RESUMEN

Objective: This study aims to investigate the pathogenesis of hyperglycemia and its associated vasculopathy using multiomics analyses in diabetes and impaired glucose tolerance, and validate the mechanism using the cell experiments. Methods: In this study, we conducted a comprehensive analysis of the metagenomic sequencing data of diabetes to explore the key genera related to its occurrence. Subsequently, participants diagnosed with impaired glucose tolerance (IGT), and healthy subjects, were recruited for fecal and blood sample collection. The dysbiosis of the gut microbiota (GM) and its associated metabolites were analyzed using 16S rDNA sequencing and liquid chromatograph mass spectrometry, respectively. The regulation of gene and protein expression was evaluated through mRNA sequencing and data-independent acquisition technology, respectively. The specific mechanism by which GM dysbiosis affects hyperglycemia and its related vasculopathy was investigated using real-time qPCR, Western blotting, and enzyme-linked immunosorbent assay techniques in HepG2 cells and neutrophils. Results: Based on the published data, the key alterable genera in the GM associated with diabetes were identified as Blautia, Lactobacillus, Bacteroides, Prevotella, Faecalibacterium, Bifidobacterium, Ruminococcus, Clostridium, and Lachnoclostridium. The related metabolic pathways were identified as cholate degradation and L-histidine biosynthesis. Noteworthy, Blautia and Faecalibacterium displayed similar alterations in patients with IGT compared to those observed in patients with diabetes, and the GM metabolites, tauroursodeoxycholic acid (TUDCA) and carnosine (CARN, a downstream metabolite of histidine and alanine) were both found to be decreased, which in turn regulated the expression of proteins in plasma and mRNAs in neutrophils. Subsequent experiments focused on insulin-like growth factor-binding protein 3 and interleukin-6 due to their impact on blood glucose regulation and associated vascular inflammation. Both proteins were found to be suppressed by TUDCA and CARN in HepG2 cells and neutrophils. Conclusion: Dysbiosis of the GM occurred throughout the entire progression from IGT to diabetes, characterized by an increase in Blautia and a decrease in Faecalibacterium, leading to reduced levels of TUDCA and CARN, which alleviated their inhibition on the expression of insulin-like growth factor-binding protein 3 and interleukin-6, contributing to the development of hyperglycemia and associated vasculopathy.

Asunto(s)

Carnosina , Disbiosis , Heces , Microbioma Gastrointestinal , Humanos , Disbiosis/microbiología , Carnosina/metabolismo , Masculino , Heces/microbiología , Intolerancia a la Glucosa/metabolismo , Inflamación/metabolismo , Células Hep G2 , Metagenómica , Femenino , Persona de Mediana Edad , Ácido Tauroquenodesoxicólico/metabolismo , Ácido Tauroquenodesoxicólico/farmacología , Hiperglucemia/metabolismo , Neutrófilos/metabolismo , ARN Ribosómico 16S/genética , Bacterias/clasificación , Bacterias/metabolismo , Bacterias/genética

RESUMEN

Thermogenic adipose tissue, consisting of brown and beige fat, regulates nutrient utilization and energy metabolism. Human brown fat is relatively scarce and decreases with obesity and aging. Hence, inducing thermogenic differentiation of white fat offers an attractive way to enhance whole-body metabolic capacity. Here, we show the role of endothelin 3 (EDN3) and endothelin receptor type B (EDNRB) in promoting the browning of white adipose tissue (WAT). EDNRB overexpression stimulates thermogenic differentiation of human white preadipocytes through cAMP-EPAC1-ERK activation. In mice, cold induces the expression of EDN3 and EDNRB in WAT. Deletion of EDNRB in adipose progenitor cells impairs cold-induced beige adipocyte formation in WAT, leading to excessive weight gain, glucose intolerance, and insulin resistance upon high-fat feeding. Injection of EDN3 into WAT promotes browning and improved whole-body glucose metabolism. The findings shed light on the mechanism of WAT browning and offer potential therapeutics for obesity and metabolic disorders.

Asunto(s)

Tejido Adiposo Blanco , Diferenciación Celular , Endotelina-3 , Receptor de Endotelina B , Transducción de Señal , Termogénesis , Animales , Tejido Adiposo Blanco/metabolismo , Termogénesis/genética , Humanos , Ratones , Receptor de Endotelina B/metabolismo , Receptor de Endotelina B/genética , Endotelina-3/metabolismo , Endotelina-3/genética , Masculino , Obesidad/metabolismo , Obesidad/genética , Ratones Endogámicos C57BL , Dieta Alta en Grasa , Resistencia a la Insulina , Adipocitos Blancos/metabolismo , Ratones Noqueados , Adipocitos Beige/metabolismo , Tejido Adiposo Pardo/metabolismo , Intolerancia a la Glucosa/metabolismo , Frío

RESUMEN

Highland barley is a natural source for the development of phenolic compounds that exhibit potential in preventing type 2 diabetes, which is important for the agricultural and industrial utilization of highland barley. However, very few studies have focused on their effect on small intestinal absorption and barrier dysfunction, as well as the direct target for the modulation of hepatic glucose metabolism. In this study, procyanidin B1 (PB) and p-coumaric acid (CA) isolated from highland barley supplementation in impaired glucose tolerance (IGT) mice significantly increased lactase-phlorizin hydrolase (LPH), sulfotransferase 1A1 (SULT1A1), UDP glucuronosyltransferase 1A (UGT1A) families and sodium-dependent glucose transporter 1 (SGLT1) expression in the small intestine of IGT mice, indicating beneficial effects on polyphenol deglycosylation and transportation. Supplementation with PB and CA also exhibited attenuation of small intestinal barrier dysfunction by improving the mucus layer and tight junctions, which was closely related to the transportation of phenolic compounds. In addition, PB and CA supplementation were explored directly to bind to the insulin receptor and activate the insulin receptor substrate-1 (IRS-1)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway, thereby modulating hepatic glucose metabolism and ameliorating hyperglycemic in IGT mice. These results offer crucial insights into the potential development of PB and CA as non-food nutraceuticals, as well as the extensive utilization of highland barley as an industrial crop.

Asunto(s)

Biflavonoides , Catequina , Ácidos Cumáricos , Intolerancia a la Glucosa , Glucosa , Hordeum , Intestino Delgado , Hígado , Proantocianidinas , Animales , Hordeum/química , Proantocianidinas/farmacología , Ratones , Masculino , Intolerancia a la Glucosa/tratamiento farmacológico , Intolerancia a la Glucosa/metabolismo , Biflavonoides/farmacología , Ácidos Cumáricos/farmacología , Catequina/farmacología , Hígado/metabolismo , Hígado/efectos de los fármacos , Intestino Delgado/metabolismo , Intestino Delgado/efectos de los fármacos , Glucosa/metabolismo , Dieta Alta en Grasa/efectos adversos , Ratones Endogámicos C57BL , Propionatos , Transportador 1 de Sodio-Glucosa/metabolismo , Transportador 1 de Sodio-Glucosa/genética , Humanos

RESUMEN

OBJECTIVE: Maternal obesity is increasingly common and negatively impacts offspring health. Children of mothers with obesity are at higher risk of developing diseases linked to hematopoietic system abnormalities and metabolism such as type 2 diabetes. Interestingly, disease risks are often dependent on the offspring's sex, suggesting sex-specific reprogramming effect of maternal obesity on offspring hematopoietic stem and progenitor cell (HSPC) function. However, the impact of maternal obesity exposure on offspring HSPC function, and the capability of HSPC to regulate offspring metabolic health is largely understudied. This study aims to test the hypothesis that offspring of obese mice exhibit sex-differences in HSPC function that affect offspring's metabolic health. METHODS: We first assessed bone marrow hematopoietic stem and progenitor cell phenotype using postnatal day 21 (P21) and 8-week-old C57BL/6J mice born to control and diet-induced obese dams. We also sorted HSPC (Lineage-, Sca1+, cKit + cells) from P21 mice for competitive primary and secondary transplant, as well as transcriptomic analysis. Body weight, adiposity, insulin tolerance test and glucose tolerance tests were performed in primary and secondary transplant recipient animals. RESULTS: We discovered sex-differences in offspring HSPC function in response to maternal obesity exposure, where male offspring of obese dams (MatOb) showed decreased HSPC numbers and engraftment, while female MatOb offspring remained largely unaffected. RNA-seq revealed immune stimulatory pathways in female MatOb offspring. Finally, only recipients of male MatOb offspring HSPC exhibited glucose intolerance. CONCLUSIONS: This study demonstrated the lasting effect of maternal obesity exposure on offspring HSPC function and implicates HSPC in metabolic regulation.

Asunto(s)

Intolerancia a la Glucosa , Células Madre Hematopoyéticas , Ratones Endogámicos C57BL , Animales , Intolerancia a la Glucosa/metabolismo , Femenino , Ratones , Masculino , Células Madre Hematopoyéticas/metabolismo , Embarazo , Obesidad Materna/metabolismo , Ratones Obesos , Efectos Tardíos de la Exposición Prenatal/metabolismo , Obesidad/metabolismo , Dieta Alta en Grasa/efectos adversos

RESUMEN

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with obesity. Sex and age affect MASLD prevalence and pathophysiology. The use of animal models fed Western-style diets is vital for investigating the molecular mechanisms contributing to metabolic dysregulation and for facilitating novel drug target identification. However, the sex-associated and age-associated mechanisms underlying the pathophysiology remain poorly understood. This knowledge gap limits the development of personalized sex-specific and age-specific drug treatments. METHODS: Young (7 wk) and aged (52 wk) male and female mice were fed a high-fat diet (HFD) or low-fat diet. Liver metabolome (>600 molecules) and transcriptome profiles were analyzed. RESULTS: Male and female mice fed an HFD developed obesity, glucose intolerance, and hepatic steatosis. However, fasting blood glucose, insulin, and serum alanine aminotransferase levels were higher in males fed an HFD, indicating a more severe metabolic disease. In addition, males showed significant increases in liver diacylglycerides and glycosylceramides (known mediators of insulin resistance and fibrosis), and more changes in the transcriptome: extracellular matrix organization and proinflammatory genes were elevated only in males. In contrast, no major increase in damaging lipid classes was observed in females fed an HFD. However, aging affected the liver to a greater extent in females. Acylcarnitine levels were significantly reduced, suggestive of changes in fatty acid oxidation, and broad changes in the transcriptome were observed, including reduced oxidative stress response gene expression and alterations in lipid partitioning genes. CONCLUSIONS: Here, we show distinct responses to an HFD between males and females. Our study underscores the need for using both sexes in drug target identification studies, and characterizing the molecular mechanisms contributing to the MASLD pathophysiology in aging animals.

Asunto(s)

Dieta Alta en Grasa , Obesidad , Animales , Femenino , Masculino , Ratones , Dieta Alta en Grasa/efectos adversos , Factores Sexuales , Factores de Edad , Obesidad/metabolismo , Obesidad/fisiopatología , Modelos Animales de Enfermedad , Hígado/metabolismo , Hígado/fisiopatología , Transcriptoma , Hígado Graso/metabolismo , Hígado Graso/fisiopatología , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Enfermedad del Hígado Graso no Alcohólico/etiología , Resistencia a la Insulina , Metaboloma , Intolerancia a la Glucosa/fisiopatología , Intolerancia a la Glucosa/metabolismo

RESUMEN

AIMS: To determine risk factors for 1-year postpartum weight retention (PPWR) and glucose intolerance (prediabetes + diabetes) in women with a previous history of gestational diabetes (GDM) and prediabetes in early postpartum. METHODS: In this exploratory analysis of the MELINDA randomized controlled trial, we report data of 167 women with prediabetes at the 6-16 weeks (early) postpartum oral glucose tolerance test after a recent history of GDM. RESULTS: Of all participants, 45% (75) had PPWR >0 kg at 1-year postpartum. Compared to women without PPWR, women with PPWR had higher gestational weight gain [10.5 ± 6.4 vs. 6.5 ± 4.5 kg, p < 0.001], higher BMI (p < 0.01) and a worse metabolic profile (higher waist circumference, worse lipid profile and more insulin resistance) (all p < 0.05) both in early and late postpartum. Of all women with PPWR, 40.0% developed metabolic syndrome, compared to 18.9% of women without late PPWR (p = 0.003). The only independent predictor for late PPWR was weight retention in early postpartum (p < 0.001). Of all participants, 55.1% (92) had glucose intolerance (84 prediabetes, 8 diabetes) 1-year postpartum. Independent predictors for late postpartum glucose intolerance were lower gestational age at start insulin therapy in pregnancy and delivery by caesarean section (resp. p = 0.044 and 0.014). CONCLUSIONS: In women with a previous history of GDM and prediabetes in early postpartum, PPWR in early postpartum was a strong independent predictor for late PPWR, while earlier start of insulin therapy during pregnancy and delivery by caesarean section were independent predictors of glucose intolerance in late postpartum.

Asunto(s)

Diabetes Gestacional , Intolerancia a la Glucosa , Prueba de Tolerancia a la Glucosa , Periodo Posparto , Estado Prediabético , Humanos , Femenino , Diabetes Gestacional/epidemiología , Diabetes Gestacional/metabolismo , Embarazo , Estado Prediabético/epidemiología , Estado Prediabético/metabolismo , Adulto , Intolerancia a la Glucosa/epidemiología , Intolerancia a la Glucosa/metabolismo , Factores de Riesgo , Ganancia de Peso Gestacional , Síndrome Metabólico/epidemiología , Índice de Masa Corporal , Aumento de Peso/fisiología

RESUMEN

Classic hereditary hemochromatosis (HH) is an autosomal recessive iron-overload disorder resulting from loss-of-function mutations of the HFE gene. Patients with HH exhibit excessive hepatic iron accumulation that predisposes these patients to liver disease, including the risk for developing liver cancer. Chronic iron overload also poses a risk for the development of metabolic disorders such as obesity, type 2 diabetes, and insulin resistance. We hypothesized that liraglutide, GLP1 receptor agonist, alters iron metabolism while also reducing body weight and glucose tolerance in a mouse model of HH (global HFE knockout, HFE KO) and diet-induced obesity and glucose intolerance. The total body HFE KO and wild-type control mice were fed high-fat diet for 8 weeks. Mice were subdivided into liraglutide and vehicle-treated groups and received daily subcutaneous administration of the respective treatment once daily for 18 weeks. Liraglutide improved glucose tolerance and hepatic lipid markers and reduced body weight in a mouse model of HH, the HFE KO mouse, similar to wild-type controls. Importantly, our data show that liraglutide alters iron metabolism in HFE KO mice, leading to decreased circulating and stored iron levels in HFE KO mice. These observations highlight the potential that GLP1 receptor agonist could be used to reduce iron overload in addition to reducing body weight and improving glucose regulation in HH patients.

Asunto(s)

Modelos Animales de Enfermedad , Proteína de la Hemocromatosis , Hemocromatosis , Homeostasis , Hierro , Liraglutida , Ratones Noqueados , Animales , Hemocromatosis/genética , Hemocromatosis/metabolismo , Hemocromatosis/tratamiento farmacológico , Liraglutida/farmacología , Liraglutida/uso terapéutico , Hierro/metabolismo , Homeostasis/efectos de los fármacos , Ratones , Proteína de la Hemocromatosis/genética , Proteína de la Hemocromatosis/metabolismo , Hígado/metabolismo , Hígado/efectos de los fármacos , Masculino , Dieta Alta en Grasa/efectos adversos , Intolerancia a la Glucosa/metabolismo , Intolerancia a la Glucosa/tratamiento farmacológico , Intolerancia a la Glucosa/genética , Obesidad/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/genética , Ratones Endogámicos C57BL , Peso Corporal/efectos de los fármacos

RESUMEN

OBJECTIVES: We here assessed whether typical pathogens of laboratory mice affect the development of diet-induced obesity and glucose intolerance, and whether colonization affects the efficacy of the GLP-1R agonist liraglutide and of the GLP-1/GIP co-agonist MAR709 to treat obesity and diabetes. METHODS: Male C57BL/6J mice were experimentally infected with Helicobacter hepaticus, Rodentibacter pneumotropicus and Staphylococcus aureus and compared to a group of uninfected specific and opportunistic pathogen free (SOPF) mice. The development of diet-induced obesity and glucose intolerance was monitored over a period of 26 weeks. To study the influence of pathogens on drug treatment, mice were then subjected for 6 days daily treatment with either the GLP-1 receptor agonist liraglutide or the GLP-1/GIP co-agonist MAR709. RESULTS: Colonized mice did not differ from SOPF controls regarding HFD-induced body weight gain, food intake, body composition, glycemic control, or responsiveness to treatment with liraglutide or the GLP-1/GIP co-agonist MAR709. CONCLUSIONS: We conclude that the occurrence of H. hepaticus, R. pneumotropicus and S. aureus does neither affect the development of diet-induced obesity or type 2 diabetes, nor the efficacy of GLP-1-based drugs to decrease body weight and to improve glucose control in mice.

Asunto(s)

Dieta Alta en Grasa , Intolerancia a la Glucosa , Incretinas , Liraglutida , Ratones Endogámicos C57BL , Obesidad , Staphylococcus aureus , Animales , Dieta Alta en Grasa/efectos adversos , Ratones , Masculino , Staphylococcus aureus/efectos de los fármacos , Incretinas/metabolismo , Obesidad/metabolismo , Liraglutida/farmacología , Intolerancia a la Glucosa/metabolismo , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Organismos Libres de Patógenos Específicos , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/metabolismo

RESUMEN

PM2.5 exposure has been found to cause gut dysbiosis and impair glucose homeostasis in human and animals, yet their underlying biological connection remain unclear. In the present study, we aim to investigate the biological significance of gut microbiota in PM2.5-induced glucose metabolic abnormalities. Our results showed that microbiota depletion by antibiotics treatment significantly alleviated PM2.5-induced glucose intolerance and insulin resistance, as indicated by the intraperitoneal glucose tolerance test, glucose-induced insulin secretion, insulin tolerance test, insulin-induced phosphorylation levels of Akt and GSK-3ß in insulin sensitive tissues. In addition, faecal microbiota transplantation (FMT) from PM2.5-exposed donor mice successfully remodeled the glucose metabolism abnormalities in recipient mice, while the transplantation of autoclaved faecal materials did not. Faecal microbiota analysis demonstrated that the composition and alpha diversity of the gut bacterial community were altered by PM2.5 exposure and in FMT recipient mice. Furthermore, short-chain fatty acids levels analysis showed that the circulating acetate was significantly decreased in PM2.5-exposed donor and FMT recipient mice, and supplementation of sodium acetate for 3 months successfully improved the glucose metabolism abnormalities induced by PM2.5 exposure. These results indicate that manipulating gut microbiota or its metabolites could be a potential strategy for preventing the adverse health effects of ambient PM2.5.

Asunto(s)

Ácidos Grasos Volátiles , Microbioma Gastrointestinal , Resistencia a la Insulina , Material Particulado , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Ácidos Grasos Volátiles/metabolismo , Material Particulado/toxicidad , Masculino , Ratones Endogámicos C57BL , Trasplante de Microbiota Fecal , Glucosa/metabolismo , Intolerancia a la Glucosa/metabolismo , Contaminantes Atmosféricos/toxicidad , Ratones , Antibacterianos/farmacología , Disbiosis/inducido químicamente , Disbiosis/metabolismo , Heces/microbiología , Acetato de Sodio/farmacología , Prueba de Tolerancia a la Glucosa , Insulina/metabolismo , Insulina/sangre

RESUMEN

Circadian disruption causes glucose intolerance, cardiac fibrosis, and adipocyte dysfunction in sand rats (Psammomys obesus). Exercise intervention can improve glucose metabolism, insulin sensitivity, adipose tissue function and protect against inflammation. We investigated the influence of exercise on male P. obesus exposed to a short photoperiod (5 h light:19 h dark) and high-energy diet. Exercise reduced glucose intolerance. Exercise reduced cardiac expression of inflammatory marker Ccl2 and Bax:Bcl2 apoptosis ratio. Exercise increased heart:body weight ratio and hypertrophy marker Myh7:Myh6, yet reduced Gata4 expression. No phenotypic changes were observed in perivascular fibrosis and myocyte area. Exercise reduced visceral adipose expression of inflammatory transcription factor Rela, adipogenesis marker Ppard and browning marker Ppargc1a, but visceral adipocyte size was unaffected. Conversely, exercise reduced subcutaneous adipocyte size but did not affect any molecular mediators. Exercise increased ZT7 Bmal1 and Per2 in the suprachiasmatic nucleus and subcutaneous Per2. Our study provides new molecular insights and histological assessments on the effect of exercise on cardiac inflammation, adipose tissue dysfunction and circadian gene expression in P. obesus exposed to short photoperiod and high-energy diet. These findings have implications for the protective benefits of exercise for shift workers in order to reduce the risk of diabetes and cardiovascular disease.

Asunto(s)

Tejido Adiposo , Gerbillinae , Intolerancia a la Glucosa , Fotoperiodo , Condicionamiento Físico Animal , Animales , Masculino , Intolerancia a la Glucosa/metabolismo , Tejido Adiposo/metabolismo , Inflamación/metabolismo , Inflamación/patología , Dieta Alta en Grasa/efectos adversos , Miocardio/metabolismo , Miocardio/patología

RESUMEN

Introduction: Obesity is associated with a plethora of health complications, including increased susceptibility to infections or decreased vaccine efficacy, partly due to dysregulated immune responses. Monocytes play a crucial role in innate immunity, yet their functional alterations in obesity remain poorly understood. Methods: Here, we employed proteomic and metabolomic analyses to investigate monocyte characteristics in individuals with overweight, obesity, impaired glucose tolerance (IGT), and type 2 diabetes (T2D), compared to lean donors. Results and discussion: Our results revealed distinct molecular signatures in monocytes from individuals with obesity, with significant alterations in pathways related to metabolism, cellular migration, and phagocytosis. Moreover, LPS-induced activation of monocytes unveiled heightened metabolic reprogramming towards glycolysis in subjects with obesity accompanied by dysregulated cytokine responses and elevated oxidative stress. Additionally, monocytes from donors with obesity exhibited increased lipid droplet accumulation. These findings shed light on the immunometabolic dysregulation underlying obesity-associated immune dysfunction, highlighting potential targets for therapeutic intervention.

Asunto(s)

Citocinas , Glucólisis , Monocitos , Obesidad , Estrés Oxidativo , Humanos , Obesidad/inmunología , Obesidad/metabolismo , Monocitos/inmunología , Monocitos/metabolismo , Citocinas/metabolismo , Masculino , Femenino , Adulto , Persona de Mediana Edad , Diabetes Mellitus Tipo 2/inmunología , Diabetes Mellitus Tipo 2/metabolismo , Proteómica/métodos , Intolerancia a la Glucosa/inmunología , Intolerancia a la Glucosa/metabolismo

RESUMEN

BACKGROUND: Nephrin is a transmembrane protein with well-established signaling roles in kidney podocytes, and a smaller set of secretory functions in pancreatic ß cells are implicated in diabetes. Nephrin signaling is mediated in part through its 3 cytoplasmic YDxV motifs, which can be tyrosine phosphorylated by high glucose and ß cell injuries. Although in vitro studies demonstrate these phosphorylated motifs can regulate ß cell vesicle trafficking and insulin release, in vivo evidence of their role in this cell type remains to be determined. METHODS: To further explore the role of nephrin YDxV phosphorylation in ß cells, we used a mouse line with tyrosine to phenylalanine substitutions at each YDxV motif (nephrin-Y3F) to inhibit phosphorylation. We assessed islet function via primary islet glucose-stimulated insulin secretion assays and oral glucose tolerance tests. RESULTS: Nephrin-Y3F mice successfully developed pancreatic endocrine and exocrine tissues with minimal structural differences. Unexpectedly, male and female nephrin-Y3F mice showed elevated insulin secretion, with a stronger increase observed in male mice. At 8 months of age, no differences in glucose tolerance were observed between wild-type (WT) and nephrin-Y3F mice. However, aged nephrin-Y3F mice (16 months of age) demonstrated more rapid glucose clearance compared to WT controls. CONCLUSION: Taken together, loss of nephrin YDxV phosphorylation does not alter baseline islet function. Instead, our data suggest a mechanism linking impaired nephrin YDxV phosphorylation to improved islet secretory ability with age. Targeting nephrin phosphorylation could provide novel therapeutic opportunities to improve ß cell function.

Asunto(s)

Prueba de Tolerancia a la Glucosa , Secreción de Insulina , Células Secretoras de Insulina , Insulina , Proteínas de la Membrana , Animales , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Fosforilación , Ratones , Masculino , Secreción de Insulina/fisiología , Células Secretoras de Insulina/metabolismo , Femenino , Insulina/metabolismo , Tirosina/metabolismo , Envejecimiento/metabolismo , Intolerancia a la Glucosa/metabolismo , Ratones Endogámicos C57BL , Glucosa/metabolismo

RESUMEN

The prevalence of different metabolic syndromes has grown globally, and the farnesoid X receptor (FXR), a metabolic homeostat for glucose, lipid, and bile acid metabolisms, may serve an important role in the progression of metabolic disorders. Glucose intolerance by FXR deficiency was previously reported and observed in our study, but the underlying biology remained unclear. To investigate the ambiguity, we collected the nontargeted profiles of the fecal metaproteome, serum metabolome, and liver proteome in Fxr-null (Fxr-/-) and wild-type (WT) mice with LC-HRMS. FXR deficiency showed a global impact on the different molecular levels we monitored, suggesting its serious disruption in the gut microbiota, hepatic metabolism, and circulating biomolecules. The network and enrichment analyses of the dysregulated metabolites and proteins suggested the perturbation of carbohydrate and lipid metabolism by FXR deficiency. Fxr-/- mice presented lower levels of hepatic proteins involved in glycogenesis. The impairment of glycogenesis by an FXR deficiency may leave glucose to accumulate in the circulation, which may deteriorate glucose tolerance. Lipid metabolism was dysregulated by FXR deficiency in a structural-dependent manner. Fatty acid ß-oxidations were alleviated, but cholesterol metabolism was promoted by an FXR deficiency. Together, we explored the molecular events associated with glucose intolerance by impaired FXR with integrated novel multiomic data.

Asunto(s)

Intolerancia a la Glucosa , Metabolismo de los Lípidos , Hígado , Ratones Noqueados , Multiómica , Receptores Citoplasmáticos y Nucleares , Animales , Masculino , Ratones , Heces/química , Microbioma Gastrointestinal , Glucosa/metabolismo , Intolerancia a la Glucosa/metabolismo , Intolerancia a la Glucosa/sangre , Intolerancia a la Glucosa/genética , Metabolismo de los Lípidos/genética , Hígado/metabolismo , Metaboloma , Multiómica/métodos , Proteoma/metabolismo , Proteómica/métodos , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/deficiencia

RESUMEN

Circadian disruption increases the development of cardiovascular disease and diabetes. We found that circadian disruption causes glucose intolerance, cardiac fibrosis and adipocyte tissue dysfunction in male sand rats, Psammomys obesus. Whether these effects occur in female P. obesus is unknown. Male and female P. obesus were fed a high energy diet and exposed to a neutral (12 light:12 dark, control) or short (5 light:19 dark, circadian disruption) photoperiod for 20 weeks. Circadian disruption impaired glucose tolerance in males but not females. It also increased cardiac perivascular fibrosis and cardiac expression of inflammatory marker Ccl2 in males, with no effect in females. Females had reduced proapoptotic Bax mRNA and cardiac Myh7:Myh6 hypertrophy ratio. Cardiac protection in females occurred despite reductions in the clock gene Per2. Circadian disruption increased adipocyte hypertrophy in both males and females. This was concomitant with a reduction in adipocyte differentiation markers Pparg and Cebpa in males and females, respectively. Circadian disruption increased visceral adipose expression of inflammatory mediators Ccl2, Tgfb1 and Cd68 and reduced browning marker Ucp1 in males. However, these changes were not observed in females. Collectively, our study show that sex differentially influences the effects of circadian disruption on glucose tolerance, cardiac function and adipose tissue dysfunction.

Asunto(s)

Adipocitos , Fibrosis , Gerbillinae , Intolerancia a la Glucosa , Animales , Femenino , Adipocitos/metabolismo , Adipocitos/patología , Masculino , Intolerancia a la Glucosa/metabolismo , Miocardio/metabolismo , Miocardio/patología , Ritmo Circadiano

RESUMEN

BACKGROUND AND AIM: Diacylglycerol kinase (DGK) isoforms catalyze an enzymatic reaction that removes diacylglycerol (DAG) and thereby terminates protein kinase C signaling by converting DAG to phosphatidic acid. DGKδ (type II isozyme) downregulation causes insulin resistance, metabolic inflexibility, and obesity. Here we determined whether DGKδ overexpression prevents these metabolic impairments. METHODS: We generated a transgenic mouse model overexpressing human DGKδ2 under the myosin light chain promoter (DGKδ TG). We performed deep metabolic phenotyping of DGKδ TG mice and wild-type littermates fed chow or high-fat diet (HFD). Mice were also provided free access to running wheels to examine the effects of DGKδ overexpression on exercise-induced metabolic outcomes. RESULTS: DGKδ TG mice were leaner than wild-type littermates, with improved glucose tolerance and increased skeletal muscle glycogen content. DGKδ TG mice were protected against HFD-induced glucose intolerance and obesity. DGKδ TG mice had reduced epididymal fat and enhanced lipolysis. Strikingly, DGKδ overexpression recapitulated the beneficial effects of exercise on metabolic outcomes. DGKδ overexpression and exercise had a synergistic effect on body weight reduction. Microarray analysis of skeletal muscle revealed common gene ontology signatures of exercise and DGKδ overexpression that were related to lipid storage, extracellular matrix, and glycerophospholipids biosynthesis pathways. CONCLUSION: Overexpression of DGKδ induces adaptive changes in both skeletal muscle and adipose tissue, resulting in protection against HFD-induced obesity. DGKδ overexpression recapitulates exercise-induced adaptations on energy homeostasis and skeletal muscle gene expression profiles.

Asunto(s)

Diacilglicerol Quinasa , Dieta Alta en Grasa , Ratones Transgénicos , Obesidad , Animales , Diacilglicerol Quinasa/metabolismo , Diacilglicerol Quinasa/genética , Obesidad/metabolismo , Obesidad/genética , Ratones , Dieta Alta en Grasa/efectos adversos , Masculino , Glucosa/metabolismo , Condicionamiento Físico Animal/fisiología , Músculo Esquelético/metabolismo , Humanos , Intolerancia a la Glucosa/metabolismo , Intolerancia a la Glucosa/genética , Intolerancia a la Glucosa/prevención & control , Ratones Endogámicos C57BL , Resistencia a la Insulina/genética

RESUMEN

The T allele at rs7903146 in TCF7L2 increases the rate of conversion from prediabetes to type 2 diabetes. This has been associated with impaired ß-cell function and with defective suppression of α-cell secretion by glucose. However, the temporal relationship of these abnormalities is uncertain. To study the longitudinal changes in islet function, we recruited 128 subjects, with 67 homozygous for the diabetes-associated allele (TT) at rs7903146 and 61 homozygous for the protective allele. Subjects were studied on two occasions, 3 years apart, using an oral 75-g glucose challenge. The oral minimal model was used to quantitate ß-cell function; the glucagon secretion rate was estimated from deconvolution of glucagon concentrations. Glucose tolerance worsened in subjects with the TT genotype. This was accompanied by impaired postchallenge glucagon suppression but appropriate ß-cell responsivity to rising glucose concentrations. These data suggest that α-cell abnormalities associated with the TT genotype (rs7903146) occur early and may precede ß-cell dysfunction in people as they develop glucose intolerance and type 2 diabetes.

Asunto(s)

Diabetes Mellitus Tipo 2 , Glucagón , Prueba de Tolerancia a la Glucosa , Células Secretoras de Insulina , Proteína 2 Similar al Factor de Transcripción 7 , Humanos , Proteína 2 Similar al Factor de Transcripción 7/genética , Proteína 2 Similar al Factor de Transcripción 7/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Glucagón/metabolismo , Masculino , Femenino , Adulto , Persona de Mediana Edad , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/fisiología , Estudios Longitudinales , Células Secretoras de Glucagón/metabolismo , Islotes Pancreáticos/metabolismo , Genotipo , Glucemia/metabolismo , Intolerancia a la Glucosa/genética , Intolerancia a la Glucosa/metabolismo , Alelos

RESUMEN

INTRODUCTION: High-fat diet (HFD) consumption and being exposed to daily psychological stress, common environmental factors in modern lifestyle, play an important role on metabolic disorders such as glucose homeostasis impairment. The aim of this study was to investigate the effects of high-fat diet (HFD) and psychological stress combination on metabolic response to chronic psychological stress in male rats. METHOD: Male Wistar rats were divided into HFD, and normal diet (ND) groups and then into stress and nonstress subgroups. The diets were applied for 5 weeks, and psychological stress was induced for 7 consecutive days. Then, blood samples were taken to measure glucose, insulin, free fatty acids (FFA), and leptin and corticosterone concentrations. Subsequently, glucose-stimulated insulin release from pancreatic isolated islets was assessed. RESULTS: HFD did not significantly change fasting plasma glucose, insulin and corticosterone levels, whereas increased plasma leptin (7.05 ± 0.33) and FFA (p < 0.01) levels and impaired glucose tolerance. Additionally, HFD and stress combination induced more profound glucose intolerance associated with increased plasma corticosterone (p < 0.01) and leptin (8.63 ± 0.38) levels. However, insulin secretion from isolated islets did not change in the presence of high-fat diet and/or stress. CONCLUSION: HFD should be considered as an intensified factor of metabolic impairments caused by chronic psychological stress.

Asunto(s)

Glucemia , Corticosterona , Dieta Alta en Grasa , Insulina , Leptina , Ratas Wistar , Estrés Psicológico , Animales , Masculino , Estrés Psicológico/metabolismo , Dieta Alta en Grasa/efectos adversos , Ratas , Corticosterona/sangre , Insulina/sangre , Leptina/sangre , Glucemia/metabolismo , Ácidos Grasos no Esterificados/sangre , Islotes Pancreáticos/metabolismo , Intolerancia a la Glucosa/etiología , Intolerancia a la Glucosa/metabolismo

RESUMEN

Type 2 diabetes predisposes patients to heart disease, which is the primary cause of death across the globe. Type 2 diabetes often accompanies obesity and is defined by insulin resistance and abnormal glucose handling. Insulin resistance impairs glucose uptake and results in hyperglycemia, which damages tissues such as kidneys, liver, and heart. 2-oxoglutarate (2-OG)- and iron-dependent oxygenases (2-OGDOs), a family of enzymes regulating various aspects of cellular physiology, have been studied for their role in obesity and diet-induced insulin resistance. However, nothing is known of the 2-OGDO family member 2-oxoglutarate and iron-dependent prolyl hydroxylase domain containing protein 1 (OGFOD1) in this setting. OGFOD1 deletion leads to protection in cardiac ischemia-reperfusion injury and cardiac hypertrophy, which are two cardiac events that can lead to heart failure. Considering the remarkable correlation between heart disease and diabetes, the cardioprotection observed in OGFOD1-knockout mice led us to challenge these knockouts with high-fat diet. Wildtype mice fed a high-fat diet developed diet-induced obesity, insulin resistance, and glucose intolerance, but OGFOD1 knockout mice fed this same diet were resistant to diet-induced obesity and insulin resistance. These results support OGFOD1 down-regulation as a strategy for preventing obesity and insulin handling defects.

Asunto(s)

Dieta Alta en Grasa , Resistencia a la Insulina , Ratones Noqueados , Obesidad , Animales , Obesidad/metabolismo , Obesidad/genética , Ratones , Dieta Alta en Grasa/efectos adversos , Masculino , Prolil Hidroxilasas/metabolismo , Prolil Hidroxilasas/genética , Intolerancia a la Glucosa/metabolismo , Intolerancia a la Glucosa/genética , Ratones Endogámicos C57BL , Eliminación de Gen , Cardiomegalia/metabolismo , Cardiomegalia/prevención & control , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/genética

RESUMEN

Impaired intestinal permeability induces systemic inflammation and metabolic disturbance. The effect of a leaky gut on metabolism in skeletal muscle, a major nutrient consumer, remains unclear. In this study, we aimed to investigate the glucose metabolic function of the whole body and skeletal muscles in a mouse model of diet-induced intestinal barrier dysfunction. At Week 2, we observed higher intestinal permeability in mice fed a titanium dioxide (TiO2)-containing diet than that of mice fed a normal control diet. Subsequently, systemic glucose and insulin tolerance were found to be impaired. In the skeletal muscle, glucose uptake and phosphorylation levels in insulin signaling were lower in the TiO2 group than those in the control group. Additionally, the levels of pro-inflammatory factors were higher in TiO2-fed mice than those in the control group. We observed higher carboxymethyl-lysin (CML) levels in the plasma and intestines of TiO2-fed mice and lower insulin-dependent glucose uptake in CML-treated cultured myotubes than those in the controls. Finally, soluble dietary fiber supplementation improved glucose and insulin intolerance, suppressed plasma CML, and improved intestinal barrier function. These results suggest that an impaired intestinal barrier leads to systemic glucose intolerance, which is associated with glucose metabolism dysfunction in the skeletal muscles due to circulating CML derived from the intestine. This study highlights that the intestinal condition regulates muscle and systemic metabolic health.

Asunto(s)

Lisina , Músculo Esquelético , Titanio , Animales , Ratones , Músculo Esquelético/metabolismo , Músculo Esquelético/efectos de los fármacos , Masculino , Lisina/análogos & derivados , Lisina/metabolismo , Ratones Endogámicos C57BL , Aditivos Alimentarios/farmacología , Insulina/sangre , Insulina/metabolismo , Glucosa/metabolismo , Intolerancia a la Glucosa/metabolismo , Mucosa Intestinal/metabolismo

RESUMEN

Our previous study revealed that over 50% of recipients with pretransplant impaired glucose tolerance (IGT) improved to normal glucose tolerance after kidney transplantation. However, the mechanism is unclear. We aimed to investigate whether the changes in glucose tolerance are associated with ß-cell function and insulin resistance in Japanese kidney transplant recipients with pretransplant IGT. Of the 265 recipients who received kidney transplantation, 54 with pretransplant IGT were included. We divided the recipients into improvement and nonimprovement groups according to the change in the area under the curve for glucose obtained from the oral glucose tolerance test (OGTT). ß-Cell function was estimated by the insulin secretion sensitivity index-2 (ISSI-2) and the disposition index (DI). Insulin resistance was estimated by the Matsuda index (MI) and the homeostasis model assessment of insulin resistance (HOMA-IR). ISSI-2 and DI increased significantly after transplantation in the improved group (P < 0.01, P < 0.05, respectively), but not in the nonimproved group. ΔISSI-2 and ΔDI were significantly and positively associated with pretransplant 60-min OGTT plasma glucose levels (both P < 0.01). There were no differences in MI or HOMA-IR between these two groups after transplantation. In recipients not on pretransplant dialysis, a significant negative association was found between Δblood urea nitrogen (BUN) and ΔDI (correlation coefficient = -0.48, P < 0.05). In pretransplant IGT recipients, improvements in glucose tolerance after kidney transplantation were linked to improvements in ß-cell function. The higher the 60-min OGTT plasma glucose level, the greater the improvement in posttransplant ß-cell function. Improvements in BUN after transplantation were associated with improvements in ß-cell function.NEW & NOTEWORTHY In recipients with pretransplant impaired glucose tolerance, improvements in glucose tolerance after kidney transplantation were associated with improvements in ß-cell function. The higher the pretransplant 60-min OGTT plasma glucose level, the greater the improvement in posttransplant ß-cell function. Although glucose tolerance is known to be impaired after transplantation, the present study focused on the reason for the improvement in glucose tolerance rather than the development of posttransplantation diabetes mellitus.

Asunto(s)

Glucemia , Intolerancia a la Glucosa , Prueba de Tolerancia a la Glucosa , Resistencia a la Insulina , Células Secretoras de Insulina , Trasplante de Riñón , Humanos , Células Secretoras de Insulina/metabolismo , Masculino , Intolerancia a la Glucosa/metabolismo , Femenino , Persona de Mediana Edad , Resistencia a la Insulina/fisiología , Adulto , Glucemia/metabolismo , Anciano