Diabetes & Metabolism[JOURNAL]
Sun
200 papers
Phenome-wide associations of coffee intake in the human phenotype project.
Dai J, Dai W, Heianza Y … +1 more , Qi L
Metabolism · 2026 Jan · PMID 41047001 · Full text
OBJECTIVE: Coffee is one of the most widely consumed beverages globally and has been linked to favorable health outcomes. However, its system-wide relationships with human biology and the underlying mechanisms remain poo...
OBJECTIVE: Coffee is one of the most widely consumed beverages globally and has been linked to favorable health outcomes. However, its system-wide relationships with human biology and the underlying mechanisms remain poorly characterized. This study aimed to investigate the relationship between coffee consumption and continuous glucose monitoring (CGM) metrics and other biological systems in healthy adults. RESEARCH DESIGN AND METHODS: In the Human Phenotype Project, 8666 generally healthy Israeli adults provided two weeks of real-time dietary logs, from which coffee intake was estimated. Participants wore CGM devices throughout this period, and multimodal data spanning 11 additional systems (e.g., gut microbiome, serum lipidomics, and body composition) were collected. We employed machine learning approaches to quantify the extent to which each system reflected coffee intake. We performed linear regression to identify individual traits associated with coffee intake, with false discovery rates < 0.05 considered significant. RESULTS: This cross-sectional study identified continuously-monitored glucose regulation and gut microbial composition as the most reflective systems of coffee intake, with further analyses revealing favorable glycemic profiles spanning diverse aspects of glucose regulation with increasing coffee intake, and Clostridium phoceensis (i.e., Lawsonibacter asaccharolyticus) as the most significant species positively associated with coffee intake. Additionally, coffee intake was favorably associated with traits across body composition, serum lipidomics, and hepatic, hematopoietic, and renal systems. CONCLUSIONS: This study found that habitual coffee intake was linked to multifaceted favorable glucose control captured by CGM and favorable profiles across multiple biological systems, providing mechanistic insights that may guide precision nutrition strategies for diabetes prevention.
Administration of the K channel activator SKA-31 improves long-term endothelial function, blood pressure regulation and cardiac performance in rats with type 2 diabetes.
Mishra RC, Khaddaj Mallat R, John CM … +8 more , Belke DD, Hamm L, Singh L, Kim T, George G, Chen YX, Wulff H, Braun AP
Metabolism · 2026 Jan · PMID 41043591 · Publisher ↗
OBJECTIVE: Our goal in the present study was to examine whether long-term administration of the selective K channel activator SKA-31 would mitigate the development/severity of type 2 diabetes (T2D)-associated cardiovascu...
OBJECTIVE: Our goal in the present study was to examine whether long-term administration of the selective K channel activator SKA-31 would mitigate the development/severity of type 2 diabetes (T2D)-associated cardiovascular (CV) complications in adult male Goto-Kakizaki (GK) rats with spontaneous T2D. METHODS: Adult male T2D GK rats instrumented with radio-telemeters were administered either vehicle or the K channel activator SKA-31 (10 mg/kg) at ~14 weeks of age by daily intraperitoneal injection for 12 consecutive weeks. In vivo and ex vivo analyses of CV function, immune system status, vascular signaling and metabolic hormones were performed following treatment. RESULTS: Vehicle-treated T2D GK rats exhibited gradual increases in systolic and diastolic blood pressure, whereas SKA-31 administration led to lower mean arterial pressure, along with improvements in cardiac function (i.e., ejection fraction, fractional shortening) and structure (i.e., end systolic and diastolic volumes), as determined by echocardiography. SKA-31 treatment in vivo further improved vascular endothelial function in small mesenteric arteries, as determined by arterial pressure myography, and increased the protein expression of vasodilatory signaling molecules in the vascular wall. Prolonged SKA-31 treatment did not impair vasodilatory responsiveness in skeletal muscle and coronary arteries, elicit a pro-inflammatory profile in T2D GK rats or produce any adverse histological effects in brain, kidney or liver. CONCLUSIONS: The results of our study demonstrate that low-dose administration of the K channel activator SKA-31 improved CV function in an established rat model of spontaneous T2D and reveal a potential novel strategy to oppose CV-related morbidity in T2D.
BMAL2 controls adipose tissue inflammation and metabolic adaptation during obesity.
Philippe MA, Fruchet B, Cagninacci L … +8 more , Beaudoin L, Gadault A, Aznar B, Venteclef N, Challet E, Lehuen A, Rogner UC, Toubal A
Metabolism · 2026 Jan · PMID 40983272 · Publisher ↗
Contemporary lifestyle modifications such as changes in nutritional and sleep/wake rhythms increase the risk of metabolic and inflammatory complications linked to obesity, including type 2 diabetes (T2D) and metabolic dy...
Contemporary lifestyle modifications such as changes in nutritional and sleep/wake rhythms increase the risk of metabolic and inflammatory complications linked to obesity, including type 2 diabetes (T2D) and metabolic dysfunction-associated steatohepatitis (MASH). BMAL2 (Brain and Muscle ARNT Like Protein 2) is a transcription factor belonging to the circadian clock transcriptional feedback loop which synchronizes internal biological rhythms to environment. In humans, reduced expression in white adipose tissue (WAT) and specific polymorphisms of BMAL2 are associated with obesity and T2D. In this study we report that Bmal2 deletion in mice leads to increased body weight gain during diet-induced obesity. Loss of BMAL2 triggers the inflammatory response by increasing Tnfα expression and modifying adipocyte progenitor fate. This results in reduced lipid storage capacity within the WAT and increased ectopic storage in the liver. These functional and structural alterations culminate in the onset of hepatic steatosis and insulin resistance in liver and WAT. Overall, our investigations underscore the role of BMAL2 in the development and function of adipocytes, as well as in their inflammatory potential within the WAT. Our findings contribute to the understanding of the role of circadian clock genes in obesity and interconnected metabolic complications.
27-Hydroxycholesterol exacerbates hepatic insulin resistance via plasma membrane cholesterol remodeling.
Yang J, Yang X, Zheng Y … +8 more , Wang A, Kong Z, Xiao Q, Tian Y, Dong H, Zhang Z, Wang M, Song R
Metabolism · 2025 Dec · PMID 40962175 · Publisher ↗
BACKGROUND AND AIMS: Insulin resistance is a key driver of metabolic disorders, yet its molecular mechanisms remain elusive. This study identifies 27-hydroxycholesterol (27HC), a cholesterol-derived metabolite, and inves...
BACKGROUND AND AIMS: Insulin resistance is a key driver of metabolic disorders, yet its molecular mechanisms remain elusive. This study identifies 27-hydroxycholesterol (27HC), a cholesterol-derived metabolite, and investigates its role in insulin resistance. METHODS: Targeted metabolomics quantified absolute and relative levels of 27HC (27HC/cholesterol ratio) in patients, mice, and hepatocytes. Insulin resistant mouse models were established to characterize spatiotemporal dynamics of 27HC and related enzymes. Functional analyses assessed 27HC's effect on insulin signaling across multiple hepatocyte types. Transcriptomic analysis identified key effector pathways. Plasma membrane cholesterol accessibility was evaluated using biosensors and validated by cholesterol rescue. Membrane protein extraction, immunofluorescence, and flow cytometry were employed to assess the impact of 27HC on insulin receptor (IR) distribution and binding capacity. RESULTS: Elevated 27HC levels were observed in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), obese and type 2 diabetic mice (T2DM), and PA-treated HepG2 and primary hepatocytes, correlating with impaired insulin sensitivity. CYP27A1 was identified as the key enzyme regulating liver 27HC levels. In vitro studies demonstrated that 27HC disrupts insulin signaling in HepG2, AML12, and primary hepatocytes, whereas CYP27A1 knockdown restored IR responsiveness. 27HC suppresses SREBP2-dependent cholesterol biosynthesis, depleting accessible cholesterol in the plasma membrane, triggering IR mislocalization and signal attenuation. Liver-specific CYP27A1 silencing in mice fed a high-fat diet improved systemic insulin sensitivity and restored metabolic homeostasis. CONCLUSION: Our findings establish 27HC as a key effector linking cholesterol metabolism to insulin resistance and propose CYP27A1 inhibition as a potential therapeutic strategy for insulin resistance.
Disruption of mitochondria-associated membranes contributes to the dysregulation of insulin secretion in undernutrition, obesity, and double burden of malnutrition.
Dos Reis Araujo T, da Silva Junior JA, Alves BL … +5 more , Guimarães DSPSF, Barreto LM, Muniz MRR, Rieusset J, Carneiro EM
Metabolism · 2025 Dec · PMID 40962174 · Publisher ↗
AIMS/HYPOTHESIS: Nutritional disorders directly affect the endocrine pancreas, increasing the susceptibility to type 2 diabetes mellitus. However, the molecular mechanisms underlying these alterations remain unknown. Thi...
AIMS/HYPOTHESIS: Nutritional disorders directly affect the endocrine pancreas, increasing the susceptibility to type 2 diabetes mellitus. However, the molecular mechanisms underlying these alterations remain unknown. This study aims to characterize the role of endoplasmic reticulum (ER)-mitochondria contact sites, known as mitochondrial-associated membranes (MAMs), in insulin secretion dysfunctions associated with undernutrition, obesity, and the double burden of malnutrition (DBM). METHODS: Rat pancreatic INS-1E β-cells were cultured in a medium without amino acids supplemented with 1 × (control) or 0.25 × (amino acid restriction) of an amino acid solution for 48 h, and then cells were exposed to a fatty acid mix for 48 h. Male C57BL/6 mice were fed a normoprotein diet (14 % protein) or protein-restricted diet (6 % protein) for 6 weeks and subsequently a high-fat diet (35 % kcal) for 12 weeks. ER-mitochondria interactions were evaluated by in situ proximity ligation assay and transmission electronic microscopy. RESULTS: Our findings indicate that protein restriction reduces ER-mitochondria contacts in pancreatic beta-cells, leading to decreased mitochondrial metabolism and glucose-stimulated insulin secretion (GSIS). In contrast, obesity increases ER-mitochondria contact points, mitochondrial metabolism, and GSIS in pancreatic beta-cells, without alterations in viability. DBM results in a significant increase in ER-mitochondria contacts, elevated mitochondrial calcium levels, increased production of reactive oxygen species, and cell death, collectively contributing to impaired GSIS response in the context of obesity. CONCLUSIONS/INTERPRETATION: These data indicates that MAMs play a crucial role in GSIS during nutritional disorders such as undernutrition, obesity, and DBM. Importantly, changes in MAMs precede GSIS impairment, therefore targeting these interactions might prevent further disruption in beta-cell function.
Relationship of GDF15 with hepatic mitochondrial respiration is depending on the presence of fibrosis in obese individuals.
Giannakogeorgou A, Kahl S, Granata C … +12 more , Heilmann G, Mastrototaro L, Dewidar B, Bobrov P, Esposito I, Yavas A, Trenkamp S, Granderath FA, Schlensak M, Mantzoros CS, Roden M, Schrauwen P
Metabolism · 2025 Dec · PMID 40953731 · Publisher ↗
BACKGROUND AND PURPOSE: Preclinical studies reported elevated growth differentiation factor 15 (GDF15) when mitochondrial function is reduced. In humans, metabolic dysfunction-associated steatotic liver disease (MASLD) a...
BACKGROUND AND PURPOSE: Preclinical studies reported elevated growth differentiation factor 15 (GDF15) when mitochondrial function is reduced. In humans, metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) exhibit different hepatic mitochondrial adaptation. We hypothesized that circulating GDF15 differently correlates with hepatic mitochondrial respiration in obesity and/or MASLD/MASH. METHODS: Humans without (n = 20) and with biopsy-confirmed MASLD (n = 20) or MASH (n = 20) underwent hyperinsulinemic-euglycemic clamps to assess whole-body (M-value) and adipose-tissue (insulin-induced NEFA suppression) insulin sensitivity. Fasting serum GDF15 and glucagon were quantified by ELISA. Mitochondrial respiration was measured in liver obtained during bariatric surgery by high-resolution respirometry. Associations were assessed with Spearman's nonparametric correlation. RESULTS: Serum GDF15 correlated negatively with M-value (r = -0.35, p = 0.017) and NEFA suppression (r = -0.29, p = 0.046), but not with hepatic mitochondrial respiration across the whole cohort. However, correlations were found upon stratification into groups based on the presence (n = 37, age: 41 ± 2y, BMI: 49 ± 1 kg/m) or absence of hepatic fibrosis (n = 23, 44 ± 2 years, BMI: 49 ± 1 kg/m). In persons without fibrosis, GDF15 correlated positively with fatty acid oxidation-linked (F; r = 0.35, p = 0.035) and maximal coupled (FNS; r = 0.42, p = 0.010) mitochondrial respiration. Conversely, GDF15 correlated negatively with hepatic FN in persons with fibrosis (r = -0.48, p = 0.022). CONCLUSIONS: In humans with obesity, serum GDF15 correlates positively with hepatic mitochondrial respiration in persons without, but negatively in persons with hepatic fibrosis. Future studies are needed to investigate whether and how GDF15 affects hepatic mitochondrial respiration in a fibrosis-dependent manner and/or, conversely, how fibrosis might modulate hepatic GDF15 secretion through altered mitochondrial function.
SerpinA3N in leptin-sensitive neurons is required for energy and glucose homeostasis and autonomic regulation.
Guo DF, Luo Z, Olson A … +3 more , Morgan DA, Newell EA, Rahmouni K
Metabolism · 2025 Dec · PMID 40935321 · Full text
AIMS: SerpinA3N (Serpin peptidase inhibitor clade A member 3) is a serine protease inhibitor upregulated in the hypothalamus by leptin and obesity, yet its role in physiological regulation remains poorly understood. This...
AIMS: SerpinA3N (Serpin peptidase inhibitor clade A member 3) is a serine protease inhibitor upregulated in the hypothalamus by leptin and obesity, yet its role in physiological regulation remains poorly understood. This study aims to elucidate the role of hypothalamic SerpinA3N in regulation of energy balance, glucose homeostasis, and autonomic and cardiovascular functions. METHODS AND RESULTS: Immunostaining revealed that SerpinA3N is primarily expressed in neurons, including those expressing the leptin receptor (LepRb). Targeted deletion of SerpinA3N in LepRb neurons reduced body weight and adiposity and improved insulin sensitivity in female mice. SerpinA3N deficiency also enhanced leptin sensitivity, evidenced by amplified leptin-induced anorexia, weight loss, and LepRb signaling in the hypothalamic arcuate nucleus. Upon exposure to an obesogenic diet, mice lacking SerpinA3N in LepRb neurons exhibited attenuated weight gain, hepatic lipid accumulation and microgliosis. Notably, SerpinA3N deletion in LepRb neurons impaired baroreflex sensitivity and elevated renal sympathetic nerve activity, with dietary obesity further exacerbating sympathetic tone. CONCLUSIONS: These findings identify neuronal SerpinA3N as a key regulator of energy balance, leptin and insulin sensitivity, and autonomic function.
Mini-review of the EAT-Lancet planetary health diet and its role in cardiometabolic disease prevention.
Stubbendorff A, Janzi S, Jukkola J … +4 more , Morency M, Zhang S, Borné Y, Sonestedt E
Metabolism · 2025 Nov · PMID 40780481 · Publisher ↗
Human diets play a crucial role in both human health and environmental sustainability. In 2019, the EAT-Lancet Commission on healthy diets from sustainable food systems introduced the EAT-Lancet planetary health diet, a...
Human diets play a crucial role in both human health and environmental sustainability. In 2019, the EAT-Lancet Commission on healthy diets from sustainable food systems introduced the EAT-Lancet planetary health diet, a universal reference diet designed to promote human health while minimizing environmental degradation. It is a predominantly plant-based dietary pattern, rich in whole grains, vegetables, fruits, legumes, and nuts, while low in red meat and added sugars. In this mini-review, we summarize findings from prospective cohorts examining the EAT-Lancet diet in relation to mortality and cardiometabolic outcomes. Higher adherence to this diet was generally associated with lower risk of all-cause mortality, cardiovascular disease, and type 2 diabetes. However, the magnitude of associations varied depending on cohort characteristics, scoring systems, and methodological factors. In addition, adherence to the EAT-Lancet diet was generally low in the studies reviewed. These results suggest potential public health benefits of adopting the EAT-Lancet diet but also highlight the need for harmonized definitions and further research on underlying mechanisms.
Exercise training increases skeletal muscle sphingomyelinases and affects mitochondrial quality control in men with type 2 diabetes.
Hendlinger M, Mastrototaro L, Exterkate M … +8 more , Apostolopoulou M, Karusheva Y, Heilmann G, Lipaeva P, Straßburger K, Gancheva S, Kahl S, Roden M
Metabolism · 2025 Nov · PMID 40759392 · Publisher ↗
Lipotoxic ceramides (CERs) are implicated in the development of insulin resistance, type 2 diabetes (T2D) and related complications. Exercise training improves insulin sensitivity, potentially via reducing intracellular...
Lipotoxic ceramides (CERs) are implicated in the development of insulin resistance, type 2 diabetes (T2D) and related complications. Exercise training improves insulin sensitivity, potentially via reducing intracellular lipids or enhancing mitochondrial oxidation. Acid sphingomyelinase (ASM), which hydrolyzes sphingomyelin (SM) to CERs, is crucial for muscle repair and development, yet its role in insulin-resistant states and response to exercise remain unclear. We assessed ASM protein and activity, neutral sphingomyelinase (NSM) and sphingolipid species in skeletal muscle of insulin-sensitive (IS, n = 12), insulin-resistant (IR, n = 11) and T2D men (n = 20), before and after a 12-week high-intensity interval training (HIIT). Comprehensive phenotyping comprised hyperinsulinemic-euglycemic clamps, spiroergometry, targeted lipidomics and assessment of markers of mitochondrial quality control. ASM protein was lower at baseline and increased after HIIT only in T2D (p < 0.05), while ASM activity rose across all groups (IS p < 0.01; IR and T2D p < 0.001). HIIT also increased NSM protein in all groups (p < 0.05). Despite lower baseline SM levels in T2D, HIIT led to elevated CERs species in T2D (C16:0, C20:0, C22:0, C24:1, C24:0) and in IR (C16:0, C20:0) (all p < 0.05). Regression analysis suggested that changes in ASM protein and activity relate to changes in mitochondrial fusion and fission as well as AMP-activated protein kinase (AMPK)-mediated mitophagy. In conclusion, HIIT induces expression of both ASM and NSM and alters CER profiles in insulin-resistant skeletal muscle, independently of changes in insulin sensitivity. ASM could therefore rather contribute to exercise-induced mitochondrial remodeling than driving lipotoxicity, warranting further investigation of ASM as a potential target for exercise mimetic therapies.
A key role of polyamine metabolism in adipose tissue homeostasis that regulates obesity.
Mund C, Sinha A, Aderhold A … +27 more , Mateska I, Hagag E, Traikov S, Gercken B, Soto A, Pollock J, Arndt L, Wölk M, Werner N, Fodelianaki G, Subramanian P, Chung KJ, Grossklaus S, Langner M, Elgendy M, Grinenko T, Wielockx B, Dahl A, Gericke M, Blüher M, Coskun Ü, Voehringer D, Fedorova M, Peitzsch M, Murray PJ, Chavakis T, Alexaki VI
Metabolism · 2025 Nov · PMID 40754155 · Publisher ↗
BACKGROUND AND AIMS: Adipose tissue function is integral to systemic metabolic homeostasis. Excessive adipose tissue growth is associated with development of chronic low-grade inflammation and whole body dysmetabolism. T...
BACKGROUND AND AIMS: Adipose tissue function is integral to systemic metabolic homeostasis. Excessive adipose tissue growth is associated with development of chronic low-grade inflammation and whole body dysmetabolism. The cell metabolic pathways regulating adipose tissue growth and homeostasis are little understood. Here we studied the role of polyamine metabolism in adipose tissue (patho)physiology. METHODS: We generated mice with global and adipocyte progenitor (AP)-specific Antizyme inhibitor 2 (AZIN2) deficiency and performed diet-induced obesity studies. APs were isolated from the subcutaneous and gonadal adipose tissue of mice and cultured. RESULTS: Polyamine metabolism components, including AZIN2, were highly expressed in APs and their expression in the adipose tissue was downregulated with obesity. IL4 induced Azin2 expression in APs. AZIN2 facilitated polyamine synthesis and acetylation, and regulated total acetyl-CoA levels in APs. AZIN2 deficiency upregulated histone acetylation in genes related to lipid metabolism. Azin2 APs committed more efficiently to adipogenesis in vivo and in vitro, and were more prone to senescence compared to wild-type counterparts. Upon diet-induced obesity, global and AP-specific AZIN2 deficiency in mice provoked AP depletion, adipocyte hypertrophy, obesity, inflammation, glucose intolerance and insulin resistance. In human adipose tissue, AZIN2 expression strongly correlated with expression of progenitor markers. CONCLUSIONS: Altogether, we identified AZIN2 as a novel AP marker that regulates AP fate and preserves adipose tissue health.
Lactiplantibacillus plantarum strain 84-3-derived l-glutamine ameliorates glucose homeostasis via AMPK/PPARγ signaling pathway activation in type 2 diabetes.
Liang T, Jiang T, Liang Z … +6 more , Chen Y, Chen T, Dong B, Xie X, Gu B, Wu Q
Metabolism · 2025 Nov · PMID 40738384 · Publisher ↗
BACKGROUND: Gut microbiota and their metabolites play an essential role in type 2 diabetes (T2D). However, contributions of individual bacterial strains and their metabolites to T2D pathogenesis remain poorly understood....
BACKGROUND: Gut microbiota and their metabolites play an essential role in type 2 diabetes (T2D). However, contributions of individual bacterial strains and their metabolites to T2D pathogenesis remain poorly understood. We investigated T2D regulation by Lactobacillus in various animal models to understand its therapeutic effects. METHODS AND RESULTS: We performed a case-control study of Chinese adults using metabolome profiling and identified an inverse correlation between l-glutamine and T2D serum concentrations. The glnA and GLUL genes encoding glutamine synthetase (GS) in L. plantarum 84-3 were also identified. L. plantarum 84-3 treatment significantly decreased serum inflammation and improved metabolic phenotypes in streptozotocin- or tetraoxypyrimidine-induced T2D rats, including blood glucose, glucose tolerance, insulin resistance, and lipids. We confirmed elevated serum l-glutamine levels in the L. plantarum 84-3 group. RNA sequencing analysis demonstrated that L. plantarum 84-3-derived l-glutamine is a vital bioactive molecule, improving glucose homeostasis by activating the liver AMPK/PPAR signaling pathway and ameliorating T2D. We conducted co-culture fermentation experiments in vitro and in vivo, and metagenomic and metabolomic analyses revealed that resistance starch combined with L. plantarum 84-3 significantly enriched of Lactobacillus abundance and increased the l-glutamine level, affecting of alanine, aspartate, and glutamate metabolism pathways, which was confirmed in vivo in rats. The reduced L. plantarum and l-glutamine levels were validated in a human T2D cohort. CONCLUSIONS: These findings revealed a novel therapeutic effect of L. plantarum in alleviating T2D-related glucose homeostasis by increasing circulating l-glutamine, which suggests viable preventive and therapeutic strategies for metabolic disorders.
Flot2 protects against podocyte injury by maintaining the stability of synaptopodin in diabetic nephropathy.
Zhang H, Wang W, Liu P … +6 more , Zhang T, Zhang L, Ye Z, Yang W, Bai X, Yu X
Metabolism · 2025 Oct · PMID 40681143 · Publisher ↗
Podocyte injury is a major determinant of diabetic nephropathy (DN). Critical structural proteins such as synaptopodin play an important role in maintaining podocyte morphology and function. Herein, we uncover a protecti...
Podocyte injury is a major determinant of diabetic nephropathy (DN). Critical structural proteins such as synaptopodin play an important role in maintaining podocyte morphology and function. Herein, we uncover a protective role of Flotillin-2 (Flot2), a lipid microdomain-associated protein, in the development of DN by maintaining the stability of synaptopodin. We found that Flot2 was downregulated in podocytes and its expression was correlated with glomerular filtration rate and proteinuria in patients with DN. Functionally, Flot2 is protective in DN as global and podocyte-specific Flot2 knockout (KO) worsened podocyte injury and aggravated the disease as demonstrated by increasing albuminuria, thickening of glomerular basement membrane, and expansion of mesangium matrix in diabetic mice. In contrast, podocyte-specific Flot2 overexpression ameliorated diabetes-induced renal dysfunction and pathology. Mechanistically, we found that Flot2 directly interacted with synaptopodin and protected synaptopodin from ubiquitin degradation via the K48-linked polyubiquitination mediated proteasome pathway. Thus, our findings demonstrate that Flot2 is protective in DN and exerts its protective role by stabilizing synaptopodin. Targeting Flot2 may be a potential therapeutic approach in DN.
Time for a change? Threshold for obesity in contemporary Japanese population.
Kasahara K, Ichikawa Y, Hironaka J … +11 more , Shinozaki T, Okada H, Nakajima H, Ushigome E, Hamaguchi M, Kurogi K, Murata H, Tsuda E, Yoshida N, Ito M, Fukui M
Metabolism · 2025 Oct · PMID 40675545 · Publisher ↗
BACKGROUND: The obesity criteria for Japanese population are defined based on a cross-sectional study conducted 30 years ago. We aimed to examine the validity of a BMI of 25 kg/m as a determinant of obesity in the Japane...
BACKGROUND: The obesity criteria for Japanese population are defined based on a cross-sectional study conducted 30 years ago. We aimed to examine the validity of a BMI of 25 kg/m as a determinant of obesity in the Japanese population by assessing the association between BMI and the lifestyle-related diseases in a large and long-term cohort. METHODS: This cohort study included 162,136 individuals aged ≥40 years who participated in a medical health checkup program at Panasonic Corporation covering 166 operational sites from 2008 to 2023. The associations between BMI and the development of lifestyle-related diseases during the follow-up period were assessed using a multivariate Cox proportional hazards model. A restricted cubic spline function was applied to model the associations between BMI and disease risk. The BMI values associated with the doubling of HRs (compared with a reference BMI of 22 kg/m) were examined. FINDINGS: The average follow-up duration ranged from 6 to 8 years depending on the outcome. Restricted cubic spline curves showed BMI values (kg/m) associated with an HR of 2 (vs. 22 kg/m): 24.6 for diabetes, 26.8 for hypertension, 32.3 for hypertriglyceridemia, 26.4 for low high-density lipoprotein cholesterol, 25 for high low-density lipoprotein cholesterol, 30.8 for coronary artery disease, 32.0 for stroke, and 25 for CKD after adjusting for covariates. Similar results were observed in subgroup analyses stratified by gender and age. CONCLUSION: The appropriateness of the conventional BMI threshold of 25 kg/m in Japan warrants reconsideration.
AEBP1 as a promising therapeutic target for skeletal muscle insulin resistance in type 2 diabetes mellitus: Convergent evidence from Mendelian randomization and functional validation.
Guo C, Li J, Yang X … +6 more , Xie W, Zeng F, Chen K, Mi W, Tang C, Wang H
Metabolism · 2025 Oct · PMID 40618921 · Publisher ↗
BACKGROUND: The pathogenesis of type 2 diabetes mellitus (T2DM) is closely related to skeletal muscle insulin resistance (IR). Currently, there is still a lack of relevant treatments. Summary-data-based Mendelian randomi...
BACKGROUND: The pathogenesis of type 2 diabetes mellitus (T2DM) is closely related to skeletal muscle insulin resistance (IR). Currently, there is still a lack of relevant treatments. Summary-data-based Mendelian randomization (SMR) is a vital tool for identifying druggable targets in skeletal muscle to develop T2DM treatments. METHODS: Potential causative genetic factors in skeletal muscle and blood causally associated with T2DM were identified by SMR analysis. Bayesian colocalisation were used to validate causality. Pleiotropic impact of drug targets was assessed using phenome-wide MR (Phe-MR). Then, targeted overexpression or knockdown of AEBP1 in mouse myoblast cell lines (C2C12) and human skeletal muscle cells (HSkMCs) further validated the functional phenotype. Protein docking, co-IP and SPR were used to demonstrate protein-protein interactions. RESULTS: Both European and Asian populations revealed that AEBP1 was significantly associated with T2DM and its glycemic profile in blood and skeletal muscle, and was identified as a risk factor. Co-localisation analyses suggest that AEBP1 and T2DM originate from the same genetic variants. Meanwhile, targeted AEBP1 therapy has no potential adverse effects. Furthermore, AEBP1 was significantly expressed in in vivo and in vitro IR models and was consistent with the SMR results. Overexpression of AEBP1 further impaired insulin signalling and glucose transport mechanisms, exacerbating skeletal muscle IR. Targeting AEBP1 knockdown reversed these changes. Protein interaction experiments revealed that PI3K (p110β) is a direct target protein for AEBP1 to exert molecular functions. CONCLUSION: Targeting AEBP1 therapy is expected to be a pivotal approach for the prevention and treatment of T2DM.
Best practice recommendations for the diagnosis and management of hypoparathyroidism.
Khan AA, Ali DS, Bilezikian JP … +33 more , Björnsdottir S, Collins MT, Cusano NE, Ebeling PR, Fuleihan GEH, Fukumoto S, Giustina A, Kaiser SM, Koch CA, Khan T, Keating P, Liu JM, Mantzoros CS, Mannstadt M, Mithal A, Perrier ND, Rayes M, Rizzoli R, Rhee Y, Rubin MR, Roszko KL, Shrayyef M, Shoback DM, Sikjær T, Siggelkow H, Sfeir J, Thakker R, Van Uum S, Winer KK, Yavuz DG, Yildiz BO, AbuAlrob H, Brandi ML
Metabolism · 2025 Oct · PMID 40581321 · Publisher ↗
BACKGROUND: Hypoparathyroidism (HypoPT) is characterized by low serum calcium due to insufficient parathyroid hormone (PTH). This manuscript builds upon the 2022 international HypoPT guidelines and three systematic revie...
BACKGROUND: Hypoparathyroidism (HypoPT) is characterized by low serum calcium due to insufficient parathyroid hormone (PTH). This manuscript builds upon the 2022 international HypoPT guidelines and three systematic reviews, which have been further informed by updated narrative reviews and expert consensus. This paper presents current best practice consensus recommendations for the diagnosis and management of HypoPT. METHODS: An International Panel of Experts updated the previous systematic reviews (SR's), conducted narrative reviews, developed, and subsequently approved these best practice recommendations at the Parathyroid Summit, held as a pre-Endocrine Society meeting in May 2024 (Boston, USA). RESULTS: Diagnostic criteria for chronic HypoPT require hypocalcemia with inappropriately normal or low PTH levels. Conventional therapy is recommended as first line therapy and includes calcium supplementation, active vitamin D, correction of vitamin D inadequacy and correction of abnormalities in serum magnesium. Monitoring is required to achieve optimal serum calcium while avoiding hyperphosphatemia, hypercalciuria and declines in renal function. Assessment of HypoPT complications is required including skeletal health assessment in postmenopausal women and men over the age of 50 years. Specific strategies are provided for managing HypoPT during pregnancy and lactation as well as in children. PTH replacement with palopegteriparatide has been approved and is an important therapeutic option, especially when conventional therapy is inadequate or not tolerated. CONCLUSION: These best practice recommendations provide a framework for HypoPT diagnosis and management, emphasizing individualized care, role of DNA analysis in the diagnosis of nonsurgical HypoPT, and role of PTH or PTH analogue therapy as appropriate. They complement the 2022 international guidelines and incorporate updated therapeutic recommendations from the past 3 years including the positioning of the newly approved molecule palopegteriparatide based on recent clinical trial data and expert consensus.
Glycine as a conditionally essential amino acid and its relationship to l-serine.
Holeček M
Metabolism · 2025 Sep · PMID 40527450 · Publisher ↗
Glycine is a conditionally essential amino acid obtained from food and synthesized in the body, primarily from l-serine. Glycine deficiency has been reported due to inadequate protein intake, malnutrition, late gestation...
Glycine is a conditionally essential amino acid obtained from food and synthesized in the body, primarily from l-serine. Glycine deficiency has been reported due to inadequate protein intake, malnutrition, late gestation, diabetes, insulin resistance, and increased exposure to xenobiotics. Because of the close links in glycine and l-serine metabolism mediated by serine hydroxymethyltransferase (SHMT), decreased concentrations of both amino acids coincide in most glycine-deficient states. The consequence is a widespread impact on metabolism, including altered synthesis of glutathione, collagen, nucleotides, and one‑carbon units, impaired antioxidant defense, cytoprotection, conjugation, and neurotransmission and increased levels of homocysteine and deoxysphingolipids. It can, therefore, be assumed that, rather than glycine alone, its coadministration with l-serine is more appropriate in glycine-deficient conditions. Replacing a part of the glycine with l-serine should avoid (i) glycine flux through SHMT towards l-serine associated with the loss of methylenetetrahydrofolate, a substance essential for methylation reactions, and (ii) ammonia formation due to glycine flux through the glycine cleavage system. Unfortunately, studies comparing the effects of separate administration of glycine and its coadministration with l-serine do not exist. Well-controlled studies in subjects without glycine deficit are required to examine the potential benefits of high doses of glycine as a pharmaconutrient.
USP48 protects against myocardial ischemia-reperfusion injury by stabilizing and upregulating CNN1 in type 1 diabetes mice.
Su JB, Chen G, Sun QY … +11 more , Fu X, Wu LX, Qiu HB, Lv ZL, Hu JY, Wang Y, Zhuang YY, Sun HJ, Lu QB, Zhang JR, Zhu XX
Metabolism · 2025 Sep · PMID 40513941 · Publisher ↗
Ubiquitin-specific protease 48 (USP48) plays an important role in the regulation of DNA repair and immune signaling in health and diseases. Nonetheless, its implication in the development of diabetes-accelerated myocardi...
Ubiquitin-specific protease 48 (USP48) plays an important role in the regulation of DNA repair and immune signaling in health and diseases. Nonetheless, its implication in the development of diabetes-accelerated myocardial ischemia/reperfusion (I/R) injury (MI/RI) has yet to be clarified. Diabetic mice were constructed by streptozotocin (STZ) injection, and MI/RI was then induced by coronary artery occlusion and reperfusion. H9c2 cells were exposed to high glucose (HG) for 24 h, followed by hypoxia/reoxygenation (H/R) for 4 and 2 h, respectively. USP48 protein and mRNA levels were downregulated in MI/RI mice or H/R-exposed cardiomyocytes, but were unexpectedly upregulated in diabetic mice following MI/RI and H9c2 cells exposed to HG and H/R. Cardiac-specific deficiency of USP48 worsened cardiac dysfunction, increased post-ischemic infarction size, promoted mitochondrial damage in myocardial cells, accelerated cardiomyocyte inflammation, oxidative stress, and apoptosis in diabetic mice. Conversely, such pathological conditions were ameliorated by cardiac-specific overexpression of USP48. Proteomics and experimental validation showed that USP48 stabilized and upregulated calponin 1 (CNN1) to confer cardioprotection, since silencing CNN1 minimized the benefits of USP48 in diabetes-aggravated cardiomyocyte injury. RNA sequencing and experimental data demonstrated that the USP48/CNN1 axis inhibited the release of CXC motif chemokine ligand 1 (CXCL1) and CXCL2 through inactivating the ERK1/2 pathway. Eventually, blockade of CXCL1/2 with specific antibodies protected against diabetes-exacerbated MI/RI, akin to USP48 overexpression. Together, these results highlight USP48 as a potential therapeutic target for managing diabetes-aggravated MI/RI by regulating the CNN1/ERK1/2/CXCL1/2 signaling pathway.
Synergistic effects of C-C chemokine receptor 2 inhibitor and transforming growth factor-β type I receptor kinase inhibitor combination in metabolic dysfunction-associated steatohepatitis.
Jo SH, Lee ES, Lee SB … +2 more , Ha KB, Chung CH
Metabolism · 2025 Sep · PMID 40494442 · Publisher ↗
BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive hepatic disorder characterized by its association with metabolic abnormalities, including obesity, hyperlipidemia, and type 2 diabetes...
BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive hepatic disorder characterized by its association with metabolic abnormalities, including obesity, hyperlipidemia, and type 2 diabetes mellitus. Characterized by hepatic steatosis, inflammation, and fibrosis, MASH presents a significant global health challenge, with limited pharmacological options available. There is a critical need for novel therapeutic strategies targeting key molecular pathways involved in MASH pathogenesis. Combination therapy with these two drugs is expected to provide complementary preventive and therapeutic effects against MASH. METHODS: This study examined the therapeutic efficacy of a C-C chemokine receptor 2 (CCR2) inhibitor (RS-102895) in combination with a TGF-β type I receptor kinase inhibitor (vactosertib) in preclinical MASH models. Histological analysis, serum biomarker quantification, and gene expression profiling were performed to assess hepatic lipid accumulation, inflammation, fibrosis, and metabolic regulatory pathways. RESULTS: Combination therapy significantly improved histological parameters and reduced liver inflammation and fibrosis markers compared with monotherapy. Notably, it led to reductions in lipid accumulation and inflammatory cytokines, alongside the restoration of AMP-activated protein kinase (AMPK) activation, a key regulator of metabolic regulator. The study also identified the Rho-associated protein kinase 1 (ROCK1)/AMPK axis as a central mediator of MASH progression. CONCLUSIONS: These findings indicate that dual inhibition of CCR2 and TGF-β signaling pathways could serve as an effective therapeutic approach for MASH. By addressing lipid accumulation, inflammation, and fibrosis while promoting metabolic balance, this strategy holds promise for improved clinical applications in treating this complex disease.
Sedentary behaviour and cardiometabolic health: Integrating the potential underlying molecular health aspects.
Franssen WMA, Nieste I, Verboven K … +1 more , Eijnde BO
Metabolism · 2025 Sep · PMID 40483777 · Publisher ↗
During the last decades, sedentary behaviour has been recognised as an interdependent risk factor for cardiometabolic health and premature mortality. Prolonged sedentary behaviour is associated with increased risks for c...
During the last decades, sedentary behaviour has been recognised as an interdependent risk factor for cardiometabolic health and premature mortality. Prolonged sedentary behaviour is associated with increased risks for chronic non-communicable diseases (NCDs) such as obesity, chronic respiratory diseases, type 2 diabetes mellitus, cardiovascular diseases and cancer due to disturbances in cardiometabolic health. However, despite the increased evidence supporting these associations, the underlying molecular mechanisms to the development of these NCDs remain largely unknown. In this review, we therefore discuss the existing evidence with regard to the potential underlying molecular mechanisms of sedentary behaviour-induced perturbations in cardiometabolic health. Here, various potential mechanisms related to carbohydrate metabolism, lipid metabolism, oxidative stress, inflammation and micro- and macro vascular function will be outlined. In addition, we summarise the current evidence on various strategies to interrupt sedentary behaviour and their effects on cardiometabolic health outcomes, including insulin sensitivity, blood lipid profiles, and cardiovascular health. Finally, we highlight key research gaps in the field of sedentary behaviour in relation to the underlying molecular mechanisms.
Revisiting gender differences in obesity and type 2 diabetes: Response letter.
Galán A, García-García F
Metabolism · 2025 Sep · PMID 40449616 · Publisher ↗
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