Diabetes & Metabolism[JOURNAL]
Sun
200 papers
Plasma metabolite profiles of meat intake and their association with cardiovascular disease risk: A population-based study in Swedish cohorts.
Arage G, Dekkers KF, Rašo LM … +16 more , Hammar U, Ericson U, Larsson SC, Engel H, Baldanzi G, Pertiwi K, Sayols-Baixeras S, Landberg R, Sundström J, Smith JG, Engström G, Ärnlöv J, Orho-Melander M, Lind L, Fall T, Ahmad S
Metabolism · 2025 Jul · PMID 40081615 · Publisher ↗
BACKGROUND: Higher meat intake has been associated with adverse health outcomes, including cardiovascular disease (CVD). This study investigated plasma metabolites associated with meat intake and their relation with card...
BACKGROUND: Higher meat intake has been associated with adverse health outcomes, including cardiovascular disease (CVD). This study investigated plasma metabolites associated with meat intake and their relation with cardiometabolic biomarkers, subclinical CVD markers, and incident CVD. METHODS: Associations between self-reported meat intake and 1272 plasma metabolites were investigated in the SCAPIS cohort (n = 8,819; ages 50-64). Meat-associated metabolites were further examined for relation with subclinical CVD markers in the POEM cohort (n = 502; age 50) and incident CVD in the EpiHealth cohort (n = 2,278; ages 45-75; 107 incident cases over 9.6 years follow-up). Meat intake was categorized into white, unprocessed red, and processed red meat. Linear regression analyzed associations between meat intake, metabolites and cardiometabolic biomarkers, and subclinical CVD markers, while Cox models evaluated association between meat-associated metabolites and incident CVD. RESULTS: After correction for multiple testing, 458, 368, and 403 metabolites were associated with white, unprocessed red, and processed red meat, respectively. Processed red meat-associated metabolites were associated with higher levels of fasting insulin, hemoglobin A1c, and lipoprotein(a), and were inversely associated with maximal oxygen consumption. Two metabolites, 1-palmitoyl-2-linoleoyl-GPE (16:0/18:2) (hazard ratios (HR: 1.32; 95 % CI: 1.08, 1.62)) and glutamine degradant (HR: 1.35; 95 % CI: 1.07, 1.72), that were inversely associated with intake of all meat types, were also associated with a higher risk of incident CVD. CONCLUSIONS: This study provides comprehensive analysis of self-reported meat intake and plasma metabolites. The findings may enhance our understanding of the relationship between meat intake and CVD, and provide insights into underlying mechanisms.
Fat absorption and metabolism after Roux-en-Y gastric bypass surgery.
Hindsø M, Lundsgaard A, Marinkovic B … +15 more , Jensen MH, Hedbäck N, Svane MS, Dirksen C, Jørgensen NB, London A, Jeppesen PB, Hvistendahl MK, Christoffersen C, Siebner HR, Kiens B, Holst JJ, Madsbad S, van Hall G, Bojsen-Møller KN
Metabolism · 2025 Jun · PMID 40074057 · Publisher ↗
BACKGROUND: Triacylglycerol (TAG) plasma excursions after a high-fat meal are blunted after Roux-en-Y gastric bypass (RYGB), but underlying mechanisms are poorly understood. We studied TAG absorption and metabolism in 12...
BACKGROUND: Triacylglycerol (TAG) plasma excursions after a high-fat meal are blunted after Roux-en-Y gastric bypass (RYGB), but underlying mechanisms are poorly understood. We studied TAG absorption and metabolism in 12 RYGB-operated individuals and 12 unoperated controls (CON) matched on sex, age, and BMI. METHODS: Participants followed a 7-day controlled diet and on day 4 underwent H-MR Spectroscopy of liver TAG and a high-fat liquid meal with oral and intravenous labeled stable isotope metabolites, subcutaneous abdominal fat biopsies, and indirect calorimetry. Subsequently, participants collected stool for 96 h. RESULTS: Overall fat absorption from the controlled diet was moderately lower in RYGB than CON (88 % versus 93 %, P < 0.01), without indication of greater specific malabsorption of fat from the high-fat test meal (recovery of TAG and labeled TAG in 96-h stool samples). After an overnight fast, plasma TAG concentrations and incorporation of plasma fatty acids (IV tracer) into TAG did not differ between groups. The postprandial 6-h iAUC of plasma TAG plasma concentrations was markedly lower in RYGB than CON (15 versus 70 mmol/L × min, P = 0.03). The postprandial chylomicron (CM) particle response (plasma ApoB48) was initially higher in RYGB, but with lower CM-TAG plasma concentrations and appearance of labeled palmitate from the oral tripalmitin tracer over the 6 h. CONCLUSION: Fat absorption is only moderately lower after RYGB compared with unoperated matched controls. Nevertheless, postprandial TAG and CM plasma kinetics after a high-fat meal are markedly altered after RYGB with substantially lower TAG and CM-TAG concentrations despite a faster CM particle release.
Differential risk assessment in persons at risk of type 2 diabetes using urinary peptidomics.
Schork A, Fritsche A, Schleicher ED … +9 more , Peter A, Heni M, Stefan N, von Schwartzenberg RJ, Guthoff M, Mischak H, Siwy J, Birkenfeld AL, Wagner R
Metabolism · 2025 Jun · PMID 40023439 · Publisher ↗
OBJECTIVE: Individuals at increased risk of type 2 diabetes have recently been classified into six prediabetes clusters, which stratify the risk of progression to diabetes and diabetes complications. Clusters 1, 2 and 4...
OBJECTIVE: Individuals at increased risk of type 2 diabetes have recently been classified into six prediabetes clusters, which stratify the risk of progression to diabetes and diabetes complications. Clusters 1, 2 and 4 are low-risk clusters while clusters 3, 5 and 6 are high-risk clusters; individuals in cluster 6 have an elevated risk of nephropathy and all-cause mortality despite delayed onset of diabetes. The urinary peptidome classifiers CKD273 (chronic kidney disease, CKD), HF2 (heart failure, HF) and CAD238 (coronary artery disease, CAD) are based on unique urinary peptide patterns and have shown potential for identifying individuals at risk for CKD and cardiovascular pathologies. This observational study investigates whether peptidome classifiers can differentiate complication risks across the prediabetes clusters and if a novel combination of peptides can distinguish high-risk from low-risk prediabetes clusters. METHODS: Urine peptidome analysis was performed on spot urine samples from individuals across 6 prediabetes clusters (n = 249) and 19 individuals with screen-detected diabetes (study cohorts at University Hospital Tübingen, Germany from 11/2004 to 11/2012). Predefined urinary classifiers were calculated for each participant. Lasso regression analysis was used to identify an optimal combination of peptides distinguishing low- Schlesinger et al. (2022), Wagner et al. (2021) [1,2,4] and high-risk (Rooney et al., 2021; Wagner, 2023; Latosinska et al., 2021 [3,5,6]) clusters. RESULTS: The predefined urinary peptidome classifiers CKD273, HF2 and CAD238 differed significantly across prediabetes clusters, particularly with elevated values in cluster 6 compared to the healthiest cluster 2. CKD273, HF2 and CAD238 were inversely associated with insulin sensitivity indexes. Machine Learning identified a combination of 112 urinary peptides that differentiated low-risk from high-risk prediabetes clusters (AUC-ROC 0.868 (95 % CI 0.755-0.981)). CONCLUSIONS: Urinary peptidome classifiers support the increased risk of CKD and suggest an elevated risk of heart failure and coronary artery disease in the high-risk prediabetes cluster 6. Urine peptidomics show promising potential as a tool for identifying high-risk prediabetes individuals and guiding early preventive interventions.
Metabolaging: a new geroscience perspective linking aging pathologies and metabolic dysfunction.
Khalaf F, Barayan D, Saldanha S … +1 more , Jeschke MG
Metabolism · 2025 May · PMID 39947519 · Publisher ↗
With age, our metabolic systems undergo significant alterations, which can lead to a cascade of adverse effects that are implicated in both metabolic disorders, such as diabetes, and in the body's ability to respond to a...
With age, our metabolic systems undergo significant alterations, which can lead to a cascade of adverse effects that are implicated in both metabolic disorders, such as diabetes, and in the body's ability to respond to acute stress and trauma. To elucidate the metabolic imbalances arising from aging, we introduce the concept of "metabolaging." This framework encompasses the broad spectrum of metabolic disruptions associated with the hallmarks of aging, including the functional decline of key metabolically active organs, like the adipose tissue. By examining how these organs interact with essential nutrient-sensing pathways, "metabolaging" provides a more comprehensive view of the systemic metabolic imbalances that occur with age. This concept extends to understanding how age-related metabolic disturbances can influence the response to acute stressors, like burn injuries, highlighting the interplay between metabolic dysfunction and the ability to handle severe physiological challenges. Finally, we propose potential interventions that hold promise in mitigating the effects of metabolaging and its downstream consequences.
A systematic review & updated meta-analysis on the association between higher consumption of ultra processed foods and risk of diabetes and its complications: Letter to the editor.
Huang J
Metabolism · 2025 May · PMID 39947518 · Publisher ↗
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A systematic review & updated meta-analysis on the association between higher consumption of ultra processed foods and risk of diabetes and its complications: Response Letter.
Souza M, Moura FS, Lima LCV … +1 more , Amaral MJM
Metabolism · 2025 May · PMID 39947517 · Publisher ↗
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Uncovering mechanisms of thiazolidinediones on osteogenesis and adipogenesis using spatial fluxomics.
Brejchova K, Rahm M, Benova A … +9 more , Domanska V, Reyes-Gutierez P, Dzubanova M, Trubacova R, Vondrackova M, Cajka T, Tencerova M, Vrabel M, Kuda O
Metabolism · 2025 May · PMID 39947516 · Publisher ↗
OBJECTIVE: Insulin-sensitizing drugs, despite their broad use against type 2 diabetes, can adversely affect bone health, and the mechanisms underlying these side effects remain largely unclear. Here, we investigated the...
OBJECTIVE: Insulin-sensitizing drugs, despite their broad use against type 2 diabetes, can adversely affect bone health, and the mechanisms underlying these side effects remain largely unclear. Here, we investigated the different metabolic effects of a series of thiazolidinediones, including rosiglitazone, pioglitazone, and the second-generation compound MSDC-0602K, on human mesenchymal stem cells (MSCs). METHODS: We developed C subcellular metabolomic tracer analysis measuring separate mitochondrial and cytosolic metabolite pools, lipidomic network-based isotopologue models, and bioorthogonal click chemistry, to demonstrate that MSDC-0602K differentially affected bone marrow-derived MSCs (BM-MSCs) and adipose tissue-derived MSCs (AT-MSCs). In BM-MSCs, MSDC-0602K promoted osteoblastic differentiation and suppressed adipogenesis. This effect was clearly distinct from that of the earlier drugs and that on AT-MSCs. RESULTS: Fluxomic data reveal unexpected differences between this drug's effect on MSCs and provide mechanistic insight into the pharmacologic inhibition of mitochondrial pyruvate carrier 1 (MPC). Our study demonstrates that MSDC-0602K retains the capacity to inhibit MPC, akin to rosiglitazone but unlike pioglitazone, enabling the utilization of alternative metabolic pathways. Notably, MSDC-0602K exhibits a limited lipogenic potential compared to both rosiglitazone and pioglitazone, each of which employs a distinct lipogenic strategy. CONCLUSIONS: These findings indicate that the new-generation drugs do not compromise bone structure, offering a safer alternative for treating insulin resistance. Moreover, these results highlight the ability of cell compartment-specific metabolite labeling by click reactions and tracer metabolomics analysis of complex lipids to discover molecular mechanisms within the intersection of carbohydrate and lipid metabolism.
Start small, think big: MicroRNAs in diabetes mellitus and relevant cardiorenal-liver metabolic health spectrum.
Chen J, Luo M, Xing Z … +3 more , Chen Y, Peng C, Li D
Metabolism · 2025 Apr · PMID 39914482 · Publisher ↗
Diabetes mellitus (DM), co-existing with metabolic disorder of cardio-renal-liver, is one of the most difficult problems in medicine that attracts global concern with high mortality. MicroRNAs (miRNAs) are a class of sma...
Diabetes mellitus (DM), co-existing with metabolic disorder of cardio-renal-liver, is one of the most difficult problems in medicine that attracts global concern with high mortality. MicroRNAs (miRNAs) are a class of small non-coding RNA molecules that negatively regulates gene expression and exerts active against a large proportion of the transcriptome, due to their high evolutionary conservation. Emerging evidence prove that miRNAs are involved in the pathogenesis of DM and associated metabolic disorders, manifested by their variable alteration in the blood, urine, tissues, or organs, principally contributing to modulate the interconnections between DM and cardio-renal-liver metabolism. Mechanistically, miRNAs regulate various biological processes, such as metabolism of insulin, lipid, glucose, inflammatory response, fibrosis, oxidative stress, apoptosis, and angiogenesis, etc. This review emphasizes the function of miRNAs and highlights the physiopathological regulation of miRNA in DM and related complications, especially the dysfunction of cardiovascular system, kidneys, and liver, with the aim of providing promising biomarkers for assisting early diagnosis of DM with cardio-renal-liver- specific metabolic disorders, as well as for the development of miRNA-targeting agents.
Effects of coding variants in the glucokinase regulatory protein gene on hepatic glucose and triglyceride metabolism suggest a gene regulatory function of glucokinase.
Langer S, Jagdhuhn D, Waterstradt R … +5 more , Gromoll J, Müller M, Rees MG, Gloyn AL, Baltrusch S
Metabolism · 2025 May · PMID 39894388 · Publisher ↗
BACKGROUND: Regulation of glucose metabolism after a meal is the major task of hepatic glucokinase (GCK). Inhibition and nuclear retention of glucokinase during fasting is achieved by glucokinase regulatory protein (GKRP...
BACKGROUND: Regulation of glucose metabolism after a meal is the major task of hepatic glucokinase (GCK). Inhibition and nuclear retention of glucokinase during fasting is achieved by glucokinase regulatory protein (GKRP). Compounds disrupting the GCK-GKRP interaction alter glucose but not triglyceride levels, whilst GKRP coding alleles lower glucose but elevate triglycerides. The aim of this study was to identify yet unknown functions of GKRP by examining human variants both rare (p.Q234P, p.H438Y) and common (p.P446L). METHODS: Fluorescently labelled human GKRP variant and GCK proteins were expressed in hepatoma cells or primary mouse hepatocytes to investigate the subcellular localization of both proteins, cellular glucose uptake, and triglyceride levels. Mutational effects on GKRP protein structure were analyzed with PyMOL. Nuclear-to-cytoplasmic distribution of the GCK-GKRP complex was modeled in MATLAB. RESULTS: Nuclear localization of the GKRP variants was decreased compared to wild-type. Only H438Y-GKRP still evoked WT-like GCK nuclear accumulation. Nuclear localization of Q234P-GKRP was most impaired and depended on the presence of GCK, which, supported by structural analyses, could stabilize its conformation. Nonetheless, inhibition of glucose uptake was least impaired with Q234P-GKRP. Triglyceride contents related to the glucose uptake of hepatoma cells were disproportionately high for cells expressing wild-type or H438Y-GKRP, the two variants that induced higher nuclear sequestration of GCK. CONCLUSIONS: Our results, supported by a modeling approach, suggest that GKRP-mediated nuclear localization of GCK has a function in liver metabolism beyond GCK inhibition and sequestration. This needs further elucidation given that GKRP disruptors have been proposed for antihyperglycemic therapy.
Combined loss of glyoxalase 1 and aldehyde dehydrogenase 3a1 amplifies dicarbonyl stress, impairs proteasome activity resulting in hyperglycemia and activated retinal angiogenesis.
Li S, Li H, Bennewitz K … +6 more , Poschet G, Buettner M, Hausser I, Szendroedi J, Nawroth PP, Kroll J
Metabolism · 2025 Apr · PMID 39892865 · Publisher ↗
BACKGROUND & AIMS: Any energy consumption results in the generation of highly reactive dicarbonyls and the need to prevent excessive dicarbonyls accumulation through the activity of several interdependent detoxification...
BACKGROUND & AIMS: Any energy consumption results in the generation of highly reactive dicarbonyls and the need to prevent excessive dicarbonyls accumulation through the activity of several interdependent detoxification enzymes. Glyoxalase 1 (GLO1) knockout zebrafish showed only moderately elevated methylglyoxal (MG) levels, but increased Aldehyde Dehydrogenases (ALDH) activity and increased aldh3a1 expression. Elevated levels of 4-hydroxynonenal (4-HNE) but no MG increase were observed in ALDH3A1KO. The question of whether ALDH3A1 prevents MG formation as a compensatory mechanism in the absence of GLO1 remained unclear. METHODS: To investigate whether ALDH3A1 detoxifies MG as a compensatory mechanism in the absence of GLO1, the GLO1/ALDH3A1 double knockout (DKO) zebrafish was first generated. Various metabolites including advanced glycation end products (AGEs), as well as glucose metabolism and hyaloid vasculature were analyzed in GLO1KO, ALDH3A1KO and GLO1/ALDH3A1DKO zebrafish. RESULTS: In the absence of GLO1 and ALDH3A1, MG-H1 levels were increased. MG-H1 accumulation led to a severe deterioration of proteasome function, resulting in impaired glucose homeostasis and consequently amplified angiogenic activation of the hyaloid and retinal vasculature. Rescue of these pathological processes could be observed by using L-carnosine, and proteasome activator betulinic acid. CONCLUSION: The present data, together with previous studies, suggest that ALDH3A1 and GLO1 are important detoxification enzymes that prevent the deleterious effects of MG-H1 accumulation on proteasome function, glucose homeostasis and vascular function.
Exploring receptors for pro-resolving and non-pro-resolving mediators as therapeutic targets for sarcopenia.
Wang T, Chen S, Zhou D … +1 more , Hong Z
Metabolism · 2025 Apr · PMID 39892864 · Publisher ↗
Sarcopenia is defined by a reduction in both muscle strength and mass. Sarcopenia may be an inevitable component of the aging process, but it may also be accelerated by comorbidities and metabolic derangements. The under...
Sarcopenia is defined by a reduction in both muscle strength and mass. Sarcopenia may be an inevitable component of the aging process, but it may also be accelerated by comorbidities and metabolic derangements. The underlying mechanisms contributing to these pathological changes remain poorly understood. We propose that chronic inflammation-mediated networks and metabolic defects that exacerbate muscle dysfunction are critical factors in sarcopenia and related diseases. Consequently, utilizing specialized pro-resolving mediators (SPMs) that function through specific G-protein coupled receptors (GPCRs) may offer effective therapeutic options for these disorders. However, challenges such as a limited understanding of SPM/receptor signaling pathways, rapid inactivation of SPMs, and the complexities of SPM synthesis impede their practical application. In this context, stable small-molecule SPM mimetics and receptor agonists present promising alternatives. Moreover, the aged adipose-skeletal axis may contribute to this process. Activating non-SPM GPCRs on adipocytes, immune cells, and muscle cells under conditions of systemic, chronic, low-grade inflammation (SCLGI) could help alleviate inflammation and metabolic dysfunction. Recent preclinical studies indicate that both SPM GPCRs and non-SPM GPCRs can mitigate symptoms of aging-related diseases such as obesity and diabetes, which are driven by chronic inflammation and metabolic disturbances. These findings suggest that targeting these receptors could provide a novel strategy for addressing various chronic inflammatory conditions, including sarcopenia.
Metabolites-mediated posttranslational modifications in cardiac metabolic remodeling: Implications for disease pathology and therapeutic potential.
Guo L, Du Y, Li H … +4 more , He T, Yao L, Yang G, Yang X
Metabolism · 2025 Apr · PMID 39864796 · Publisher ↗
The nonenergy - producing functions of metabolism are attracting increasing attention, as metabolic changes are involved in discrete pathways modulating enzyme activity and gene expression. Substantial evidence suggests...
The nonenergy - producing functions of metabolism are attracting increasing attention, as metabolic changes are involved in discrete pathways modulating enzyme activity and gene expression. Substantial evidence suggests that myocardial metabolic remodeling occurring during diabetic cardiomyopathy, heart failure, and cardiac pathological stress (e.g., myocardial ischemia, pressure overload) contributes to the progression of pathology. Within the rewired metabolic network, metabolic intermediates and end-products can directly alter protein function and/or regulate epigenetic modifications by providing acyl groups for posttranslational modifications, thereby affecting the overall cardiac stress response and providing a direct link between cellular metabolism and cardiac pathology. This review provides a comprehensive overview of the functional diversity and mechanistic roles of several types of metabolite-mediated histone and nonhistone acylation, namely O-GlcNAcylation, lactylation, crotonylation, β-hydroxybutyrylation, and succinylation, as well as fatty acid-mediated modifications, in regulating physiological processes and contributing to the progression of heart disease. Furthermore, it explores the potential of these modifications as therapeutic targets for disease intervention.
Association between higher consumption of ultra-processed foods and risk of diabetes and its complications: A systematic review & updated meta-analysis.
Souza M, Moura FS, Lima LCV … +1 more , Amaral MJM
Metabolism · 2025 Apr · PMID 39848440 · Publisher ↗
BACKGROUND & AIMS: Recent epidemiologic studies on the association between higher consumption of ultra-processed foods (UPFs) and risk of incident diabetes have reported conflicting results in populations worldwide. We c...
BACKGROUND & AIMS: Recent epidemiologic studies on the association between higher consumption of ultra-processed foods (UPFs) and risk of incident diabetes have reported conflicting results in populations worldwide. We conducted an updated systematic review and meta-analysis to quantify the magnitude of this association. METHODS: PubMed and Embase databases were systematically searched (from 2009 to November 14, 2024) for prospective cohort studies reporting data on the association between UPF intake (defined by the NOVA classification) and the risk of incident diabetes or its complications in adults (>18 years). Meta-analysis was performed using random-effects modelling to obtain pooled hazard ratios (HRs) with 95 % confidence intervals (CIs), and the GRADE approach was applied to evaluate the certainty of evidence. RESULTS: We included 14 prospective cohort studies with a total of 692,508 participants. The highest UPF consumption was significantly associated with an increased risk of diabetes (n = 9 studies; HR 1.24, 95 % CI 1.14 to 1.34, I = 69 %) compared with the lowest UPF intake (very low certainty of evidence). Subgroup analysis showed that studies published in 2024 had a smaller effect size compared with earlier studies. There were no significant differences between subgroups based on study location, duration of follow-up, method and frequency of dietary intake assessment, and risk of bias. Sensitivity analyses did not change these findings. Each 10 % increase in total UPF consumption was associated with a 13 % (n = 4 studies; HR 1.13, 95 % CI 1.08 to 1.18, I = 37 %) increased risk of diabetes. Preliminary data from 4 cohort studies also suggest that high UPF consumption may be associated with complications in diabetic patients, including microvascular/cardiovascular disease, chronic kidney disease, and mortality. CONCLUSION: UPF consumption is associated with a higher risk of incident diabetes and may contribute to its complications. Urgent public health efforts should prioritize the reduction of UPF consumption.
DOC2b enrichment mitigates proinflammatory cytokine-induced CXCL10 expression by attenuating IKKβ and STAT-1 signaling in human islets.
Bhowmick DC, Ahn M, Bhattacharya S … +2 more , Aslamy A, Thurmond DC
Metabolism · 2025 Mar · PMID 39805534 · Full text
INTRODUCTION: Type 1 diabetic human islet β-cells are deficient in double C 2 like domain beta (DOC2b) protein. Further, DOC2b protects against cytokine-induced pancreatic islet β-cell stress and apoptosis. However, the...
INTRODUCTION: Type 1 diabetic human islet β-cells are deficient in double C 2 like domain beta (DOC2b) protein. Further, DOC2b protects against cytokine-induced pancreatic islet β-cell stress and apoptosis. However, the mechanisms underpinning the protective effects of DOC2b remain unknown. METHODS: Biochemical studies, qPCR, proteomics, and immuno-confocal microscopy were conducted to determine the underlying protective mechanisms of DOC2b in β-cells. DOC2b-enriched or -depleted primary islets (human and mouse) and β-cell lines challenged with or without proinflammatory cytokines, global DOC2b heterozygous knockout mice subjected to multiple-low-dose-streptozotocin (MLD-STZ), were used for these studies. RESULTS: A significant elevation of stress-induced CXCL10 mRNA was observed in DOC2b-depleted β-cells and primary mouse islets. Further, DOC2b enrichment markedly attenuated cytokine-induced CXCL10 levels in primary non-diabetic human islets and β-cells. DOC2b enrichment also reduced total-NF-κB p65 protein levels in human islets challenged with T1D mimicking proinflammatory cytokines. IKKβ, NF-κB p65, and STAT-1 are capable of associating with DOC2b in cytokine-challenged β-cells. DOC2b enrichment in cytokine-stressed human islets and β-cells corresponded with a significant reduction in activated and total IKKβ protein levels. Total IκBβ protein was increased in DOC2b-enriched human islets subjected to acute cytokine challenge. Cytokine-induced activated and total STAT-1 protein and mRNA levels were markedly reduced in DOC2b-enriched human islets. Intriguingly, DOC2b also prevents ER-stress-IKKβ and STAT-1 crosstalk in the rat INS1-832/13 β-cell line. CONCLUSION: The mechanisms underpinning the protective effects of DOC2b involve attenuation of IKKβ-NF-κB p65 and STAT-1 signaling, and reduced CXCL10 expression.
PPARα-ERRα crosstalk mitigates metabolic dysfunction-associated steatotic liver disease progression.
Antwi MB, Lefere S, Clarisse D … +11 more , Koorneef L, Heldens A, Onghena L, Decroix K, Fijalkowska D, Thommis J, Hellemans M, Hoorens A, Geerts A, Devisscher L, De Bosscher K
Metabolism · 2025 Mar · PMID 39743041 · Publisher ↗
BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent liver disease worldwide, continues to rise. More effective therapeutic strategies are urgently needed. We investig...
BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent liver disease worldwide, continues to rise. More effective therapeutic strategies are urgently needed. We investigated how targeting two key nuclear receptors involved in hepatic energy metabolism, peroxisome proliferator-activated receptor alpha (PPARα) and estrogen-related receptor alpha (ERRα), ameliorates MASLD. METHODS: The PPARα agonist pemafibrate and/or ERRα inverse agonist C29 were administered in a short- and long-term Western diet plus fructose model, and a diabetic-background streptozotocin-Western diet model (STZ-WD). Liver and adipose tissue morphology, histological samples, serum metabolites, RNA and protein levels were analysed and scanning electron microscopy was performed. In addition, we performed cell-based assays and immunohistochemistry and immunofluorescence stainings with light and super-resolution confocal microscopy of healthy, MASLD and MASH human livers. RESULTS: The ligand combinations' efficacy was highlighted by reduced liver steatosis across all mouse models, alongside improvements in body weight, inflammation, and fibrosis in both long-term models. Additionally, tumour formation was prevented in the STZ-WD mice model. Cell-based assays demonstrated that ERRα inhibits PPARα's activity, explaining why ERRα blockage improves inflammatory and lipid metabolism gene profiles and enhances lipid-lowering effects. Complementary RNA sequencing and shotgun proteomics, combined with enrichment analysis, jointly identified downregulated serum amyloid A1/A2 as essential components underlying the combination treatment's effectiveness. MASLD/MASH patient livers showed reduced PPARα and increased ERRα levels supporting disrupted NR crosstalk in the hepatocyte nucleus. CONCLUSION: Our study supports that dual nuclear receptor targeting, which simultaneously increases PPARα and diminishes ERRα activity, may represent a viable novel strategy against MASLD. IMPACT AND IMPLICATIONS: Our research introduces a novel therapeutic strategy against MASLD by simultaneously increasing PPARα activity while diminishing ERRα activity. With PPARα agonists already tested in phase III clinical trials, ERRα ligands/modulators need further (clinical) development to make our findings applicable to both MASLD patients and physicians.
Subphenotypes of body composition and their association with cardiometabolic risk - Magnetic resonance imaging in a population-based sample.
Grune E, Nattenmüller J, Kiefer LS … +5 more , Machann J, Peters A, Bamberg F, Schlett CL, Rospleszcz S
Metabolism · 2025 Mar · PMID 39743039 · Publisher ↗
BACKGROUND: For characterizing health states, fat distribution is more informative than overall body size. We used population-based whole-body magnetic resonance imaging (MRI) to identify distinct body composition subphe...
BACKGROUND: For characterizing health states, fat distribution is more informative than overall body size. We used population-based whole-body magnetic resonance imaging (MRI) to identify distinct body composition subphenotypes and characterize associations with cardiovascular disease (CVD) risk. METHODS: Bone marrow, visceral, subcutaneous, cardiac, renal, hepatic, skeletal muscle and pancreatic adipose tissue were measured by MRI in n = 299 individuals from the population-based KORA cohort. Body composition subphenotypes were identified by data-driven k-means clustering. CVD risk was calculated by established scores. RESULTS: We identified five body composition subphenotypes, which differed substantially in CVD risk factor distribution and CVD risk. Compared to reference subphenotype I with favorable risk profile, two high-risk phenotypes, III&V, had a 3.8-fold increased CVD risk. High-risk subphenotype III had increased bone marrow and skeletal muscle fat (26.3 % vs 11.4 % in subphenotype I), indicating ageing effects, whereas subphenotype V showed overall high fat contents, and particularly elevated pancreatic fat (25.0 % vs 3.7 % in subphenotype I), indicating metabolic impairment. Subphenotype II had a 2.7-fold increased CVD risk, and an unfavorable fat distribution, probably smoking-related, while BMI was only slightly elevated. Subphenotype IV had a 2.8-fold increased CVD risk with comparably young individuals, who showed high blood pressure and hepatic fat (17.7 % vs 3.0 % in subphenotype I). CONCLUSIONS: Whole-body MRI can identify distinct body composition subphenotypes associated with different degrees of cardiometabolic risk. Body composition profiling may enable a more comprehensive risk assessment than individual fat compartments, with potential benefits for individualized prevention.
Retraction notice "to Loss of mitochondrial adaptation associates with deterioration of mitochondrial turnover and structure in metabolic dysfunction-associated steatotic liver disease" [Metabolism 151 (2024) 155762].
Sarabhai T, Kahl S, Gancheva S … +9 more , Mastrototaro L, Dewidar B, Pesta D, Ratter-Rieck JM, Bobrov P, Jeruschke K, Esposito I, Schlensak M, Roden M
Metabolism · 2025 Mar · PMID 39721563 · Publisher ↗
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Effect of glucagon-like peptide-1 receptor agonists and co-agonists on body composition: Systematic review and network meta-analysis.
Karakasis P, Patoulias D, Fragakis N … +1 more , Mantzoros CS
Metabolism · 2025 Mar · PMID 39719170 · Publisher ↗
BACKGROUND AND AIMS: While glucagon-like peptide-1 receptor agonists (GLP-1RAs) effectively reduce body weight, their impact on lean mass remains uncertain. This meta-analysis evaluated the effects of GLP-1RAs and GLP-1/...
BACKGROUND AND AIMS: While glucagon-like peptide-1 receptor agonists (GLP-1RAs) effectively reduce body weight, their impact on lean mass remains uncertain. This meta-analysis evaluated the effects of GLP-1RAs and GLP-1/GIP receptor dual agonists (GLP-1/GIP-RAs) on body composition, focusing on total weight, fat mass, and lean mass in adults with diabetes and/or overweight/obesity. METHODS: A systematic search of Medline, Embase, and the Cochrane Library was conducted through November 12, 2024. Data were analyzed using random-effects pairwise and network meta-analyses to compare interventions with placebo or active comparators. RESULTS: Twenty-two randomized controlled trials (2258 participants) were included. GLP-1RAs significantly reduced total body weight (MD -3.55 kg, 95 %-CI [-4.81, -2.29]), fat mass (MD -2.95 kg, 95 %-CI [-4.11, -1.79]), and lean mass (MD -0.86 kg, 95 %-CI [-1.30, -0.42]), with lean mass loss comprising approximately 25 % of the total weight loss. However, the relative lean mass, defined as percentage change from baseline, was unaffected. Liraglutide, at 3.0 mg weekly or 1.8 mg daily, was the only GLP-1RA to achieve significant weight reduction without significantly reducing lean mass. Tirzepatide (15 mg weekly) and semaglutide (2.4 mg weekly) were the most effective for weight and fat mass reduction but were among the least effective in preserving lean mass. CONCLUSIONS: Potent GLP-1 RAs, such as tirzepatide and semaglutide, demonstrate greater overall weight loss but are associated with a significant reduction in lean mass.
Shared genetic architecture of type 2 diabetes with muscle mass and function and frailty reveals comorbidity etiology and pleiotropic druggable targets.
Dou C, Liu D, Kong L … +14 more , Chen M, Ye C, Zhu Z, Zheng J, Xu M, Xu Y, Li M, Zhao Z, Lu J, Chen Y, Ning G, Wang W, Bi Y, Wang T
Metabolism · 2025 Mar · PMID 39710002 · Publisher ↗
BACKGROUND: Delineating the shared genetic architecture of type 2 diabetes with muscle mass and function and frailty is essential for unraveling the common etiology and developing holistic therapeutic strategies for thes...
BACKGROUND: Delineating the shared genetic architecture of type 2 diabetes with muscle mass and function and frailty is essential for unraveling the common etiology and developing holistic therapeutic strategies for these co-existing conditions. METHODS: In this genome-wide pleiotropic association study, we performed multi-level pairwise trait pleiotropic analyses using genome-wide association study summary statistics from up to 461,026 European ancestry individuals to dissect the shared genetic factors and causal relationships of type 2 diabetes and seven glycemic traits with four muscle mass- and function-related phenotypes and the frailty index. RESULTS: We first identified 27 pairs with significant genetic correlations through the linkage disequilibrium score regression and high-definition likelihood analysis. Then we determined 79 pleiotropic loci and 109 pleiotropic genes across linkage pairs via the pleiotropic analysis under the composite null hypothesis (PLACO), the colocalization, and the Multi-marker Analysis of GenoMic Annotation (MAGMA) analyses. We subsequently performed transcriptome-wide association study (TWAS) analyses using joint-tissue imputation, refined by gene-based integrative fine-mapping through a conditional TWAS approach, and identified 44 unique causal shared genes across 13 tissues in linkage pairs, including eight druggable genes (ABO, AOC1, FTO, GCKR, MTOR, POLK, PPARG, and APEH), with MTOR and PPARG categorized as clinically actionable. Two-sample Mendelian randomization analysis supported bidirectional causality between diabetes and frailty index and unidirectional causal effects of muscle phenotypes on glycemic profiles. CONCLUSIONS: Our findings highlight the common genetic underpinnings between type 2 diabetes and muscle loss and frailty and inform drug targets with pleiotropic effects on both of these aging-related challenges.
NRH, a potent NAD enhancer, improves glucose homeostasis and lipid metabolism in diet-induced obese mice through an active adenosine kinase pathway.
Zeng X, Wang Y, Farias K … +6 more , Rappa A, Darko C, Sauve A, Huang Q, Alonso LC, Yang Y
Metabolism · 2025 Mar · PMID 39710001 · Full text
AIMS: NAD deficiency underlies obesity-induced metabolic disturbances. This study evaluated dihydronicotinamide riboside (NRH), a potent NAD enhancer, in lean and obese mice and explored whether NRH operates through a un...
AIMS: NAD deficiency underlies obesity-induced metabolic disturbances. This study evaluated dihydronicotinamide riboside (NRH), a potent NAD enhancer, in lean and obese mice and explored whether NRH operates through a unique mechanism involving adenosine kinase (ADK), an enzyme critical for NRH-driven NAD synthesis. METHODS: Pharmacokinetic and pharmacodynamic analyses were performed following a single 250 mg/kg intraperitoneal injection of NRH in healthy mice. In long-term studies, lean and high-fat diet-induced obese mice were treated with 250 mg/kg NRH thrice weekly for 7 weeks. Blood NAD levels, body composition, energy expenditure, and glucose and lipid metabolism were monitored. To test ADK's role, the ADK inhibitor ABT702 was co-administered with NRH in obese mice. RESULTS: NRH entered tissues unassisted and was rapidly metabolized for NAD biosynthesis, while ADK inhibition blocked its phosphorylation, leading to NRH accumulation in all examined tissues and possible release back into circulation. The 7-week NRH administration was well-tolerated in both lean and obese mice. In obese mice, NRH improved glucose homeostasis by boosting insulin secretion, enhancing muscle insulin signaling, and reducing hepatic gluconeogenesis. It also lowered fat mass, decreased serum lipids, and improved white adipose function. These benefits were linked to elevated tissue NAD levels, enhanced Sirtuin activities, and increased mitochondrial antioxidant defenses. ADK inhibition abolished these effects, confirming that NRH's direct entry into tissues and subsequent phosphorylation is essential for its full benefits. CONCLUSION: This study establishes NRH as a promising therapeutic agent for obesity-induced metabolic dysfunction, correcting glucose intolerance and hyperlipidemia through ADK-dependent NAD enhancement.
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