showed significantly greater weight loss than SG at both 12 (30.3% vs. 25.4%; p < 0.001) and 24 months (26.3% vs. 21.4%; p < 0.001). SG revealed greater variability with bimodal weight loss distributions. Unsupervised clustering of SG patients highligheted three phenotypes: the highest responders were women with favourable metabolic profiles; the lowest responders were mostly men with insulin resistance and diabetes. A NN achieved an overall accuracy of 72.5% in predicting 12-month weight loss from baseline characteristics. In RYGB, clustering was less distinct, though baseline metabolic health influenced weight trajectories. A NN predicted weight recurrence versus sustained loss with 74% accuracy. Poor outcomes were associated with higher baseline glucose, insulin resistance, and dyslipidemia; younger age and absence of diabetes predicted better responses. RYGB was superior to SG, even for metabolic high-risk individuals. INTERPRETATION: Baseline metabolic health predicts weight-loss outcomes and recurrence risk. RYGB offered greater and more consistent mid-term weight loss, especially benefiting metabolically high-risk patients. Procedure choice must be individualized accounting for specific risk profile and potential complications. These results advocate for a precision-medicine approach in bariatric procedure selection.
Bone inflammation in postmenopausal women with type 2 diabetes or obesity in relation to Wnt signaling and bone strength.
Leanza G, Faraj M, Cannata F … +14 more , Viola V, Pellegrini N, Tramontana F, Pedone C, Vadalà G, Piccoli A, Strollo R, Zalfa F, Nevi L, Carotti S, Civitelli R, Maccarrone M, Papalia R, Napoli N
Metabolism · 2026 Apr · PMID 41519225 · Publisher ↗
BACKGROUND AND AIM: Type 2 diabetes (T2D) and obesity (OB) are associated with chronic inflammation and increased fracture risk. We aimed to study the impact of inflammation and Wnt pathway regulation on bone health in s...
BACKGROUND AND AIM: Type 2 diabetes (T2D) and obesity (OB) are associated with chronic inflammation and increased fracture risk. We aimed to study the impact of inflammation and Wnt pathway regulation on bone health in subjects with T2D or OB. METHODS: This study involved 63 postmenopausal women (aged ≥65 years) undergoing hip arthroplasty, including 19 with T2D, 17 with OB, and 27 controls (CTRL). We assessed body composition using dual-energy X-ray absorptiometry (DXA), bone microarchitecture with microcomputed tomography (μCT), and bone strength through compression tests. Bone tissue was collected for gene and protein expression analysis, and serum samples were obtained for cytokine measurement. RESULTS: Bone gene expression analysis revealed increased tumor necrosis factor-alpha (TNF-α; p < 0.0001) and reduced adiponectin (ADIPOQ; p = 0.0041) in T2D. Secreted frizzled-related protein 5 (SFRP5) was elevated in both T2D (p < 0.0001), whereas the OB group showed only a trend toward higher expression (p = 0.060) after BMI adjustment. Interleukin-10 (IL10) was reduced in both T2D (p = 0.0005), while in the OB group IL10 was not reduced after BMI adjustment. Importantly, the Wnt inhibitor sclerostin (SOST) was elevated in both T2D and OB subjects (p < 0.0001), while wingless-type family member 10B (WNT10B) and lymphoid enhancer-binding factor 1 (LEF1) were reduced in both T2D (WNT10B: p = 0.0070, LEF1: p < 0.0001) and OB (WNT10B: p = 0.0078, LEF1: p = 0.0199), even after BMI adjustment. Protein expression analysis by immunohistochemistry confirmed reduced non-phosphorylated (active) β-catenin in bone tissue of both T2D and OB subjects. Moreover, key inflammatory markers were associated with alterations in Wnt pathway-related genes. Consistently, serum cytokine analysis showed increased inflammation, with higher TNF-α (p = 0.0084) and lower ADIPOQ (p = 0.0402) levels in T2D, and higher interleukin-6 (IL-6; p = 0.0003) in OB compared to CTRL. Finally, serum TNF-α (r = -0.3557, p = 0.0112) and IL-6 (r = -0.3881, p = 0.0194) levels negatively correlated with bone strength. CONCLUSIONS: In conclusion, our results suggest that T2D is associated with increased bone inflammation, and Wnt signaling is downregulated in both T2D and obesity. These observations lay the groundwork for future mechanistic studies on bone fragility in metabolic diseases.
Global glucagon-like peptide-2 receptor activation linked to increased obesity risk in the UK Biobank.
Gerlach PA, Gadgaard S, Madsen JS … +6 more , Lindquist P, Lorente JS, Faas F, Gabe MBN, Rosenkilde MM, Hauser AS
Metabolism · 2026 Apr · PMID 41519224 · Publisher ↗
OBJECTIVE: The glucagon-like peptide-2 receptor (GLP-2R) is recognized as a potential target for the treatment of obesity and type 2 diabetes (T2D). Yet, the impact and mechanism of GLP-2R activation on these metabolic t...
OBJECTIVE: The glucagon-like peptide-2 receptor (GLP-2R) is recognized as a potential target for the treatment of obesity and type 2 diabetes (T2D). Yet, the impact and mechanism of GLP-2R activation on these metabolic traits remain unclear in humans. METHODS: We conducted in vitro pharmacological characterization of 30 naturally occurring GLP-2R missense variants identified from the UK Biobank, assessing receptor activity via cyclic adenosine monophosphate (cAMP) production and β-arrestin 2 recruitment. To study the effect of GLP-2R activation on metabolic traits, we categorized variants into functional groups based on their signaling profiles and performed genetic association tests in ∼500,000 UK Biobank participants. RESULTS: We experimentally identified variants with both increased and decreased effects on receptor signaling and computationally identified an additional 34 predicted Loss-of-Function (pLoF) variants. Notably, the most frequent GLP-2R variant, D470N, with an allele frequency of 32% in the UK population, displayed increased cAMP production. Mechanistically, the increased cAMP production of D470N is likely linked to reduced β-arrestin recruitment and reduced internalization. Genetic associations showed that D470N was linked to increased risk of obesity, T2D, and higher Body Mass Index (BMI), body fat, glycated hemoglobin (HbA1c), and diastolic/systolic blood pressure. In contrast, Loss-of-Function (LoF) variants were associated with a decreased risk of obesity and reduced body fat percentage. CONCLUSION: Our findings suggest that global GLP-2R activation, encompassing the effects across all tissues, is associated with increased risk of obesity. This study highlights the role of the GLP-2R in metabolic diseases, guiding the future development of biased GLP-2R ligands and the potential adverse effects of GLP-2R modulation.
Proteomic effects of short-term liraglutide vs. placebo in a blinded crossover RCT: Implications for efficacy, safety, and comparison with semaglutide.
Stefanakis K, Gutierrez de Piñeres V, Veeragandham P … +1 more , Mantzoros CS
Metabolism · 2026 Apr · PMID 41513169 · Publisher ↗
BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert cardiometabolic benefits beyond weight loss, yet their systemic proteomic mechanisms remain incompletely defined. We profiled short-term liraglutide-...
BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert cardiometabolic benefits beyond weight loss, yet their systemic proteomic mechanisms remain incompletely defined. We profiled short-term liraglutide-induced protein changes and compared them with published semaglutide signatures. METHODS: In a randomized, double-blind, placebo-controlled, crossover trial (NCT02944500), 20 adults with obesity received liraglutide 3 mg daily or placebo for 5 weeks, separated by a 3-week washout. Plasma and serum samples underwent SomaScan v4.1 profiling of 6249 proteins. Mixed-effects models tested Time×Treatment interactions with and without weight adjustment. Results were benchmarked against the 30-protein semaglutide STEP 1/2 signature. RESULTS: Liraglutide significantly modulated 124 proteins (57 FDR < 0.05); 85 % of effects persisted after weight adjustment, indicating largely weight-independent actions. Upregulated proteins included pancreatic enzymes (PNLIP, CTRB1/2, PRSS2), while endothelial and fibrotic markers (ACE, NOS3, FAP) were downregulated. Myostatin (MSTN) was strongly suppressed (log₂ fold change -0.41; p = 1.7 × 10), with concurrent rises in its inhibitors WFIKKN2 and BMPR1A. Liraglutide shared 70-75 % directional overlap with semaglutide, with 25-30 % unique effects enriched in vascular, neurodevelopmental, and musculoskeletal pathways. A semaglutide-based classifier distinguished liraglutide from placebo (AUC = 0.82; sensitivity 0.89; specificity 0.60). Downregulated proteins were genetically linked to coronary artery disease and type 2 diabetes (FDR < 0.05). CONCLUSIONS/INTERPRETATION: Short-term liraglutide reproduces the core GLP-1RA proteomic fingerprint while uniquely suppressing myostatin and vascular remodeling pathways. These rapid, largely weight-independent molecular responses indicate early cardioprotective and myostatin-inhibitor signaling changes that could be relevant for future muscle-preserving strategies, supporting individualized GLP-1RA use beyond weight loss alone.
Essential role of endothelial T-cadherin in the transcytosis of circulating high-molecular-weight adiponectin to sub-vascular tissues.
Shiode S, Fujishima Y, Fukuoka K … +16 more , Inoue S, Shirono A, Shirakura K, Okada Y, Koyama Y, Kondo Y, Fujii K, Kawada K, Nagao H, Obata Y, Fukuda S, Kita S, Shimada S, Maeda N, Nishizawa H, Shimomura I
Metabolism · 2026 Apr · PMID 41490662 · Publisher ↗
BACKGROUND: Adiponectin, an adipocyte-derived protein, has diverse organ-protective effects, which are associated with its accumulation in vascular endothelial cells (VECs) as well as in various extravascular cell types,...
BACKGROUND: Adiponectin, an adipocyte-derived protein, has diverse organ-protective effects, which are associated with its accumulation in vascular endothelial cells (VECs) as well as in various extravascular cell types, including skeletal muscle cells and cardiomyocytes. T-cadherin, a high-affinity binding partner for multimeric adiponectin, facilitates this accumulation; however, the mechanism by which high-molecular-weight (HMW) adiponectin transverses the endothelium remains unclear. METHOD AND RESULTS: We showed that tamoxifen-induced T-cadherin deficiency in VECs alone significantly increased plasma adiponectin levels, similar to inducible systemic T-cadherin deletion. The intravenous administration of adiponectin to adiponectin-deficient VEC-specific T-cadherin knockout mice markedly impaired the clearance of intravenously injected adiponectin, resulting in significant reductions in the accumulation of hexameric and HMW adiponectin, particularly the octadecameric (18-mer) form, not only in VECs, to note, but also in skeletal muscle and heart tissues. Furthermore, endothelial T-cadherin deficiency led to activation of innate immune signaling and cardiac remodeling, even under physiological conditions. In vitro experiments using MDCK II cells demonstrated that T-cadherin mediated the apical-to-basolateral transport of 18-mer adiponectin, largely preserving its HMW form. Additionally, intracellular adiponectin colocalized with the recycling endosome marker RAB11, and Rab11 deficiency significantly impaired its transcytosis. Similarly, in human VECs, T-cadherin knockdown significantly reduced basolateral adiponectin transport. CONCLUSIONS: These findings identify vascular endothelial T-cadherin as a key mediator of HMW adiponectin transcytosis via the recycling endosome pathway, enabling its traversal from the circulation to sub-vascular tissues/cells and offering a mechanistic basis for the systemic organ-protective effects of adiponectin.
Consensus statement on vitamin D role in metabolic health.
Giustina A, di Filippo L, Aleksova A … +18 more , Bollerslev J, Colao AM, Dawson-Hughes B, Donini LM, Ebeling PR, Lazaretti-Castro M, Lorusso R, Luzi L, Marcocci C, Minisola S, Napoli N, Pittas AG, Rizzoli R, Rovere Querini P, Santini F, Schafer AL, Virtanen JK, Bilezikian JP
Metabolism · 2026 Mar · PMID 41435994 · Publisher ↗
The 8th International Conference Controversies in Vitamin D, held in September 2024, convened leading experts to address the multifaceted role of vitamin D in human health. Key discussions focused on its influence on met...
The 8th International Conference Controversies in Vitamin D, held in September 2024, convened leading experts to address the multifaceted role of vitamin D in human health. Key discussions focused on its influence on metabolic health, including effects on sarcopenia, muscle function, and energy metabolism, as well as its role in obesity, cardiovascular health, and diabetes. Preclinical evidence was presented, suggesting a pivotal role of vitamin D in regulating muscle function and repair, potentially preventing sarcopenia. A relationship between low vitamin D (25[OH]D) concentrations and increased risk of cardiovascular diseases and diabetes was supported by several preclinical and clinical studies. Vitamin D supplementation was recently demonstrated to help improve glycemia and reduce the progression to diabetes and increase the likelihood of regression to normal glucose regulation in adults with prediabetes. Despite mixed outcomes from large, population-based randomized clinical trials, the conference underscored the critical need for personalized research, through disease-specific clinical trials, to fully elucidate the therapeutic potential of vitamin D supplementation, particularly in chronic conditions such as cardiovascular diseases and diabetes. In conclusion, while vitamin D demonstrates considerable promise in modifying a wide array of metabolic health concerns, rigorous scientific inquiry is essential to deepen our understanding of its mechanisms as well as potential protective effects and establish evidence-based guidelines for supplementation. This growing body of work has the potential to significantly enhance clinical outcomes and improve public health strategies, calling for continued exploration and collaboration in the field of vitamin D research.
Metabolic and immune dysfunction at the crossroads between type 1 diabetes and neurodegeneration.
D'Addio F, Bucciarelli L, Lunati ME … +1 more , Fiorina P
Metabolism · 2026 Mar · PMID 41418944 · Publisher ↗
A growing body of evidence suggests that neurogenerative disorders are increasingly common in individuals with type 1 diabetes (T1D) and should be considered part of the heterogeneous impairment of the nervous system lin...
A growing body of evidence suggests that neurogenerative disorders are increasingly common in individuals with type 1 diabetes (T1D) and should be considered part of the heterogeneous impairment of the nervous system linked to the T1D condition. The already established association between brain health and blood glucose metabolic control pushes to normalize glycemia in individuals with neurodegenerative diseases as well as in those with T1D. Normoglycemia has, indeed, been associated with reduced brain atrophy and preserved neuronal plasticity and function. Interestingly, immune dysregulation recently demonstrated in neurodegenerative diseases may be highly relevant given the autoimmune nature of T1D. Poor glycemic control and a disrupted immune response may act as common pathogenic mechanisms that increase the incidence of neurodegenerative disorders in individuals with T1D and may unveil new diagnostic and therapeutic paths for future clinical advancements. In this narrative review, we summarize new evidence showing that brain damage and cognitive dysfunction are linked to T1D and delineate the role of altered glycemic control, neuronal loss and immune dysregulation. We also discuss novel therapeutic approaches that target the aforementioned mechanisms and may help prevent the onset of neurodegenerative disorders in individuals with T1D.
Epicardial adipose tissue produces L-3-hydroxybutyrate in advanced heart failure: direct analysis of fat metabolic remodeling.
Riecan M, Kasperova BJ, Vondrackova M … +14 more , Janovska P, Haasova E, Adamcova K, Ivak P, Hlavacek D, Kroupova K, Cajka T, Kopecky J, Štemberková Hubáčková S, Mraz M, Netuka I, Melenovsky V, Haluzik M, Kuda O
Metabolism · 2026 Feb · PMID 41349791 · Publisher ↗
BACKGROUND: Heart failure (HF) progression involves complex metabolic and multi-organ alterations, but the specific adaptations in adipose tissue are not fully understood. AIMS: We aimed to characterize the metabolic rem...
BACKGROUND: Heart failure (HF) progression involves complex metabolic and multi-organ alterations, but the specific adaptations in adipose tissue are not fully understood. AIMS: We aimed to characterize the metabolic remodeling of epicardial (EAT) and subcutaneous (SAT) adipose tissues in HF with reduced ejection fraction (HFrEF), focusing on lipid metabolism, fatty acid oxidation, and ketogenesis. METHODS: Clinical and metabolomic profiling were performed on metabolically stable controls (n = 34), patients with mild HFrEF (n = 45), and severe HFrEF (n = 129). Metabolomics profiling identified over 800 metabolites in EAT and SAT. Clustering and pathway enrichment analyses defined depot-specific metabolic shifts across HF stages, while gene expression analyses provided mechanistic support. RESULTS: Advancing HF was associated with declining cardiac function, systemic congestion, and a metabolic shift toward catabolism. Metabolomics revealed depot-specific adaptations: SAT transitioned smoothly to enhanced lipolysis, whereas EAT demonstrated impaired triacylglycerol replenishment and disrupted final turn of β-oxidation spiral. Both depots increased reliance on acylcarnitine degradation and lipolysis; however, EAT was uniquely characterized by late-stage impairment in mitochondrial and peroxisomal fatty acid oxidation, leading to elevation of 3-hydroxybutyrate and hydroxybutyrylcarnitine tissue levels. Ex vivo analyses of EAT explants showed significantly increased fraction of L-3-hydroxybutyrate enantiomer, produced by EAT, compared to D-3-hydroxybutyrate enantiomer originating from the liver. CONCLUSIONS: HF progression drives major, depot-specific metabolic remodeling in adipose tissue. In advanced HF, EAT shows impaired fatty acid oxidation and enhanced local production of L-3-hydroxybutyrate in the vicinity of myocardium, highlighting the close metabolic cooperation in nutrient supply between EAT and the heart muscle through the coronary circulation.
Effect of GLP-1 receptor agonists and co-agonists on atrial fibrillation risk in overweight or obesity: systematic review and meta-analysis of randomized controlled trials.
Karakasis P, Vlachos K, Antoniadis AP … +4 more , Siontis KC, Patoulias D, Fragakis N, Mantzoros CS
Metabolism · 2026 Feb · PMID 41349790 · Publisher ↗
BACKGROUND AND AIMS: Overweight and obesity represent major modifiable determinants of atrial fibrillation (AF) incidence and arrhythmia outcomes after AF ablation therapy. Glucagon-like peptide-1 receptor agonists (GLP-...
BACKGROUND AND AIMS: Overweight and obesity represent major modifiable determinants of atrial fibrillation (AF) incidence and arrhythmia outcomes after AF ablation therapy. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and their next-generation co-agonists exert potent weight-lowering and cardiometabolic effects and may therefore confer antiarrhythmic effects. This meta-analysis aimed to quantitatively assess the effect of GLP-1-based therapies on the risk of AF among individuals with overweight or obesity. METHODS: A systematic search of Medline, Scopus, and the Cochrane Library was conducted for randomized controlled trials (RCTs) through October 29, 2025. Data were analyzed using random-effects pairwise meta-analysis. RESULTS: Twenty-four RCTs encompassing 40,694 participants were included. Compared with placebo, treatment with GLP-1RAs or co-agonists resulted in a 18 % relative reduction in AF risk (Risk Ratio = 0.82; 95 % confidence interval, 0.70-0.96; P = 0.012; I = 0 %). No significant between-subgroup differences were observed according to agent type (single-, dual-, or triple-receptor agonists), individual compound, baseline BMI category (overweight/obesity vs. obesity alone), diabetes inclusion criteria, trial design [cardiovascular outcomes trial (CVOT) vs. non-CVOT], or administration route (oral vs. subcutaneous). Meta-regression analyses identified no significant effect modification by the magnitude of weight reduction or concomitant SGLT2 inhibitor use. CONCLUSIONS: Among individuals with overweight or obesity, GLP-1RAs and co-agonists were associated with a lower risk of incident AF event. This cardioprotective benefit may, at least in part, operate independently of the magnitude of weight loss.
Imeglimin ameliorates MASLD by targeting PEN2 to activate AMPK pathway.
Li J, Zhang R, Zeng X … +9 more , Xu W, Gao L, He S, Wu B, Ma Y, Nie Y, Shirakawa J, Xia H, Li W
Metabolism · 2026 Feb · PMID 41308829 · Publisher ↗
BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent and increasingly chronic liver disorder with increasing global incidence, closely linked to prolonged high-fat d...
BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent and increasingly chronic liver disorder with increasing global incidence, closely linked to prolonged high-fat diet (HFD)-induced metabolic impairment. Although imeglimin, an antidiabetic agent known to improve insulin resistance, has demonstrated therapeutic potential in metabolic diseases, its effects and underlying molecular mechanism in MASLD remain unclear. APPROACH AND RESULTS: In this study, we employed a long-term (48-week) high-fat diet-induced murine model of MASLD to recapitulate human disease progression, then treated those mice with imeglimin for 6 months to investigate its therapeutic effects. Imeglimin treatment improved insulin resistance, restored liver function, attenuated hepatic inflammation, and promoted hepatocyte viability. PEN2, a component of the γ-secretase complex, is identified as the key target of imeglimin. The therapeutic effects of imeglimin are abrogated in liver-specific Pen2-deficient mice or upon pharmacologic inhibition of AMP-activated protein kinase (AMPK), indicating that activation of PEN2-AMPK signaling is required for its beneficial effects. Furthermore, we found that imeglimin also protected human pluripotent stem cell (hPSC)-derived hepatocyte-like cells from free fatty acid (FFA)-induced lipid accumulation. CONCLUSION: Collectively, our findings indicate that imeglimin ameliorates hepatic lipotoxicity by targeting PEN2 to activate AMPK axis, suggesting its potential as a new drug for MASLD treatment in the near future.
Metabolic reprogramming in diabetic foot ulcers: mechanisms, therapeutic implications and future perspectives.
Jinyi L, Xianguang D, Yuhan D … +4 more , Haoyue H, Zhongyu X, Lianhui W, Xu J
Metabolism · 2026 Feb · PMID 41285352 · Publisher ↗
As a devastating complication, diabetic foot ulcer (DFU) is characterized by chronic, nonhealing wounds due to vasculopathy and neuropathy. It has emerged as a most challenging chronic disease worldwide, affecting millio...
As a devastating complication, diabetic foot ulcer (DFU) is characterized by chronic, nonhealing wounds due to vasculopathy and neuropathy. It has emerged as a most challenging chronic disease worldwide, affecting millions of people worldwide. The higher mortality and disability rates urgently require innovative therapeutic strategies. Recently, different from nanotechnology, metabolic reprogramming is believed to be associated with the occurrence and progression of various diseases (including cancer, obesity and neurodegenerative diseases). They can alter their cellular metabolism (involving glucose, lipid, and amino acid metabolism) to cope with different external stimuli and pressures. As a novel potential strategy, metabolic reprogramming also exhibits great potential to improve the wound healing of DFU. This review aims to summarize the current knowledge, biological characteristics, and underlying mechanisms of metabolic reprogramming in DFU. And we propose their potential therapeutic implications to improve wound healing and prevent complications in DFU. In addition, we also highlight the current challenges and the future perspectives.
Induction of Yin Yang 1 (YY1) overexpression in mature adipocytes promotes dysfunctional adipose tissue and systemic insulin resistance in mice.
Pedersen L, Gliniak CM, Dale TM … +8 more , Zhu Q, Li C, Funcke JB, Crewe C, Luo J, Palluth L, Zhu Y, Scherer PE
Metabolism · 2026 Feb · PMID 41265559 · Full text
The ubiquitous transcription factor Ying Yang 1 (YY1) plays a fundamental role in multiple biological processes and is believed to regulate up to 10 % of all human genes. In thermogenic brown adipose tissue, YY1 has been...
The ubiquitous transcription factor Ying Yang 1 (YY1) plays a fundamental role in multiple biological processes and is believed to regulate up to 10 % of all human genes. In thermogenic brown adipose tissue, YY1 has been linked to controlling mitochondrial gene expression and regulating cellular oxidative respiration, protecting against diet-induced obesity and alterations in energy balance. The role of YY1 in non-thermogenic, white adipose tissue, on the other hand, remains largely unknown. Here, we show that adipocyte-specific induction of YY1 promotes dysfunctional adipose tissue and systemic insulin resistance in mice. Long-term YY1 induction in mature adipocytes leads to reduced weight gain, systemic insulin resistance, and increased liver steatosis in comparison to control littermates. In contrast, brown adipose tissue-specific YY1 overexpression has little effect on mice fed a high-fat diet. In an obesogenic environment, acute ectopic adiponectin promoter-driven YY1 expression promotes weight loss, cell death, and adipose tissue inflammation. Underlying the observed reduction in adipose tissue mass, we find that YY1 controls gene networks related to adipose tissue expansion, lipid anabolic pathways (hypertrophy), and hyperplasia (adipogenesis). Taken together, our results demonstrate novel roles of Yy1 in white adipose tissue. This versatile transcription factor regulates central aspects of white adipose tissue biology that are essential for maintaining whole-body physiology.
GLP-1RAs and tirzepatide may reduce heart failure risk in obese but not in non-obese patients with cardiovascular or renal disease: A systematic review and meta-analysis.
Zhang J, Guan X, Kong M … +3 more , Xia M, Yu Y, Zhang C
Metabolism · 2026 Feb · PMID 41207615 · Publisher ↗
BACKGROUND: Cardiovascular disease (CVD) and chronic kidney disease (CKD) frequently coexist, with obesity and type 2 diabetes (T2D) being major contributors to adverse outcomes. Glucagon-like peptide-1 receptor agonists...
BACKGROUND: Cardiovascular disease (CVD) and chronic kidney disease (CKD) frequently coexist, with obesity and type 2 diabetes (T2D) being major contributors to adverse outcomes. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and tirzepatide have shown cardiorenal benefits beyond glycemic control, but their efficacy across metabolic phenotypes remains unclear. METHODS: This review was prospectively registered in PROSPERO (CRD420251088042). PubMed, Embase, Web of Science, and Cochrane Library were searched (January 2015-July 2025) for RCTs comparing GLP-1RAs or tirzepatide with placebo in patients with cardiovascular or renal disease. Subgroup analyses were performed according to T2D and obesity status. RESULTS: A total of 18 RCTs (n = 97,800) involving eight GLP-1RAs and tirzepatide were included, primarily enrolling patients with established cardiovascular or renal disease. GLP-1RAs significantly reduced the risk of the primary composite outcome (RR 0.88, 95 % CI 0.84-0.91, P < 0.001). GLP-1RAs and tirzepatide also significantly reduced the risk of death from any cause (RR 0.88, 95 % CI 0.84-0.92, P < 0.001), and death from cardiovascular causes (RR 0.88, 95 % CI 0.83-0.93, P < 0.001). Although the overall effect of GLP-1RAs on hospitalization for heart failure was not statistically significant (RR 0.92, 95 % CI 0.78-1.08), a potential benefit was observed in obese patients (P for interaction = 0.02), warranting further investigation. GLP-1RAs showed favorable overall safety profile, with a lower incidence of serious adverse events (RR 0.93, 95 % CI 0.89-0.99, P = 0.01) and cardiac adverse events (RR 0.90, 95 % CI 0.85-0.96, P < 0.01) compared with placebo. CONCLUSION: In patients with cardiovascular or renal disease, GLP-1RAs and tirzepatide provide consistent cardiovascular and renal protection, with a possible benefit in reducing hospitalization for heart failure among individuals with obesity.
Lifestyle intervention is more effective in high 1-hour post-load glucose than in prediabetes for restoring β-cell function, reducing ectopic fat, and preventing type 2 diabetes.
Wang Y, Sandforth A, Jumprtz-von Schwartzenberg R … +12 more , Ganslmeier M, Cheng Y, Sandforth L, Katzenstein S, Machann J, Schick F, Kantartzis K, Preissl H, Fritsche A, Stefan N, Bergman M, Birkenfeld AL
Metabolism · 2026 Jan · PMID 41192753 · Publisher ↗
BACKGROUND: High 1-h-post-load plasma glucose (1 h-PG) is an early diabetes risk marker. We hypothesized that isolated high 1 h-PG represents an intermediate state between normal glucose regulation (NGR) and impaired glu...
BACKGROUND: High 1-h-post-load plasma glucose (1 h-PG) is an early diabetes risk marker. We hypothesized that isolated high 1 h-PG represents an intermediate state between normal glucose regulation (NGR) and impaired glucose regulation (IGR) and is amendable to greater lifestyle intervention (LI) benefit. METHODS: In the Tübingen Lifestyle Intervention Program, 317 people with either NGR, IGR or isolated high 1 h-PG without IGR underwent LI for 9 months to achieve ≥5 % weight loss. RESULTS: Before LI initiation, insulin sensitivity and β-cell function declined progressively from NGR (n = 106) to high 1 h-PG (n = 96) and to IGR (n = 115). Visceral adipose tissue (VAT) volume and liver fat content increased from NGT to high 1 h-PG and to IGR. LI improved insulin sensitivity and ß-cell function in the high 1 h-PG group to levels observed in NGR together with a marked reduction in hepatic fat content. Compared to the IGR group, T2D risk was reduced by 80 % (37-96 %, p = 0.005) in the high 1 h-PG group during a 12-year follow-up period. The odds of remission to complete normoglycemia were doubled in the high 1 h-PG group compared to the IGR group (2.18 [1.13-4.28], p = 0.021). CONCLUSION: High 1 h-PG indicates an intermediate metabolic state with pathophysiological changes more severe than in NGR but milder than in IGR. In people with high 1 h-PG, LI significantly improved insulin sensitivity and β-cell function and reduced ectopic lipid deposition and the risk of developing T2D compared to IGR. These findings highlight the value of 1 h-PG as a clinically useful biomarker, providing a critical window for early intervention to reverse core metabolic defects driving prediabetes and T2D.
Lysine potentiates insulin secretion via AASS-dependent catabolism and regulation of GABA content and signaling.
Muñoz F, Gao Q, Mattanovich M … +8 more , Trost K, Hodek O, Lindqvist A, Wierup N, Fex M, Moritz T, Mulder H, Cataldo LR
Metabolism · 2026 Jan · PMID 41167553 · Publisher ↗
Lysine is an essential amino acid with insulinotropic effects in humans. In vitro, it enhances glucose-stimulated insulin secretion (GSIS) in β-cell lines and rodent islets. While lysine is thought to act via membrane de...
Lysine is an essential amino acid with insulinotropic effects in humans. In vitro, it enhances glucose-stimulated insulin secretion (GSIS) in β-cell lines and rodent islets. While lysine is thought to act via membrane depolarization similar to arginine, the role of its intracellular metabolism in β-cell function remains unexplored. Here, we show that lysine acutely potentiates GSIS and that genes encoding enzymes in the lysine degradation pathway, including AminoAdipate-Semialdehyde Synthase (AASS), a key mitochondrial enzyme catalysing the first two steps of lysine catabolism, were present in human pancreatic islets and INS1 832/13 β cells. Some of these genes including AASS, ALDH7A1, DHTKD1, and HADH, were downregulated in pancreatic islets from type 2 diabetes (T2D) versus non-diabetic (ND) donors. Silencing AASS in human islets and INS1 832/13 β cells led to reduced GSIS. Integrated transcriptomics and metabolomics revealed altered expression of GABA metabolism genes, reduced GABA content and accumulation of glutamate in Aass-KD cells. Mitochondrial TCA cycle and OXPHOS function was impaired, evidenced by decreased ATP/ADP ratio, diminished glucose-stimulated mitochondrial respiration, and elevated lactate/pyruvate ratio. Cytosolic calcium responses to glucose and GABA were also disrupted. Pharmacological analyses demonstrated that inhibition of GABA synthesis or degradation did not account for the reduced GSIS, but providing substrates and activation of GDH partially restored insulin secretion, pointing to a diminished glutamate supply as a contributing factor. Remarkably, exogenous GABA restored insulin secretion in β cells and human islets with suppressed AASS-dependent lysine catabolism, supporting a role for GABA as both a metabolic substrate and signaling effector. Together, these findings identify AASS-mediated lysine catabolism as a critical regulator of β-cell metabolic integrity, linking impaired lysine metabolism to GABA depletion, mitochondrial dysfunction, and secretory failure in T2D islets. They also underscore the nutritional importance of essential amino acids such as lysine in sustaining GSIS and glucose homeostasis, and support therapeutic strategies aimed at restoring lysine catabolism or GABA/glutamate balance to maintain β-cell function.
SRSF1 is essential for pancreatic β-cell proliferation and the maintenance of glucose homeostasis in mice.
You X, Peng Q, Qian W … +5 more , Xie Z, Lin Y, Gai Y, Ye J, Feng Y
Metabolism · 2026 Jan · PMID 41138848 · Publisher ↗
BACKGROUND: β-Cell proliferation is vital for adapting to metabolic stress. Failure to expand β-cell mass during insulin resistance and aging contributes to dysfunction and diabetes. Understanding the mechanisms behind β...
BACKGROUND: β-Cell proliferation is vital for adapting to metabolic stress. Failure to expand β-cell mass during insulin resistance and aging contributes to dysfunction and diabetes. Understanding the mechanisms behind β-cell proliferation issues and dysfunction is crucial. SRSF1 is a central regulator of cell proliferation and survival, but its influence on β-cell proliferation and glucose control remains unclear. This study aims to investigate the role of SRSF1 in β-cell proliferation and its impact on glucose regulation. By examining the consequences of SRSF1 deficiency in pancreatic β-cells, we seek to elucidate the mechanisms linking SRSF1 to β-cell maintenance and function. METHODS: Mice with pancreatic β-cell-specific deletion of SRSF1 and a Rosa26-tdT lineage reporter were generated. Pancreatic sections were analyzed using immunostaining for insulin, glucagon, somatostatin, Ki67, tdT, proinsulin, TUNEL, and ER stress markers, as well as HE staining. Glucose tolerance tests, glucose and insulin measurements were performed in knockout and control mice. RNA-seq analyzed gene expression changes in 4-month-old islets, while scRNA-seq assessed cellular heterogeneity and gene expression profiles in 10-month-old mice islets. Knockdown assays and puromycin labeling experiments measured new protein synthesis. RESULTS: SRSF1 deficiency resulted in glucose intolerance and impaired insulin secretion, worsening with age. At early stages, knockout islets exhibited reduced β-cell proliferation accompanied by compensatory α-cell expansion. By 4 months, RNA-seq analysis showed downregulation of ribosome biogenesis and cell cycle genes, along with upregulation of α-cell determinants and progenitor-associated factors. Histological examination further revealed a decreased β-cell fraction, an increased α-cell fraction, and a small subset of α-cells co-expressing somatostatin, indicative of transient, stress-associated phenotypic plasticity. scRNA-seq identified ER stress and altered β-cell fate in knockout β-cells from 10-month-old mice. Notably, these changes were absent in 4-month-old knockout islets, indicating ER stress as a secondary response to proliferative defects from SRSF1 deficiency. Mechanistically, SRSF1 employs mechanisms similar to MYC to promote β-cell proliferation, with its effects on β-cells through the regulation of MYC expression. CONCLUSIONS: SRSF1 is essential for β-cell proliferation and function through MYC-mediated pathways. Its deficiency disrupts β-cell homeostasis and contributes to metabolic dysfunction in mice, underscoring its importance in preserving functional β-cells and maintaining glucose balance.
Angiopoietin-like protein 8 mediates inflammation and fibrosis of tubular cells in diabetic kidney disease progression by interacting with Akt2.
Pan L, He Y, Xiang Y … +13 more , Mao B, Meng X, Guo Y, Wang Z, Kan R, Wang S, Shen X, Pan T, Liu Z, Xie J, Yang Y, Li D, Yu X
Metabolism · 2026 Jan · PMID 41110501 · Publisher ↗
BACKGROUND AND AIMS: Angiopoietin-like protein 8 (ANGPTL8), an important regulator of glucose and lipid metabolism, has recently been shown to be associated with renal function decline in patients with diabetic kidney di...
BACKGROUND AND AIMS: Angiopoietin-like protein 8 (ANGPTL8), an important regulator of glucose and lipid metabolism, has recently been shown to be associated with renal function decline in patients with diabetic kidney disease (DKD). However, the underlying molecular mechanisms remain unclear. This study aimed to elucidate the novel role of ANGPTL8 in DKD progression. METHODS: The renal expression of ANGPTL8 was measured in patients and murine models with DKD. Proximal tubule-specific Angptl8 knockout mice were generated to elucidate the role of ANGPTL8 in the pathogenesis of DKD. In vitro, ANGPTL8 was inhibited in human proximal tubular epithelial cells (PTECs) under high glucose plus palmitic acid (HGPA) stress. ANGPTL8 interacting proteins were screened using the human proteome microarray and validated by complementary interaction assays. Functional validation employed the Akt2 small interfering RNA and the specific Akt2 inhibitor in vitro and proximal tubule-specific Akt2 knockout mice in vivo. RESULTS: ANGPTL8 expression was significantly increased in renal proximal tubules during DKD. Proximal tubule-specific Angptl8 knockout ameliorated tubular injury and reduced tubular inflammation and fibrosis in DKD mice. In vitro, ANGPTL8 inhibition protected human PTECs against HGPA-induced inflammation and epithelial-mesenchymal transition (EMT). Mechanistically, intracellular ANGPTL8 directly binds to and activates Akt2, triggering downstream NF-κB pathway activation and GSK3β inhibition. Akt2 inhibition abolished ANGPTL8's pathogenic effects in vitro and in vivo. CONCLUSIONS: Our findings demonstrate for the first time that elevated tubular ANGPTL8 promotes tubular inflammation and fibrosis during DKD by interacting with Akt2, highlighting the ANGPTL8-Akt2 axis as a promising target to prevent DKD progression.
Pancreas meets brain: β-hydroxybutyrate as a novel "β-cellular" metabolism therapy.
Lopa C, Pietrangelo D, Santulli G … +6 more , Gambardella J, Rubattu S, Stefan-Lifshitz M, Garcia CN, Jankauskas SS, Lombardi A
Metabolism · 2026 Jan · PMID 41109663 · Publisher ↗
β-hydroxybutyrate (BHB), the predominant ketone body in human circulation, is synthesized in liver mitochondria and rises markedly during fasting, caloric restriction, ketogenic diets, and high-intensity exercise. Once c...
β-hydroxybutyrate (BHB), the predominant ketone body in human circulation, is synthesized in liver mitochondria and rises markedly during fasting, caloric restriction, ketogenic diets, and high-intensity exercise. Once considered a mere metabolic intermediate, BHB is now recognized as a potent signaling molecule that links nutrient status to gene regulation, inflammation, and cellular stress responses. In fact, beyond serving as an energy substrate, BHB functions as a versatile signaling metabolite that integrates environmental cues to epigenetic regulation, gene expression, and cellular physiology. Accumulating evidence highlights its protective and disease-modifying effects, positioning BHB as a promising therapeutic candidate for diverse conditions associated with energy deficits or metabolic imbalances. Nevertheless, the precise mechanisms underlying these benefits remain incompletely defined. This review discusses recently identified molecular pathways regulated by BHB, with a focus on its roles in cellular signaling, inflammation, transcriptional control, and post-translational protein modifications. For the first time, we also explore the translational relevance of BHB in endocrine pancreas biology, drawing mechanistic parallels with the nervous system. Although neurons and β-cells share remarkable functional similarities, the impact of BHB on β-cell survival and function remains unexplored. Clarifying these effects may uncover new strategies to harness ketosis for the treatment of diabetes.
A melanocortin 4- and glucagon-like peptide 1 receptor multiple agonist for the treatment of diabetes and obesity.
Ashlaw EF, Elfers CT, Chichura KS … +9 more , Miranda IC, McGivney A, Chepurny OG, Holz GG, Mullins G, den Hartigh LJ, Liu Y, Roth CL, Doyle RP
Metabolism · 2026 Jan · PMID 41093057 · Full text
Obesity and its sequelae cause significant morbidity and mortality worldwide. Current glucagon-like peptide-1 (GLP-1) receptor agonist-based treatments have significant side-effects associated with high rates of treatmen...
Obesity and its sequelae cause significant morbidity and mortality worldwide. Current glucagon-like peptide-1 (GLP-1) receptor agonist-based treatments have significant side-effects associated with high rates of treatment discontinuation. Such concerns are greater still in children and adolescents. Thus, there remains a clinical unmet need to develop obesity and/or T2D mellitus therapies with significantly improved tolerability. Herein, we examined a polypharmacy approach combining melanocortin (MC) 4-, and GLP-1-receptor agonism in a single monomeric peptide based on α-MSH and Exendin-4 to bind and stimulate different peptide receptors in vitro, and to drive reductions in body weight and food intake in up to 7 weeks of treatment in comparison to semaglutide and tirzepatide as standard of care positive controls in diet-induced obese rats. Despite the monomeric peptide GLP-1-/MC4-receptor multiple agonist (KCEM1) being a non-lipidated, weaker GLP-1R agonist compared to semaglutide and tirzepatide, reductions in calorie intake and body weight were similar in all three groups after daily subcutaneous injections of the three peptides. In addition, KCEM1 offered superior glycemic control during glucose tolerance testing. In gene expression analyses, KCEM1, but not semaglutide or tirzepatide, significantly increased expression of glucose transporter 4 (GLUT4) and key glycolysis enzyme Pgk1 in skeletal muscle, while it reduced genetic markers of inflammation in different tissues, including inflammatory markers IL-6 and TNF-α in liver tissue. Furthermore, KCEM1 lowered hepatic lipid content and improved metabolic dysfunction-associated steatohepatitis (MASH) scoring. Overall, these data extend emerging concepts around the use of multi-receptor polypharmacy to treat metabolic syndrome.
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