xanthohumol and Diabetes-Mellitus--Type-2

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Fatty Liver; Fibrosis; Flavonoids; Hypoglycemic Agents; Injections, Intraperitoneal; Male; NF-E2-Related Factor 2; NF-kappa B; Propiophenones; Rats; Rats, Sprague-Dawley; Receptor for Advanced Glycation End Products; Signal Transduction; Streptozocin

Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by metabolic disturbances in specific tissues. The present work aimed to analyze the effects of xanthohumol (XN) and 8-prenylnaringenin (8PN), two beer-derived polyphenols, in liver and skeletal muscle lipid and glycolytic metabolism in T2DM mice model. Thirty C57Bl/6 mice were randomly divided into five groups: standard diet (control), high-fat diet (DM), high-fat diet plus ethanol (DM-Ethanol), high-fat diet plus 10 mg/L XN (DM-XN) and high-fat diet plus 10 mg/L 8PN (DM-8PN) during 20 weeks. Fasting blood glucose and insulin tolerance tests were performed 1 week before sacrifice. At the end of the study, blood, liver and skeletal muscle were collected. Both XN and 8PN treatments prevented body weight gain; decreased glycemia, triglyceride, cholesterol and alkaline phosphatase levels; and improved insulin sensitivity. Polyphenols promoted hepatic and skeletal muscle AMP-activated protein kinase (AMPK) activation, diminishing the expression of target lipogenic enzymes (sterol regulatory element binding protein-1c and fatty acid synthase) and acetyl-CoA carboxylase activity. Moreover, both XN and 8PN treatments decreased VEGFR-1/VEGFB pathway, involved in fatty acid uptake, and increased AS160 expression, involved in GLUT4 membrane translocation. Presented data demonstrated that both XN and 8PN treatment resulted in AMPK signaling pathway activation, thus suppressing lipogenesis. Their consumption prevented body weight gain and improved plasma lipid profile, with significant improvement of insulin resistance and glucose tolerance. XN- or 8PN-enriched diet could ameliorate diabetic-associated metabolic disturbances by regulating glucose and lipid pathways.

Topics: Acetyl-CoA Carboxylase; Animals; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; fas Receptor; Flavanones; Flavonoids; Glycolysis; Insulin Resistance; Lipids; Male; Mice, Inbred C57BL; Propiophenones; Sterol Regulatory Element Binding Protein 2; Vascular Endothelial Growth Factor Receptor-1

Imbalance in kidney and heart neovascularization is common in type2 diabetes (T2DM) patients. Nevertheless, the mechanisms governing this angiogenic paradox have not been elucidated. Xanthohumol (XN) and 8-prenylnaringenin (8PN) beer polyphenols modulate angiogenesis, being thus targets for T2DM-related complications. Our work examined whether polyphenols consumption affects angiogenic paradox and metabolism in a T2DM mouse model.. An increase in kidney and a reduction in left ventricle (LV) microvessels of diabetic C57Bl/6 mice were observed. XN consumption reduced angiogenesis, VEGFR-2 expression/activity, VEGF-A and phosphofructokinase-2/fructose-2,6-bisphosphatase-3 enzyme expression, a metabolic marker present in endothelial tip cells in T2DM mice kidney. 8PN had opposite effects in T2DM mice LV. These XN and 8PN effects were dependent on VEGF levels as revealed by in vitro assays. These findings were accompanied by tissue and plasma reduced expression levels of VEGF-B and its receptors, VEGFR1 and neuropilin-1, by both polyphenols.. Beer polyphenols modulate T2DM angiogenic paradox in a tissue-dependent manner. We also show for the first time that both polyphenols decreased VEGF-B pathway, which is implicated in endothelial-to-tissue lipid metabolism. Altogether, the effects of these polyphenols in the crosstalk between angiogenesis and metabolism render them potent agents for novel diabetic therapeutic interventions.

Topics: Angiogenesis Inducing Agents; Animals; Diabetes Complications; Diabetes Mellitus, Type 2; Disease Models, Animal; Flavanones; Flavonoids; Humans; Mice; Neovascularization, Pathologic; Polyphenols; Propiophenones; Signal Transduction; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2

Saturated fatty acids have been considered major contributing factors in type 2 diabetes, whereas unsaturated fatty acids have beneficial effects for preventing the development of diabetes. However, the effects of polyunsaturated fatty acids in pancreatic β cells have not been reported. Here, we examined the effects of arachidonic acid (AA) on palmitic acid (PA)-mediated lipotoxicity in clonal HIT-T15 pancreatic β cells. AA prevented the PA-induced lipotoxicity as indicated by cell viability, DNA fragmentation and mitochondrial membrane potential, whereas eicosatetraynoic acid (ETYA), a non-metabolizable AA, had little effect on PA-induced lipotoxicity. In parallel with its protective effects against PA-induced lipotoxicity, AA restored impaired insulin expression and secretion induced by PA. AA but not ETYA increased intracellular triglyceride (TG) in the presence of PA compared with PA alone, and xanthohumol, a diacylglycerol acyltransferase (DGAT) inhibitor, reversed AA-induced protection from PA. Taken together, our results suggest that AA protects against PA-induced lipotoxicity in clonal HIT-T15 pancreatic β cells, and the protective effects may be associated with TG accumulation, possibly through sequestration of lipotoxic PA into TG.

Topics: 5,8,11,14-Eicosatetraynoic Acid; Animals; Arachidonic Acid; Cell Survival; Cricetinae; Diabetes Mellitus, Type 2; Diacylglycerol O-Acyltransferase; DNA Fragmentation; Enzyme Inhibitors; Fatty Acids; Fatty Acids, Unsaturated; Flavonoids; Gene Expression Regulation; Insulin; Insulin-Secreting Cells; Membrane Potential, Mitochondrial; Palmitic Acid; Propiophenones; Protective Agents; Triglycerides

We have examined the modulating action of xanthohumol (XN) on the farnesoid X receptor (FXR) in vitro and in vivo. In the transient transfection assay, XN dose-dependently increased the BSEP promoter-driven luciferase activity. XN-fed KK-A(y) mice exhibited lowered levels of plasma glucose, plasma, and hepatic triglyceride. They also showed decreased amounts of water intake, lowered weights of white adipose tissue, and exhibited increased levels of plasma adiponectin, indicating that XN attenuated diabetes in KK-A(y) mice. The hepatic gene expression of XN-fed mice showed lowered levels of SREBP-1c including its targets involved in fatty acid synthesis and lowered levels of gluconeogenetic genes. However, the expression of cholesterol 7-hydroxylase (CYP7A1) was significantly induced in the liver of XN-fed mice. From the present results, it is suggested that XN acts on FXR through a selective bile acid receptor modulator (SBARM) like guggulsterone or polyunsaturated fatty acids, which have previously been reported as SBARMs.

Topics: Adiponectin; Adipose Tissue; Animals; Blood Glucose; Cell Line, Tumor; Chalcones; Chenodeoxycholic Acid; Diabetes Mellitus, Type 2; DNA-Binding Proteins; Flavonoids; Gene Expression; Glucose; Humans; Humulus; Hypoglycemic Agents; Intercellular Signaling Peptides and Proteins; Ligands; Lipid Metabolism; Liver; Male; Mice; Mice, Obese; Propiophenones; Receptors, Cytoplasmic and Nuclear; Transcription Factors; Triglycerides