glycogen and Dyslipidemias

Lipotoxicity is characterized by the ectopic accumulation of lipids in organs different from adipose tissue. Lipotoxicity is mainly associated with dysfunctional signaling and insulin resistance response in non-adipose tissue such as myocardium, pancreas, skeletal muscle, liver, and kidney. Serum lipid abnormalities and renal ectopic lipid accumulation have been associated with the development of kidney diseases, in particular diabetic nephropathy. Chronic hyperinsulinemia, often seen in type 2 diabetes, plays a crucial role in blood and liver lipid metabolism abnormalities, thus resulting in increased non-esterified fatty acids (NEFA). Excessive lipid accumulation alters cellular homeostasis and activates lipogenic and glycogenic cell-signaling pathways. Recent evidences indicate that both quantity and quality of lipids are involved in renal damage associated to lipotoxicity by activating inflammation, oxidative stress, mitochondrial dysfunction, and cell-death. The pathological effects of lipotoxicity have been observed in renal cells, thus promoting podocyte injury, tubular damage, mesangial proliferation, endothelial activation, and formation of macrophage-derived foam cells. Therefore, this review examines the recent preclinical and clinical research about the potentially harmful effects of lipids in the kidney, metabolic markers associated with these mechanisms, major signaling pathways affected, the causes of excessive lipid accumulation, and the types of lipids involved, as well as offers a comprehensive update of therapeutic strategies targeting lipotoxicity.

Topics: Adipose Tissue; Animals; Biomarkers; Clinical Decision-Making; Diabetic Nephropathies; Disease Management; Disease Susceptibility; Dyslipidemias; Fatty Acids, Nonesterified; Glycogen; Humans; Kidney; Lipid Metabolism; Mitochondria; Obesity; Prognosis; Signal Transduction

The purpose of this study was to determine whether exercise prescriptions differing in volume or intensity also differ in their ability to retain insulin sensitivity during an ensuing period of training cessation. Sedentary, overweight/obese subjects were assigned to one of three 8-mo exercise programs: 1) low volume/moderate intensity [equivalent of approximately 12 miles/wk, 1,200 kcal/wk at 40-55% peak O(2) consumption (Vo(2peak)), 200 min exercise/wk], 2) low volume/vigorous intensity ( approximately 12 miles/wk, 1,200 kcal/wk at 65-80% Vo(2peak), 125 min/wk), and 3) high volume/vigorous intensity ( approximately 20 miles/wk, 2,000 kcal/wk at 65-80% Vo(2peak), 200 min/wk). Insulin sensitivity (intravenous glucose tolerance test, S(I)) was measured when subjects were sedentary and at 16-24 h and 15 days after the final training bout. S(I) increased with training compared with the sedentary condition (P < or = 0.05) at 16-24 h with all of the exercise prescriptions. S(I) decreased to sedentary, pretraining values after 15 days of training cessation in the low-volume/vigorous-intensity group. In contrast, at 15 days S(I) was significantly elevated compared with sedentary (P < or = 0.05) in the prescriptions utilizing 200 min/wk (low volume/moderate intensity, high volume/vigorous intensity). In the high-volume/vigorous-intensity group, indexes of muscle mitochondrial density followed a pattern paralleling insulin action by being elevated at 15 days compared with pretraining; this trend was not evident in the low-volume/moderate-intensity group. These findings suggest that in overweight/obese subjects a relatively chronic persistence of enhanced insulin action may be obtained with endurance-oriented exercise training; this persistence, however, is dependent on the characteristics of the exercise training performed.

Topics: Anaerobic Threshold; Body Mass Index; Body Weight; Dyslipidemias; Exercise; Female; Glucose Tolerance Test; Glycogen; Homeostasis; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Mitochondria, Muscle; Muscle, Skeletal; Obesity; Oxygen Consumption; Physical Fitness

Salvianolic acid B (Sal B), a major polyphenolic compound of Salvia miltiorrhiza Bunge, has been shown to possess potential antidiabetic activities. However, the action mechanism of SalB in type 2 diabetes has not been investigated extensively. The present study was designed to investigate the effects of Sal B on diabetes-related metabolic changes in a spontaneous model of type 2 diabetes, as well as its potential molecular mechanism.. Male C57BL/KsJ-db/db mice were orally treated with Sal B (50 and 100 mg/kg) or metformin (positive drug, 300 mg/kg) for 6 weeks.. Both doses of Sal B significantly decreased fasting blood glucose, serum insulin, triglyceride and free fatty acid levels, reduced hepatic gluconeogenic gene expression and improved insulin intolerance in db/db mice. High dose Sal B also significantly improved glucose intolerance, increased hepatic glycolytic gene expression and muscle glycogen content, and ameliorated histopathological alterations of pancreas, similar to metformin. Sal B treatment resulted in increased phosphorylated AMP-activated protein kinase (p-AMPK) protein expression in skeletal muscle and liver, increased glucose transporter 4 (GLUT4) and glycogen synthase protein expressions in skeletal muscle, and increased peroxisome proliferator-activated receptor alpha (PPARα) and phosphorylated acetyl CoA carboxylase (p-ACC) protein expressions in liver.. Our data suggest that Sal B displays beneficial effects in the prevention and treatment of type 2 diabetes at least in part via modulation of the AMPK pathway.

Topics: AMP-Activated Protein Kinases; Animals; Benzofurans; Body Weight; Dyslipidemias; Gene Expression Regulation; Gluconeogenesis; Glucose; Glucose Intolerance; Glucose Transporter Type 4; Glycogen; Glycogen Synthase; Glycolysis; Hyperglycemia; Hyperinsulinism; Lipids; Liver; Male; Mice, Inbred C57BL; Muscle, Skeletal; Pancreas; Phosphorylation; PPAR alpha; RNA, Messenger; Signal Transduction

The present study analyzes the effect of the replacement of dietary casein by soy protein on the mechanisms underlying dyslipidemia, liver steatosis and altered glucose and lipid metabolism in the skeletal muscle which developed in rats fed long-term a sucrose-rich diet (SRD).. Wistar rats were fed a SRD for 4 months. From months 4 to 8, half the animals continued with the SRD, and the other half were fed a SRD in which the source of protein casein was replaced by soy. The control group received a diet with cornstarch as source of carbohydrate.. Compared to SRD-fed animals, the rats fed soy showed: A--in the liver: reduction of triglyceride and cholesterol storage and decreased steatosis; normalization of mature forms of the protein mass levels of SREBP-1 and the activities of lipogenic enzymes, while the protein mass level of PPAR-α and fatty acid oxidase activity increased. B-in the gastrocnemius muscle: normalization of the enhanced lipid storage and the altered glucose oxidation, improving glucose phosphorylation; decreasing protein mass level of nPKCθ in the membrane fraction; reversion of the impaired insulin-stimulated glucose transporter Glut-4, and glucose-6-phosphate and glycogen concentrations. Besides, dyslipidemia and glucose homeostasis returned to control values.. This study provides new information concerning some key mechanisms related to the effect of dietary soy on hepatic lipid metabolism and insulin action in the skeletal muscle in the presence of pre-existing dyslipidemia and insulin resistance induced by a SRD.

Topics: Animals; Blood Glucose; Cholesterol; Dietary Sucrose; Dyslipidemias; Fatty Acids, Nonesterified; Fatty Liver; Glucose Transporter Type 4; Glucose-6-Phosphate; Glycogen; Insulin; Insulin Resistance; Lipid Metabolism; Liver; Male; Muscle, Skeletal; PPAR alpha; Rats; Rats, Wistar; Soybean Proteins; Sterol Regulatory Element Binding Protein 1; Triglycerides; Weight Gain

Major aims were to determine whether exposure to the commonly used food additive carrageenan could induce fasting hyperglycemia and could increase the effects of a high fat diet on glucose intolerance and dyslipidemia.. C57BL/6J mice were exposed to either carrageenan, high fat diet, or the combination of high fat diet and carrageenan, or untreated, for one year. Effects on fasting blood glucose, glucose tolerance, lipid parameters, weight, glycogen stores, and inflammation were compared.. Exposure to carrageenan led to glucose intolerance by six days and produced elevated fasting blood glucose by 23 weeks. Effects of carrageenan on glucose tolerance were more severe than from high fat alone. Carrageenan in combination with high fat produced earlier onset of fasting hyperglycemia and higher glucose levels in glucose tolerance tests and exacerbated dyslipidemia. In contrast to high fat, carrageenan did not lead to weight gain. In hyperinsulinemic, euglycemic clamp studies, the carrageenan-exposed mice had higher early glucose levels and lower glucose infusion rate and longer interval to achieve the steady-state.. Carrageenan in the Western diet may contribute to the development of diabetes and the effects of high fat consumption. Carrageenan may be useful as a nonobese model of diabetes in the mouse.

Topics: Animals; Blood Glucose; Body Weight; Carrageenan; Diet; Diet, High-Fat; Disease Models, Animal; Dyslipidemias; Food Additives; Food Deprivation; Glucose; Glucose Tolerance Test; Glycated Hemoglobin; Glycogen; Hyperglycemia; Hyperlipidemias; Inflammation; Lipids; Male; Mice; Mice, Inbred C57BL; Risk Factors

Recently, there has been a growing interest in alternative therapies and in the therapeutic use of natural products for the treatment of diabetes. Therefore, in this study, we investigated the hypoglycemic and hypolipidemic effects of brown algae, Padina arborescens, in an animal model of type 2 diabetes. For 6 weeks, male C57BL/KsJ-db/db mice were administrated either control diet with no treatment or were treated with rosiglitazone (RG; 0.005%, w/w) or P. arborescens extract (PAE; 0.5%, w/w). At the end of the experimental period, the blood glucose levels, glycosylated hemoglobin levels, and plasma insulin levels were significantly lower in the RG and PAE groups compared with the control group. In addition, glucose tolerance was significantly improved in the RG and PAE groups. The homeostatic index of insulin resistance was lower in the RG and PAE groups than the diabetic control group. Also, the total cholesterol, LDL-cholesterol, triglyceride, and free fatty acid levels were lower in the PAE group than in the control group, whereas the HDL-C level was higher in the PAE group. Supplementation with PAE significantly lowered hepatic glucose-6-phosphatase and phosphoenolpyruvate carboxykinase activities, and increased glucokinase activity in the liver. Consequently, these results suggest that PAE may be beneficial in improving insulin resistance, hyperglycemia, and dyslipidemia in type 2 diabetics.

Topics: Adiponectin; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Diet; Disease Models, Animal; Dyslipidemias; Fasting; Glucose Tolerance Test; Glycated Hemoglobin; Glycogen; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Lipids; Male; Mice; Mice, Inbred C57BL; Phaeophyceae; Rosiglitazone; Thiazolidinediones

The aim of this study was to investigate the mechanisms underlying the involvement of gut microbes in body weight gain of high-fat diet-fed obesity-prone (obese) and obesity-resistant (lean) mice. C57BL/6 mice were grouped into an obese group, a lean group and a normal control group. Both obese and lean mice were fed a high-fat diet while normal control mice were fed a normal diet; they were observed for six weeks. The results showed that lean mice had lower serum lipid levels, body fat and weight gain than obese mice. The ATPase, succinate dehydrogenase and malate dehydrogenase activities in liver as well as oxygen expenditure and rectal temperature of lean mice were significantly lower than in obese mice. As compared with obese mice, the absorption of intestinal carbohydrates but not of fats or proteins was significantly attenuated in lean mice. Furthermore, 16S rRNA abundances of faecal Firmicutes and Bacteroidetes were significantly reduced in lean mice. In addition, faecal β-D-galactosidase activity and short chain fatty acid levels were significantly decreased in lean mice. Expressions of peroxisome proliferator-activated receptor gamma 2 and CCAAT/enhancer binding protein-β in visceral adipose tissues were significantly downregulated in lean mice as compared with obese mice. Resistance to dyslipidaemia and high-fat diet-induced obesity was mediated by ineffective absorption of intestinal carbohydrates but not of fats or proteins, probably through reducing gut Bacteroidetes and Firmicutes contents and lowering of gut carbohydrate metabolism. The regulation of intestinal carbohydrates instead of fat absorption by gut microbes might be a potential treatment strategy for high-fat diet-induced obesity.

Topics: Adenosine Triphosphatases; Adipose Tissue; Animals; Bacteroidetes; beta-Galactosidase; Body Weight; Carbohydrate Metabolism; CCAAT-Enhancer-Binding Protein-beta; Diet, High-Fat; Dyslipidemias; Fatty Acids, Volatile; Feces; Glucose Tolerance Test; Glycogen; Insulin Resistance; Intestinal Mucosa; Intestines; Lipid Metabolism; Lipids; Liver; Malate Dehydrogenase; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Oxygen Consumption; PPAR gamma; Random Allocation; RNA, Ribosomal, 16S; Succinate Dehydrogenase; Weight Gain

Ursolic acid (UA) is a pentacyclic triterpenoid compound that naturally occurs in fruits, leaves and flowers of medicinal herbs. This study investigated the dose-response efficacy of UA (0.01 and 0.05%) on glucose metabolism, the polyol pathway and dyslipidemia in streptozotocin/nicotinamide-induced diabetic mice. Supplement with both UA doses reduced fasting blood glucose and plasma triglyceride levels in non-obese type 2 diabetic mice. High-dose UA significantly lowered plasma free fatty acid, total cholesterol and VLDL-cholesterol levels compared with the diabetic control mice, while LDL-cholesterol levels were reduced with both doses. UA supplement effectively decreased hepatic glucose-6-phosphatase activity and increased glucokinase activity, the glucokinase/glucose-6-phosphatase ratio, GLUT2 mRNA levels and glycogen content compared with the diabetic control mice. UA supplement attenuated hyperglycemia-induced renal hypertrophy and histological changes. Renal aldose reductase activity was higher, whereas sorbitol dehydrogenase activity was lower in the diabetic control group than in the non-diabetic group. However, UA supplement reversed the biochemical changes in polyol pathway to normal values. These results demonstrated that low-dose UA had preventive potency for diabetic renal complications, which could be mediated by changes in hepatic glucose metabolism and the renal polyol pathway. High-dose UA was more effective anti-dyslipidemia therapy in non-obese type 2 diabetic mice.

Topics: Animals; Antineoplastic Agents, Phytogenic; Blotting, Western; Diabetes Complications; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dyslipidemias; Glucokinase; Glucose; Glucose Transporter Type 2; Glucose-6-Phosphatase; Glycogen; Hyperglycemia; Kidney Diseases; Male; Mice; Mice, Inbred ICR; Mice, Inbred NOD; Polymers; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Triterpenes; Ursolic Acid

This study investigated the effects of resveratrol (RV) on diabetes-related metabolic changes in a spontaneous model of type 2 diabetes, as well as activation of AMP-activated protein kinase (AMPK) and downstream targets.. C57BL/KsJ-db/db mice were fed a normal diet with RV (0.005% and 0.02%, w/w) or rosiglitazone (RG, 0.001%, w/w) for 6 weeks. Both doses of RV significantly decreased blood glucose, plasma free fatty acid, triglyceride, apo B/apo AІ levels and increased plasma adiponectin levels. RV activated AMPK and downstream targets leading to decreased blood HbA1c levels, hepatic gluconeogenic enzyme activity, and hepatic glycogen, while plasma insulin levels, pancreatic insulin protein, and skeletal muscle GLUT4 protein were higher after RV supplementation. The high RV dose also significantly increased hepatic glycolytic gene expression and enzyme activity, along with skeletal muscle glycogen synthase protein expression, similar to RG. Furthermore, RV dose dependently decreased hepatic triglyceride content and phosphorylated I kappa B kinase (p-IKK) protein expression, while hepatic uncoupling protein (UCP) and skeletal muscle UCP expression were increased.. RV potentiates improving glycemic control, glucose uptake, and dyslipidemia, as well as protecting against pancreatic β-cell failure in a spontaneous type 2 diabetes model. Dietary RV has potential as an antidiabetic agent via activation of AMPK and its downstream targets.

Topics: Adiponectin; AMP-Activated Protein Kinases; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dietary Supplements; Dyslipidemias; Glucose Transporter Type 4; Glycated Hemoglobin; Glycogen; Insulin; Insulin Secretion; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Muscle, Skeletal; Resveratrol; Rosiglitazone; Stilbenes; Thiazolidinediones; Triglycerides

Persimmon Leaf (PL), commonly consumed as herbal tea and traditional medicines, contains a variety of compounds that exert antioxidant, α-amylase and α-glucosidase inhibitory activity. However, little is known about the in vivo effects and underlying mechanisms of PL on hyperglycemia, hyperlipidemia and hepatic steatosis in type 2 diabetes. Powered PL (5%, w/w) was supplemented with a normal diet to C57BL/KsJ-db/db mice for 5 weeks. PL decreased blood glucose, HOMA-IR, plasma triglyceride and total cholesterol levels, as well as liver weight, hepatic lipid droplets, triglycerides and cholesterol contents, while increasing plasma HDL-cholesterol and adiponectin levels. The anti-hyperglycemic effect was linked to decreased activity of gluconeogenic enzymes as well as increased glycogen content, glucokinase activity and its mRNA level in the liver. PL also led to a decrease in lipogenic transcriptional factor PPARγ as well as gene expression and activity of enzymes involved in lipogenesis, with a simultaneous increase in fecal lipids, which are seemingly attributable to the improved hyperlipidemia and hepatic steatosis and decreased hepatic fatty acid oxidation. Furthermore, PL ameliorated plasma and hepatic oxidative stress. Supplementation with PL may be an effective dietary strategy to improve type 2 diabetes accompanied by dyslipidemia and hepatic steatosis by partly modulating the activity or gene expression of enzymes related to antioxidant, glucose and lipid homeostasis.

Topics: Adiponectin; Animals; Antioxidants; Blood Glucose; Cholesterol; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dietary Supplements; Diospyros; Dyslipidemias; Fatty Liver; Gene Expression; Glucokinase; Glycogen; Hyperglycemia; Hypoglycemic Agents; Insulin Resistance; Lipid Metabolism; Lipogenesis; Liver; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Phytotherapy; Plant Leaves; Plant Preparations; PPAR gamma; RNA, Messenger; Triglycerides