glycogen and Metabolic-Syndrome

The prevalence of cardiometabolic disease has reached an exponential rate of rise over the last decades owing to high fat/high caloric diet intake and satiety life style. Although the presence of dyslipidemia, insulin resistance, hypertension and obesity mainly contributes to the increased incidence of cardiometabolic diseases, population-based, clinical and genetic studies have revealed a rather important role for inherited myopathies and endocrine disorders in the ever-rising metabolic anomalies. Inherited metabolic and endocrine diseases such as glycogen storage and lysosomal disorders have greatly contributed to the overall prevalence of cardiometabolic diseases. Recent evidence has demonstrated an essential role for proteotoxicity due to autophagy failure and/or dysregulation in the onset of inherited metabolic and endocrine disorders. Given the key role for autophagy in the degradation and removal of long-lived or injured proteins and organelles for the maintenance of cellular and organismal homeostasis, this mini-review will discuss the potential contribution of autophagy dysregulation in the pathogenesis of inherited myopathies and endocrine disorders, which greatly contribute to an overall rise in prevalence of cardiometabolic disorders. Molecular, clinical, and epidemiological aspects will be covered as well as the potential link between autophagy and metabolic anomalies thus target therapy may be engaged for these comorbidities.

Topics: Autophagy; Cardiovascular Diseases; Endocrine System Diseases; Glycogen; Homeostasis; Humans; Insulin Resistance; Lysosomes; Metabolic Syndrome; Metabolism, Inborn Errors; Muscular Diseases; Obesity

The metabolic syndrome that occurs in preeclampsia reflects the complex interactions between immunological alterations and the systemic inflammation that have been shown to take place during this complication of human pregnancy. Inositol phosphoglycans play a definite role in the insulin resistance in preeclampsia with a higher production and urinary excretion of this molecule before and during preeclampsia. Recent researches suggest that the feto-placental glucose metabolism in the first and early second trimester is mainly linked to the nonoxidative pathway of glycogen catabolism supporting the pivotal role of the inositol phosphoglycan P-type. In this article we present the results of a case-control study carried out in the first trimester to evaluate the potential of urinary P-IPG release as a early marker of the disease. A single mid-stream sample of maternal urine was collected at 11 weeks of gestation for this single centre retrospective study. Twenty-seven patients out of 331 women recruited (8.1%) went on to develop preeclampsia but no sample attained positivity. Further details about the development of the metabolic syndrome during preeclampsia were retrieved also from other studies to implement our knowledge about the pathophysiology of this syndrome and to identify biochemical aspects that could help in clinical practice.

Topics: Female; Fetus; Glucose; Glycogen; Humans; Inflammation; Inositol Phosphates; Metabolic Syndrome; Placenta; Polysaccharides; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, First; Pregnancy Trimester, Third

Troxerutin (TRX) has a beneficial effect on blood viscosity and platelet aggregation, and is currently used for the treatment of chronic varicosity. Recently, TRX can improve lipid abnormalities, glucose intolerance and oxidative stress in high-fat diet-induced metabolic disorders. In this study, we tested the effect of TRX on metabolic syndrome-associated disorders using a non-obese model of metabolic syndrome-the Hereditary Hypertriglyceridaemic rats (HHTg).. Adult male HHTg rats were fed standard diet without or with TRX (150 mg/kg bwt/day for 4 weeks).. Compared to untreated rats, TRX supplementation in HHTg rats decreased serum glucose (p<0.05) and insulin (p<0.05). Although blood lipids were not affected, TRX decreased hepatic cholesterol concentrations (p<0.01) and reduced gene expression of HMGCR, SREBP2 and SCD1 (p<0.01), involved in cholesterol synthesis and lipid homeostasis. TRX-treated rats exhibited decreased lipoperoxidation and increased activity of antioxidant enzymes SOD and GPx (p<0.05) in the liver. In addition, TRX supplementation increased insulin sensitivity in muscles and epididymal adipose tissue (p<0.05). Elevated serum adiponectin (p<0.05) and decreased muscle triglyceride (p<0.05) helped improve insulin sensitivity. Among the beneficial effects of TRX were changes to cytochrome P450 family enzymes. Hepatic gene expression of CYP4A1, CYP4A3 and CYP5A1 (p<0.01) decreased, while there was a marked elevation in gene expression of CYP1A1 (p<0.01).. Our results indicate that TRX improves hepatic lipid metabolism and insulin sensitivity in peripheral tissues. As well as ameliorating oxidative stress, TRX can reduce ectopic lipid deposition, affect genes involved in lipid metabolism, and influence the activity of CYP family enzymes.

Topics: Animals; Disease Models, Animal; Glucose; Glycogen; Hydroxyethylrutoside; Hypolipidemic Agents; Insulin Resistance; Lipid Metabolism; Male; Metabolic Syndrome; Muscle, Skeletal; Oxidative Stress; Rats; Rats, Inbred Strains; Real-Time Polymerase Chain Reaction; Transcriptome

To evaluate the incidence of insulin resistance and metabolic syndrome (MetS) in patients with glycogenic acanthosis (GA).. Thirty patients with GA, detected upon endoscopy, and 30 age- and sex-matched control patients without GA were included in this case-control study. Patients with GA were considered group 1 and control group was considered group 2. Anthropometric measurements [height, weight, and waist circumference (WC)], biochemical parameters [fasting plasma glucose (FPG), triglyceride, high-density lipoprotein (HDL), and low-density lipoprotein (LDL)], and serum fasting insulin levels were evaluated. Insulin resistance (IR) was estimated by the homeostatic model assessment of IR. MetS was diagnosed using the criteria of the National Cholesterol Education Program Adult Treatment Panel III. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to evaluate associations with GA.. There were no differences in terms of FPG, triglyceride, HDL, and LDL between groups (p-values 0.118, 0.114, 0.192, 0.086, respectively). WC was significantly higher in group 1 than in group 2 (103.77 vs 97.03, p=0.032). The number of patients with IR and MetS were significantly higher in group 1 than in group 2 (53.3% vs 13.3%, p=0.003 and 53.3% vs 23.3%, p=0.034). ORs [95% CI] of WC, IR, and MetS for GA were 0.68 [0.17-2.62], 7.12 [1.89-26.72], and 4.11 [1.04-16.21], respectively.. These findings showed that IR and MetS were significantly associated with the presence of GA.

Topics: Adult; Case-Control Studies; Esophageal Diseases; Female; Glycogen; Humans; Incidence; Insulin; Insulin Resistance; Male; Metabolic Syndrome; Middle Aged; Risk Factors; Waist Circumference

The objective of this study is to determine whether muscle water content (H2Omuscle) expands with training in deconditioned middle-age men and the effects of this expansion in other muscle metabolites.. Eighteen obese (BMI = 33 ± 3 kg⁻¹·m⁻²) untrained (V˙O2peak = 29 ± 7 mL⁻¹·kg⁻¹·min⁻¹) metabolic syndrome men completed a 4-month aerobic cycling training program. Vastus lateralis muscle biopsies were collected before and 72 h after the completion of the last training bout. Water content, total protein, glycogen concentration, and citrate synthase activity were measured in biopsy tissue. Body composition was assessed using dual-energy X-ray absorptiometry, and cardiometabolic fitness was measured during an incremental cycling test.. Body weight and fat mass were reduced -1.9% and -5.4%, respectively (P < 0.05), whereas leg fat free mass increased with training (1.8%, P = 0.023). Cardiorespiratory fitness (i.e., V˙O2peak), exercise maximal fat oxidation (i.e., FOmax), and maximal cycling power (i.e., Wmax) improved with training (11%, 33%, and 10%, respectively; P < 0.05). After 4 months of training, H2Omuscle increased from 783 ± 18 to 799 ± 24 g·kg⁻¹ wet weight (ww) (2%, P = 0.011), whereas muscle protein concentration decreased 11% (145 ± 15 to 129 ± 13 g·kg⁻¹ ww, P = 0.007). Citrate synthase activity (proxy for mitochondrial density) increased by 31% (17 ± 5 to 22 ± 5 mmol·min⁻¹·kg⁻¹ ww, P = 0.024). Muscle glycogen concentration increased by 14% (22 ± 7 to 25 ± 7 g·kg⁻¹ ww) although without reaching statistical significance when expressed as per kilogram of wet weight (P = 0.15).. Our findings suggest that aerobic cycling training increases quadriceps muscle water although reduces muscle protein concentration in obese metabolic syndrome men. Reduced protein concentration coexists with increased leg lean mass suggestive of a water dilution effect that however does not impair increased cycling leg power with training.

Topics: Adult; Bicycling; Body Composition; Cardiorespiratory Fitness; Exercise; Glycogen; Humans; Male; Metabolic Syndrome; Middle Aged; Muscle Proteins; Obesity; Quadriceps Muscle; Water

This work investigated the underlying mechanism of high-fructose/sucrose and high-fat diets, which rapidly induce metabolic syndrome in vivo, via a new cell model.. Glucose and/or fructose were used to induce the human hepatoma cell (HepG2) in the presence of palmitic acid, oleic acid, or combined fatty acids (CFA) for 24 h. The alterations in lipid and uric acid production, glucose metabolism, oxidative status, and related genes and proteins were monitored. The cell model that featured metabolic disorders was established by treatment of 10 mM glucose and 15 mM fructose plus 1 mM CFA. Results showed that palmitic acid mainly induced insulin resistance, oxidative stress, and triglyceride (TG) secretion, whereas oleic acid mainly contributed to intracellular TG. Fructose was mainly responsible for uric acid and cholesterol production. In addition, fructose synergistically elevated the intra- and extracellular TG and extracellular malonaldehyde with glucose and CFA. Regulations of genes and proteins associated with carbohydrate metabolism and lipogenesis partially explained the action of fructose in inducing the metabolic disorders in cell.. The combination of glucose, fructose, and CFA could successfully induce metabolic disorders in HepG2 cells, including dyslipidemia, insulin resistance, hyperuricemia, and oxidative stress.

Topics: Cell Cycle; Cholesterol; Diet, High-Fat; Fatty Acids, Nonesterified; Fructokinases; Fructose; Glucose; Glycogen; Hep G2 Cells; Humans; Insulin Resistance; Lipid Metabolism; Malondialdehyde; Metabolic Syndrome; Oxidative Stress; Triglycerides; Uric Acid

Glucose homeostasis is a complex indispensable process, and its dysregulation causes hyperglycemia and type 2 diabetes mellitus. Glucokinase (GK) takes a central role in these pathways and is thus rate limiting for glucose-stimulated insulin secretion (GSIS) from pancreatic islets. Several reports have described the transcriptional regulation of Gck mRNA, whereas its posttranscriptional mechanisms of regulation, especially those involving microRNAs (miR), are poorly understood. In this study, we investigated the role of miR-206 as a posttranscriptional regulator of Gck In addition, we examined the effects of miR-206 on glucose tolerance, GSIS, and gene expression in control and germ line miR-206 knockout (KO) mice fed either with chow or high-fat diet (HFD). MiR-206 was found in Gck-expressing tissues and was differentially altered in response to HFD feeding. Pancreatic islets showed the most profound induction in the expression of miR-206 in response to HFD. Chow- and HFD-fed miR-206KO mice have improved glucose tolerance and GSIS but unaltered insulin sensitivity. In silico analysis of Gck mRNA revealed a conserved 8-mer miR-206 binding site. Hence, the predicted regulation of Gck by miR-206 was confirmed in reporter and GK activity assays. Concomitant with increased GK activity, miR-206KO mice had elevated liver glycogen content and plasma lactate concentrations. Our findings revealed a novel mechanism of posttranscriptional regulation of Gck by miR-206 and underline the crucial role of pancreatic islet miR-206 in the regulation of whole body glucose homeostasis in a murine model that mimics the metabolic syndrome.

Topics: Animals; Computer Simulation; Diet, High-Fat; Glucokinase; Glucose; Glucose Tolerance Test; Glycogen; Insulin; Insulin Secretion; Islets of Langerhans; Lactic Acid; Liver; Male; Metabolic Syndrome; Mice; Mice, Knockout; MicroRNAs; Real-Time Polymerase Chain Reaction; RNA Processing, Post-Transcriptional; RNA, Messenger; Transcriptome

Some studies refer that the entire plant of Anoda cristata is consumed as food and medicine; in particular for treating diabetes, inflammation, fever, cough, and wounds. The aim of this study was to establish the preclinical efficacy of Anoda cristata as hypoglycemic and/or antihyperglycemic agent using well-known animal models.. The acute toxicity was analyzed by the Lorke method. Acute hypoglycemic as well as oral glucose and sucrose tolerance tests were used to determine the hypoglycemic and antihyperglycemic action of Anoda cristata. Several preparations of the plant, including a mucilage (M), an aqueous (T-AE), a free mucilage aqueous (FM-AE), and an organic (OE) extracts, were tested in healthy and NA-STZ-hyperglycemic mice. Glibenclamide (15mg/kg), acarbose (5mg/kg ) and metformin (200mg/kg) were used as positive controls. The major compounds acacetin (1) and diosmetin (2), isolated from an infusion of the plant applying chromatographic methods, were evaluated as hypoglycemic agents using the same assays. The FM-AE was tested also in rats with metabolic syndrome induced by a high-fructose fed. Finally some assays were performed to determine the antioxidant capacity of the FM-AE in vitro.. The results demonstrated that the extracts and compounds from Anoda cristata were effective for reducing blood glucose levels in healthy and NA-STZ-hyperglycemic mice when compared with vehicle groups (p<0.05). The FM-AE exerted also positive effect over different biochemical parameters altered in rats with metabolic syndrome induced by a fructose diet. FM-AE has also antioxidant action effectively trapping ONOO(-) and ROO(•) radicals. The major flavonoids isolated from the plant, namely acacetin (1) and diosmetin (2), caused significant hypoglycemic effect and possessed antioxidant activity.. Anoda cristata is effective to diminish glucose levels in vivo and to ameliorate different disorders related with the metabolic syndrome in rats. According to the results, the efficacy of Anoda cristata preparations could be due to the presence of active principles with different mode of actions at the molecular level, including α-glycosidases inhibitors, insulin secretagogues, glucose entrapment and radical trapping agents.

Topics: Animals; Antioxidants; Blood Glucose; Diabetes Mellitus, Experimental; Flavones; Flavonoids; Free Radicals; Glycogen; Hyperglycemia; Hypoglycemic Agents; Insulin; Lipid Metabolism; Liver; Male; Malvaceae; Metabolic Syndrome; Mice, Inbred ICR; Phytotherapy; Plant Components, Aerial; Plant Preparations; Plants, Edible; Rats; Rats, Sprague-Dawley; Uric Acid

We evaluated effects of chronic intracerebroventricular infusion of angiotensin (Ang)-(1-7) on cardiovascular and metabolic parameters in fructose-fed (FF) rats. After 6 weeks of fructose intake (10% in drinking water), Sprague-Dawley rats were subjected to intracerebroventricular infusion of Ang-(1-7) (200 ng/h; FF+A7 group) or 0.9% sterile saline (FF group) for 4 weeks with continued access to fructose. Compared with control rats, FF rats had increased mean arterial pressure and cardiac sympathetic tone with impaired baroreflex sensitivity. FF rats also presented increased circulating triglycerides, leptin, insulin, and glucose with impaired glucose tolerance. Furthermore, relative weights of liver and retroperitoneal adipose tissue were increased in FF rats. Glycogen content was reduced in liver, but increased in muscle. In contrast, fructose-fed rats subjected to chronic intracerebroventricular infusion of Ang-(1-7) presented reduced cardiac sympathetic tone with normalized mean arterial pressure, baroreflex sensitivity, glucose and insulin levels, and improved glucose tolerance. Relative weight of liver, and hepatic and muscle glycogen contents were also normalized in FF+A7 rats. In addition, FF+A7 rats had reduced mRNA expression for neuronal nitric oxide synthase and NR1 subunit of N-methyl-d-aspartate receptor in hypothalamus and dorsomedial medulla. Ang-(1-7) infusion did not alter fructose-induced hyperleptinemia and increased relative weight of retroperitoneal adipose tissue. There were no differences in body weights, neither in liver mRNA expression of phosphoenolpyruvate carboxykinase or glucose-6-phosphatase among the groups. These data indicate that chronic increase in Ang-(1-7) levels in the brain may have a beneficial role in fructose-fed rats by ameliorating cardiovascular and metabolic disorders.

Topics: Angiotensin I; Animals; Baroreflex; Blood Glucose; Blood Pressure; Body Weight; Brain; Dietary Carbohydrates; Disease Models, Animal; Fructose; Glycogen; Infusions, Intraventricular; Insulin; Metabolic Syndrome; Peptide Fragments; Rats; Rats, Sprague-Dawley; Risk Factors

Plasma glucose levels are maintained within a narrow range in normal individuals. Both insulin-dependent and insulin-independent processes contribute to fasting and postprandial plasma glucose regulation. The brain and nervous system are insulin independent. Muscle and adipose tissue are responsive to insulin and can use either glucose or ketones and free fatty acids as their primary metabolic fuel. The essential components of metabolic syndrome are obesity, glucose intolerance, insulin resistance, lipid disturbances, and hypertension. The risk of type 2 diabetes increases exponentially as body mass index increases above about 25 kg/m2. The links between obesity and type 2 diabetes include proinflammatory cytokines, insulin resistance, deranged fatty acid metabolism, and cellular processes. Modest weight reduction can improve glycaemic control and reduce diabetes risk. Obesity also leads to hyperinsulinaemia and insulin resistance, with a progressive decrease in insulin secretory function. Ageing is another important risk factor for metabolic disorders, including obesity, impaired glucose tolerance, and type 2 diabetes.

Topics: Aging; Body Mass Index; Diabetes Mellitus, Type 2; Glucagon; Glucose; Glucose Intolerance; Glucose Transport Proteins, Facilitative; Glycogen; Homeostasis; Humans; Inflammation Mediators; Insulin; Insulin Resistance; Metabolic Syndrome; Obesity; Obesity, Abdominal; Sodium-Glucose Transport Proteins

The inhibition of maternal prolactin production in late lactation leads to metabolic syndrome and hypothyroidism in adult offspring. Physical training is a therapeutic strategy that could prevent or reverse this condition. We evaluated the effects of a short-duration low-intensity running wheel training program on the metabolic and hormonal alterations in rats. Lactating Wistar rats were treated with bromocriptine (Bro, 1 mg twice a day) or saline on days 19, 20, and 21 of lactation, and the training of offspring began at 35 days of age. Offspring were divided into sedentary and trained controls (C-Sed and C-Ex) and sedentary and trained Bro-treated rats (Bro-Sed and Bro-Ex). Chronic exercise delayed the onset of weight gain in Bro-Ex offspring, and the food intake did not change during the experimental period. At 180 days, visceral fat mass was higher (+46%) in the Bro-Sed offspring than in C-Sed and Bro-Ex rats. As expected, running capacity was higher in trained animals. Most parameters observed in the Bro-Sed offspring were consistent with hypothyroidism and metabolic syndrome and were reversed in the Bro-Ex group. Chronic exercise did not influence the muscle glycogen in the C-Ex group; however, liver glycogen was higher (+30%) in C-Ex group and was unchanged in both Bro offspring groups. Bro-Ex animals had higher plasma lactate dehydrogenase levels, indicating skeletal muscle damage and intolerance of the training program. Low-intensity chronic training is able to normalize many clinical aspects in Bro animals; however, these animals might have had a lower threshold for exercise adaptation than the control rats.

Topics: Animals; Bromocriptine; Female; Glycogen; L-Lactate Dehydrogenase; Lactation; Lipid Metabolism; Male; Metabolic Syndrome; Mothers; Motor Activity; Muscles; Obesity; Physical Conditioning, Animal; Prolactin; Rats; Rats, Wistar; Weaning

The beneficial effects of green tea polyphenols (GTP) against metabolic syndrome and type 2 diabetes by suppressing appetite and nutrient absorption have been well reported. However the direct effects and mechanisms of GTP on glucose and lipid metabolism remain to be elucidated. Since the liver is an important organ involved in glucose and lipid metabolism, we examined the effects and mechanisms of GTP on glycogen synthesis and lipogenesis in HepG2 cells. Concentrations of GTP containing 68% naturally occurring (-)-epigallocatechin-3-gallate (EGCG) were incubated in HepG2 cells with high glucose (30 mM) under 100 nM of insulin stimulation for 24 h. GTP enhanced glycogen synthesis in a dose-dependent manner. 10  μM of EGCG significantly increased glycogen synthesis by 2fold (P < 0.05) compared with insulin alone. Western blotting revealed that phosphorylation of Ser9 glycogen synthase kinase 3 β and Ser641 glycogen synthase was significantly increased in GTP-treated HepG2 cells compared with nontreated cells. 10  μM of EGCG also significantly inhibited lipogenesis (P < 0.01). We further demonstrated that this mechanism involves enhanced expression of phosphorylated AMP-activated protein kinase α and acetyl-CoA carboxylase in HepG2 cells. Our results showed that GTP is capable of enhancing insulin-mediated glucose and lipid metabolism by regulating enzymes involved in glycogen synthesis and lipogenesis.

Topics: Antioxidants; Catechin; Diabetes Mellitus, Type 2; Glycogen; Hep G2 Cells; Hepatocytes; Humans; Lipid Metabolism; Lipogenesis; Metabolic Syndrome; Phosphorylation; Proto-Oncogene Proteins c-akt; Tea

In this study, we evaluated the effect of an analogue of l-carnitine on parameters involved with Metabolic Syndrome in obese Zucker rats. Twenty-four rats were treated for 5 weeks with l-carnitine (300 mg/kg) and its analogue at two concentrations (100 and 250 mg/kg) to assess their impact on glucose, triglycerides and cholesterol in liver and blood samples, as well as the amount of liver glycogen. Liver slices were also analysed. The analogue reduced the levels of glucose, triglycerides and cholesterol in liver and the level of triglycerides in serum. At 100 mg/kg, the analogue proved more effective than l-carnitine in improving the biochemical alterations present in liver. The amount of liver glycogen content was higher in obese animals treated with both l-carnitine and the analogue. No changes on insulin and leptin were observed in animals treated. l-carnitine and its analogue reduced the microvesicular fatty infiltration in liver. This study demonstrated that the analogue tested is more potent and efficient than l-carnitine and improves the pharmacological profile of l-carnitine.

Topics: Animals; Carnitine; Cholesterol; Disease Models, Animal; Dose-Response Relationship, Drug; Glucose; Glycogen; Insulin; Leptin; Liver; Male; Metabolic Syndrome; Obesity; Rats; Rats, Zucker; Triglycerides

Diabetes mellitus is one of the three most common modem diseases. A number of animal models is used in investigations of the mechanisms of development of the disease. Most of these models replicate the symptoms of type 1 diabetes mellitus. The development of type 2 diabetes is caused by the insulin resistance, hyperglycemia, structural and functional disorders of the pancreatic cells. Investigation of pathogenesis of type 2 diabetes is complicated by the lack of adequate models of this disease. In this work, based on existing hyperglycemia model, we propose the model of metabolic syndrome as a precursor of type 2 diabetes. The development of metabolic syndrome symptoms was caused by 28 days long intramuscular injection of protamine sulfate to guinea pigs at a dose of 15 mg/kg along with keeping of animals on a high glucose diet. Increased blood glucose and cholesterol levels, reduction of glycogen in liver, the structural and functional damage and reduce in the number of functionally active beta-cells in the pancreas of the experimental animals were observed. The results confirm the development of the metabolic syndrome symptoms in experimental animals, which makes it possible to use such methodical approach in creation of promising type 2 diabetes model.

Topics: Animals; Diabetes Mellitus, Type 2; Diet; Disease Models, Animal; Glucose; Glycogen; Guinea Pigs; Hyperglycemia; Injections, Intramuscular; Insulin Resistance; Insulin-Secreting Cells; Liver; Male; Metabolic Syndrome; Protamines

Maternal nutrition during pregnancy is an intrauterine factor that results in alteration of the offspring genome and associates with disease risk in the offspring. We investigated the impact of a maternal low-protein (LP) diet on the expression of glucose transporter 4 (GLUT4) in offspring skeletal muscle. GLUT4 is an insulin-regulated glucose transporter involved in insulin sensitivity and carbohydrate metabolism in muscle cells. We observed sex-dependent GLUT4 mRNA expression and increased GLUT4 protein content in female pup skeletal muscle with maternal LP. Analysis of transcriptional and epigenetic regulation of increased skeletal muscle GLUT4 expression in offspring rats revealed the regulatory mechanisms involved. The protein level of myocyte enhancer factor 2A (MEF2A), which has been known as an activator of GLUT4 transcription via the ability to carry out specific binding to the GLUT4 MEF2 binding sequence, increased in female pups whose mothers were fed a LP diet. Modifications of chromatin structure, including acetylated histone H3, acetylated histone H4 and di-methylated histone H3 at lysine 4, were detected at a significantly increased level at the GLUT4 promoter region in female pup muscle following a maternal LP diet. Glycogen content was also detected as up-regulated, accompanied by increased glycogen synthase in LP female offspring muscle. These results document that maternal protein restriction during pregnancy induces GLUT4 expression in female offspring skeletal muscle but not in males, which may indicate sex-dependent adaptation of glucose metabolism to a maternal LP diet.

Topics: Acetylation; Animals; Diet, Protein-Restricted; Epigenesis, Genetic; Female; Glucose Transporter Type 4; Glycogen; Glycogen Synthase; Histones; MADS Domain Proteins; Male; Maternal Nutritional Physiological Phenomena; MEF2 Transcription Factors; Metabolic Syndrome; Methylation; Muscle, Skeletal; Myogenic Regulatory Factors; Organ Specificity; Pregnancy; Promoter Regions, Genetic; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sex Characteristics; Up-Regulation

It has been recognized that there is a relationship between prenatal growth restriction and the development of metabolic-related diseases in later life, a process involved in mitochondrial dysfunction. In addition, intrauterine growth retardation (IUGR) increases the susceptibility of offspring to high-fat (HF) diet-induced metabolic syndrome. Recent findings suggested that HF feeding decreased mitochondrial oxidative capacity and impaired mitochondrial function in skeletal muscle. Therefore, we hypothesized that the long-term consequences of IUGR on mitochondrial biogenesis and function make the offspring more susceptible to HF diet-induced mitochondrial dysfunction. Normal birth weight (NBW), and IUGR pigs were allotted to control or HF diet in a completely randomized design, individually. After 4 weeks of feeding, growth performance and molecular pathways related to mitochondrial function were determined. The results showed that IUGR decreased growth performance and plasma insulin concentrations. In offspring fed a HF diet, IUGR was associated with enhanced plasma leptin levels, increased concentrations of triglyceride and malondialdehyde (MDA), and reduced glycogen and ATP contents in skeletal muscle. High fat diet-fed IUGR offspring exhibited decreased activities of lactate dehydrogenase (LDH) and glucose-6-phosphate dehydrogenase (G6PD). These alterations in metabolic traits of IUGR pigs were accompanied by impaired mitochondrial respiration function, reduced mitochondrial DNA (mtDNA) contents, and down-regulated mRNA expression levels of genes responsible for mitochondrial biogenesis and function. In conclusion, our results suggest that IUGR make the offspring more susceptible to HF diet-induced mitochondrial dysfunction.

Topics: Animals; Blood Glucose; Diet, High-Fat; DNA, Mitochondrial; Eating; Female; Fetal Growth Retardation; Glucosephosphate Dehydrogenase; Glycogen; Insulin; Lactic Acid; Leptin; Male; Membrane Potentials; Metabolic Syndrome; Mitochondria; Mitochondrial Diseases; Muscle, Skeletal; Pregnancy; Proton-Translocating ATPases; RNA, Messenger; Swine; Triglycerides

Aging is closely associated with muscle insulin resistance, hyperlipidemia, nonalcoholic fatty liver disease (NAFLD), and type 2 diabetes. We examined the hypothesis that muscle insulin resistance in healthy aging promotes increased hepatic de novo lipogenesis (DNL) and hyperlipidemia by altering the distribution pattern of postprandial energy storage. Healthy, normal weight, sedentary elderly subjects pair-matched to young subjects were given two high-carbohydrate meals followed by ¹³C/¹H magnetic resonance spectroscopy measurements of postprandial changes in muscle and liver glycogen and lipid content, and assessment of DNL using ²H₂O. Net muscle glycogen synthesis was reduced by 45% (P < 0.007) in the elderly subjects compared with the young, reflecting severe muscle insulin resistance. Net liver glycogen synthesis was similar between groups (elderly, 143 ± 23 mmol/L vs. young, 138 ± 13 mmol/L; P = NS). Hepatic DNL was more than twofold higher in the elderly than in the young subjects (elderly, 14.5 ± 1.4% vs. young, 6.9 ± 0.7%; P = 0.00015) and was associated with approximately threefold higher postprandial hepatic triglyceride (TG) content (P < 0.005) and increased fasting plasma TGs (elderly, 1.19 ± 0.18 mmol/L vs. young, 0.74 ± 0.11 mmol/L; P = 0.02). These results strongly support the hypothesis that muscle insulin resistance in aging promotes hyperlipidemia and NAFLD by altering the pattern of postprandial carbohydrate storage away from muscle glycogen and into hepatic DNL.

Topics: Adult; Aged; Aging; Dietary Carbohydrates; Fatty Liver; Female; Glycogen; Humans; Hyperlipidemias; Insulin Resistance; Lipogenesis; Liver; Male; Metabolic Syndrome; Muscle, Skeletal; Non-alcoholic Fatty Liver Disease; Postprandial Period; Triglycerides; Young Adult

Glucose-6-phosphatase (G6PC) plays an important role in glucose homeostasis because it catalyzes the final steps of gluconeogenesis and glycogenolysis. Maternal malnutrition during pregnancy affects G6PC activity, yet it is unknown whether epigenetic regulations of the G6PC gene are also affected. In this study, we fed primiparous, purebred Meishan sows either standard-protein (SP; 12% crude protein) or low-protein (LP; 6% crude protein) diets throughout gestation and analyzed hepatic G6PC expression in both male and female newborn piglets. The epigenetic regulation of G6PC, including DNA methylation, histone modifications, and micro RNA (miRNA), was determined to reveal potential mechanisms. Male, but not female, LP piglets had a significantly lower serum glucose concentration and greater hepatic G6PC mRNA expression and enzyme activity. Also, in LP males, glucocorticoid receptor binding to the G6PC promoter was lower compared with SP males, which was accompanied by hypomethylation of the G6PC promoter. Modifications in histones also were gender dependent; LP males had less histone H3 and histone H3 lysine 9 trimethylation and more histone H3 acetylation and histone H3 lysine 4 trimethylation on the G6PC promoter compared with the SP males, whereas LP females had more H3 and greater H3 methylation compared with their SP counterparts. Moreover, two miRNA, ssc-miR-339-5p and ssc-miR-532-3p, targeting the G6PC 3' untranslated region were significantly upregulated by the LP diet only in females. These results suggest that a maternal LP diet during pregnancy causes hepatic activation of G6PC gene expression in male piglets, which possibly contributes to adult-onset hyperglycemia.

Topics: Age Factors; Animals; Animals, Newborn; Blood Glucose; Diet, Protein-Restricted; DNA Methylation; Epigenesis, Genetic; Female; Glucose-6-Phosphatase; Glycogen; Hyperglycemia; Liver; Male; Metabolic Syndrome; MicroRNAs; Pregnancy; Prenatal Exposure Delayed Effects; Random Allocation; Sex Characteristics; Sus scrofa

11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates local glucocorticoid action in tissues by catalysing conversion of inactive glucocorticoids to active glucocorticoids. 11β-HSD1 inhibition ameliorates obesity and associated co-morbidities. Here, we tested the effect of 11β-HSD inhibitor, carbenoxolone (CBX) on obesity and associated comorbidities in obese rats of WNIN/Ob strain, a new animal model for genetic obesity.. Subcutaneous injection of CBX (50 mg/kg body weight) or volume-matched vehicle was given once daily for four weeks to three month-old WNIN/Ob lean and obese rats (n = 6 for each phenotype and for each treatment). Body composition, plasma lipids and hormones were assayed. Hepatic steatosis, adipose tissue morphology, inflammation and fibrosis were also studied. Insulin resistance and glucose intolerance were determined along with tissue glycogen content. Gene expressions were determined in liver and adipose tissue. CBX significantly inhibited 11β-HSD1 activity in liver and adipose tissue of WNIN/Ob lean and obese rats. CBX significantly decreased body fat percentage, hypertriglyceridemia, hypercholesterolemia, insulin resistance in obese rats. CBX ameliorated hepatic steatosis, adipocyte hypertrophy, adipose tissue inflammation and fibrosis in obese rats. Tissue glycogen content was significantly decreased by CBX in liver and adipose tissue of obese rats. Severe fat loss and glucose- intolerance were observed in lean rats after CBX treatment.. We conclude that 11β-HSD1 inhibition by CBX decreases obesity and associated co-morbidities in WNIN/Ob obese rats. Our study supports the hypothesis that inhibition of 11β-HSD1 is a key strategy to treat metabolic syndrome. Severe fat loss and glucose -intolerance by CBX treatment in lean rats suggest that chronic 11β-HSD1 inhibition may lead to insulin resistance in normal conditions.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Adipocytes; Adipose Tissue; Adrenal Glands; Animals; Body Composition; Carbenoxolone; Cholesterol, HDL; Corticosterone; Eating; Enzyme Inhibitors; Fibrosis; Gene Expression Regulation; Glucose Intolerance; Glycogen; Hypertrophy; Liver; Male; Metabolic Syndrome; Obesity; Organ Size; Rats; Signal Transduction; Thinness; Triglycerides

The metabolic syndrome has reached epidemic proportions worldwide, but currently there is a lack of effective therapies for this multifactorial endocrine disease. TCM (traditional Chinese medicine) has been utilized to treat a wide variety of diseases for centuries in the People's Republic of China, subsequently becoming a promising source for the development of new therapeutic agents. Chinese medicinal herbs Gynostemma pentaphyllum, Coptis chinensis and Salvia miltiorrhiza have been shown to have anti-atherosclerotic and antidiabetic properties. In this study, we have investigated the metabolic effects of a mixture of these three herbal extracts (SK0506) in a rodent model of the metabolic syndrome induced by an HFD (high-fat diet). SD (Sprague-Dawley) rats that were fed on an HFD for 4 weeks gained 33% more weight compared with chow-fed rats (P<0.05). Four weeks treatment with SK0506 prevented weight gain with decreased visceral fat (P<0.01 compared with vehicle treatment). SK0506 also significantly reduced plasma triacylglycerols (triglycerides), NEFAs (non-esterified fatty acids) and cholesterol. SK0506 exerted similar effects to RSG (rosiglitazone) on impaired glucose intolerance. SK0506 also significantly enhanced glucose uptake and glycogen synthesis in adipose tissue during hyperinsulinaemic-euglycaemic clamp. Western blotting analysis revealed that SK0506 enhanced GLUT4 (glucose transporter 4) expression in adipose tissue, and RSG markedly up-regulated GLUT4 translocation in skeletal muscle. Overall, the present study has discovered that SK0506 can reverse several components of the metabolic syndrome primarily through acting on hyperlipidaemia and visceral obesity. The results from the present study suggest that it is worthwhile to conduct a randomized clinical trial to confirm the potential that SK0506 may be a new oral agent for treating the metabolic syndrome and preventing Type 2 diabetes.

Topics: Adipose Tissue; Animals; Blood Glucose; Drug Evaluation, Preclinical; Drugs, Chinese Herbal; Glucose Clamp Technique; Glucose Tolerance Test; Glucose Transporter Type 4; Glycogen; Insulin; Lipids; Male; Metabolic Syndrome; Muscle, Skeletal; Phytotherapy; Rats; Rats, Sprague-Dawley; Translocation, Genetic; Weight Loss

Similar to metabolic syndrome, parenteral nutrition (PN) administration has also been associated with biologic abnormalities of glucose and lipids. Such complications include hyperglycemia, hypertriglyceridemia, liver dysfunction, and hepatobiliary complications. Because metabolic syndrome has been associated with altered expression of adipocytokines, and peroxisome proliferator-activated receptors (PPARs), the present study hypothesized that PN would also lead to alterations in adipocytokines and related gene abundances.. Male Wister rats received either intravenous (IV) saline and chow (control) or PN. To determine the contribution of lipids to metabolic changes, the following 2 PN groups were studied: PN with IV lipid (PN+L) and PN without lipid (PN-L). Rats were studied after 7 days.. A marked increase in hepatic glycogen staining was found in the PN-L group, and conversely, a marked increase in hepatic lipid staining was observed in the PN+L group. Both PN groups demonstrated a 30% increase in serum adiponectin levels in comparison to controls. In the liver, ACDC mRNA expression significantly increased (10%-20%), while ADIPOR1 expression significantly declined in the PN groups compared with controls. PPAR expression significantly declined (10%-30%) in the PN+L group compared with controls. In contrast to metabolic syndrome, PN+L led to a decrease in tumor necrosis factor α and interleukin 6 levels in the liver.. The study shows that PN led to specific alterations in the abundance of adipocytokines and PPARs. These changes give critical insight into many of the metabolic derangements in lipid metabolism, which patients may experience with PN.

Topics: Adiponectin; Animals; Dietary Fats; Glycogen; Interleukin-6; Lipid Metabolism; Liver; Male; Metabolic Syndrome; Models, Animal; Parenteral Nutrition; Peroxisome Proliferator-Activated Receptors; Rats; Rats, Wistar; Receptors, Adiponectin; RNA, Messenger; Tumor Necrosis Factor-alpha

Malnutrition in utero can "program" the fetal tissues, making them more vulnerable to metabolic disturbances. Also there is association between excessive consumption of fructose and the development of metabolic syndrome. However, there is little information regarding the acute effect of physical exercise on subjects recovered from malnutrition and/or fed with a fructose-rich diet. The objective of this study was to evaluate the metabolic aspects and the response to acute physical exercise in rats recovered from fetal protein malnutrition with a fructose-rich diet.. Pregnant Wistar rats were fed with a balanced (B) diet or a low-protein (L) diet. After birth and until 60 days of age, the offspring were distributed into four groups according to the diet received: B: B diet during the whole experiment; balanced/fructose (BF): B diet until birth and fructose-rich (F) diet afterwards; low protein/balanced (LB): L diet until birth and B diet afterwards; low protein/fructose (LF): L diet until birth and F diet afterwards.. The excess fructose intake reduced the body weight gain, especially in the BF group. Furthermore, the serum total cholesterol and the LDL cholesterol were elevated in this group. In the LF group, the serum total cholesterol and the muscle glycogen increased. Acute physical exercise increased the serum concentrations of glucose, triglycerides, HDL cholesterol and liver lipids and reduced the concentrations of muscle glycogen in all groups.. An excess fructose intake induced some signs of metabolic syndrome. However, protein malnutrition appeared to protect against the short term effects of fructose. In other hand, most responses to acute physical exercise were not influenced by early malnutrition and/or by the fructose overload.

Topics: Animals; Animals, Newborn; Female; Fructose; Glycogen; Hyperglycemia; Hyperlipidemias; Lactation; Lipid Metabolism; Liver; Male; Maternal Nutritional Physiological Phenomena; Metabolic Syndrome; Motor Activity; Muscle, Skeletal; Pregnancy; Protein Deficiency; Rats; Rats, Wistar; Weight Gain

There is a growing interest in identifying putative insulin sensitizers from the herbal sources.. The present study explores the effects of naringenin, a bioflavonoid, in the high fructose-induced model of insulin resistance.. Adult male Wistar rats were divided into two groups and were fed either a starch-based control diet or a high fructose diet (60 g/100 g) for 60 days. From the 16th day, rats in each group were divided into two, one of which was administered naringenin (50 mg/kg b.w.) and the other was untreated for the next 45 days. Oral glucose tolerance test (OGTT) was done on day 59. On day 60, the levels of glucose, insulin, triglycerides (TG), free fatty acids (FFA) in blood, and the activities of insulin-inducible and suppressible enzymes in the cytosolic and mitochondrial fractions of liver and skeletal muscle were assayed. The extent of protein tyrosine phosphorylation in response to insulin was determined by assaying protein tyrosine kinase (PTK) and protein tyrosine phosphatase (PTP) in liver. Liver histology with periodic acid-Schiff (PAS) staining was done to detect glycogen.. Fructose administration increased the plasma levels of glucose, insulin, TG, and FFA as compared to control rats. Insulin resistance was indicated by alterations in insulin sensitivity indices. Alterations in enzyme activities and reduced glycogen content were observed in fructose-fed rats. PTP activity was higher, while PTK activity was lower suggesting reduced tyrosine phosphorylation status. Administration of naringenin improved insulin sensitivity and enhanced tyrosine phosphorylation in fructose-fed animals, while it did not affect the parameters in control diet-fed rats.. Naringenin improves insulin signaling and sensitivity and thereby promotes the cellular actions of insulin in this model.

Topics: Animals; Diabetes Mellitus, Experimental; Diet; Flavanones; Fructose; Glycogen; Hypoglycemic Agents; Insulin; Liver; Male; Metabolic Syndrome; Muscle, Skeletal; Phosphorylation; Phytotherapy; Protein Processing, Post-Translational; Protein Tyrosine Phosphatases; Protein-Tyrosine Kinases; Rats; Rats, Wistar; Tyrosine

It has been suggested that thiazolidinediones (TZDs) ameliorate insulin resistance in muscle tissue by suppressing muscle lipid storage and the activity of novel protein kinase C (nPKC) isoforms. To test this hypothesis, we analyzed long-term metabolic effects of pioglitazone and the activation of nPKC-epsilon and -theta isoforms in an animal model of the metabolic syndrome, the spontaneously hypertensive rat (a congenic SHR strain with wild type Cd36 gene) fed a diet with 60 % sucrose from the age of 4 to 8 months. Compared to untreated controls, pioglitazone treatment was associated with significantly increased basal (809+/-36 vs 527+/-47 nmol glucose/g/2h, P<0.005) and insulin-stimulated glycogenesis (1321+/-62 vs 749+/-60 nmol glucose/g/2h, P<0.0001) in isolated gastrocnemius muscles despite increased concentrations of muscle triglycerides (3.83+/-0.33 vs 2.25+/-0.12 micromol/g, P<0.005). Pioglitazone-treated rats exhibited significantly increased membrane/total (cytosolic plus membrane) ratio of both PKC-epsilon and PKC-theta isoforms compared to untreated controls. These results suggest that amelioration of insulin resistance after long-term pioglitazone treatment is associated with increased activation of PKC-epsilon and -theta isoforms in spite of increased lipid concentration in skeletal muscles.

Topics: Animals; Animals, Congenic; Blood Glucose; CD36 Antigens; Dietary Sucrose; Disease Models, Animal; Glycogen; Hypoglycemic Agents; Insulin; Insulin Resistance; Isoenzymes; Male; Metabolic Syndrome; Muscle, Skeletal; Pioglitazone; Protein Kinase C; Protein Kinase C-epsilon; Protein Kinase C-theta; Protein Transport; Rats; Rats, Inbred SHR; Thiazolidinediones; Time Factors; Triglycerides

Dietary trans-fatty acids are associated with increased risk of cardiovascular disease and have been implicated in the incidence of obesity and type 2 diabetes mellitus (T2DM). It is established that high-fat saturated diets, relative to low-fat diets, induce adiposity and whole-body insulin resistance. Here, we test the hypothesis that markers of an obese, prediabetic state (fatty liver, visceral fat accumulation, insulin resistance) are also worsened with provision of a low-fat diet containing elaidic acid (18:1t), the predominant trans-fatty acid isomer found in the human food supply. Male 8-week-old Sprague-Dawley rats were fed a 10% trans-fatty acid enriched (LF-trans) diet for 8 weeks. At baseline, 3 and 6 weeks, in vivo magnetic resonance spectroscopy (1H-MR) assessed intramyocellular lipid (IMCL) and intrahepatic lipid (IHL) content. Euglycemic-hyperinsulinemic clamps (week 8) determined whole-body and tissue-specific insulin sensitivity followed by high-resolution ex vivo 1H-NMR to assess tissue biochemistry. Rats fed the LF-trans diet were in positive energy balance, largely explained by increased energy intake, and showed significantly increased visceral fat and liver lipid accumulation relative to the low-fat control diet. Net glycogen synthesis was also increased in the LF-trans group. A reduction in glucose disposal, independent of IMCL accumulation was observed in rats fed the LF-trans diet, whereas in rats fed a 45% saturated fat (HF-sat) diet, impaired glucose disposal corresponded to increased IMCLTA. Neither diet induced an increase in IMCLsoleus. These findings imply that trans-fatty acids may alter nutrient handling in liver, adipose tissue, and skeletal muscle and that the mechanism by which trans-fatty acids induce insulin resistance differs from diets enriched with saturated fats.

Topics: Adiposity; Animals; Blood Glucose; Diet, Fat-Restricted; Energy Intake; Energy Metabolism; Glucose Clamp Technique; Glycogen; Hyperphagia; Insulin; Insulin Resistance; Intra-Abdominal Fat; Liver; Magnetic Resonance Spectroscopy; Male; Metabolic Syndrome; Muscle, Skeletal; Obesity; Oleic Acid; Oleic Acids; Prediabetic State; Rats; Rats, Sprague-Dawley; Time Factors; Trans Fatty Acids

Thiazolidinediones are increasingly used drugs for the treatment of Type 2 diabetes. The individual response to thiazolidinedione therapy, ranging from the variable degree of metabolic improvement to harmful side-effects, is empirical, yet the underlying mechanisms remain elusive. In order to assess the pharmacogenomic component of thiazolidinediones' metabolic action, we compared the effect of rosiglitazone in two genetically defined models of metabolic syndrome, polydactylous (PD) and BN.SHR4 inbred rat strains, with their insulin-sensitive, normolipidemic counterpart, the Brown Norway (BN) rat.. 5-month-old male rats were fed a high-fat diet for 4 weeks, and the experimental groups received rosiglitazone (0.4 mg/100 g body weight) during the last 2 weeks of high-fat diet feeding. We assessed metabolic and morphometric profiles, oxidative stress parameters and gene expression in white adipose tissue.. In many followed parameters, we observed genetic background-specific effects of rosiglitazone administration. The mass and the sensitivity of visceral adipose tissue to insulin-stimulated lipogenesis increased with rosiglitazone treatment only in PD, correlating with a PD-specific significant increase in expression of prostaglandin D2 synthase. The glucose tolerance was enhanced in all strains, although fasting plasma glucose was increased by rosiglitazone in BN and BN.SHR4. Among the markers of lipid peroxidation, we observed the rosiglitazone-driven increase of plasma-conjugated dienes only in BN.SHR4. The genes with genotype-specific expression change included ADAM metallopeptidase domain 7, aquaporin 9, carnitine palmitoyltransferase 1B, caveolin 1, catechol-O-methyl transferase, leptin and prostaglandin D2 synthase 2.. Rosiglitazone's effects on lipid deposition and insulin sensitivity of peripheral tissues are largely dependent on the genetic background it acts upon.

Topics: Adipose Tissue; Adipose Tissue, White; Animals; Cholesterol, Dietary; Diet; Dietary Carbohydrates; Fatty Acids; Gene Expression; Glucose; Glucose Tolerance Test; Glycogen; Hypoglycemic Agents; Insulin Resistance; Lipids; Liver; Metabolic Syndrome; Microarray Analysis; Oxidation-Reduction; Oxidative Stress; Rats; Rats, Inbred BN; Rats, Inbred Strains; RNA; Rosiglitazone; Sucrose; Thiazolidinediones

Arginine-vasopressin (AVP) is known to be involved in maintaining glucose homeostasis, and AVP-resistance is observed in poorly controlled non-insulin-dependent diabetes mellitus subjects, resulting in a lowered plasma volume. Recently we reported that V1a vasopressin receptor-deficient (V1aR(-/-)) mice exhibited a decreased circulating blood volume and hypermetabolism of fat accompanied with impaired insulin-signaling. Here we further investigated the roles of the AVP/V1a receptor in regulating glucose homeostasis and plasma volume using V1aR(-/-) mice. The plasma glucose levels at the baseline or during a glucose tolerance test were higher in V1aR(-/-) than wild-type (WT) mice. Moreover, a hyperinsulinemic-euglycemic clamp revealed that the glucose infusion rate was significantly lower in V1aR(-/-) mice than in WT mice and that hepatic glucose production was higher in V1aR(-/-) mice than WT mice. In contrast to the increased hepatic glucose production, the liver glycogen content was decreased in the mutant mice. These results indicated that the mutant mice had impaired glucose tolerance. Furthermore, feeding V1aR(-/-) mice a high-fat diet accompanied by increased calorie intake resulted in significantly overt obesity in comparison with WT mice. In addition, we found that the circulating plasma volume and aldosterone level were decreased in V1aR(-/-) mice, although the plasma AVP level was increased. These results suggested that the effect of AVP on water recruitment was disturbed in V1aR(-/-) mice. Thus, we demonstrated that one of the AVP-resistance conditions resulting from deficiency of the V1a receptor leads to decreased plasma volume as well as impaired glucose homeostasis, which can progress to obesity under conditions of increased calorie intake.

Topics: Animals; Arginine Vasopressin; Blood Glucose; Body Weight; Dietary Fats; Energy Intake; Feeding Behavior; Glycogen; Homeostasis; Insulin; Leptin; Liver; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Obesity; Plasma Volume; Receptors, Vasopressin

We examined the hypothesis that insulin resistance in skeletal muscle promotes the development of atherogenic dyslipidemia, associated with the metabolic syndrome, by altering the distribution pattern of postprandial energy storage. Following ingestion of two high carbohydrate mixed meals, net muscle glycogen synthesis was reduced by approximately 60% in young, lean, insulin-resistant subjects compared with a similar cohort of age-weight-body mass index-activity-matched, insulin-sensitive, control subjects. In contrast, hepatic de novo lipogenesis and hepatic triglyceride synthesis were both increased by >2-fold in the insulin-resistant subjects. These changes were associated with a 60% increase in plasma triglyceride concentrations and an approximately 20% reduction in plasma high-density lipoprotein concentrations but no differences in plasma concentrations of TNF-alpha, IL-6, adiponectin, resistin, retinol binding protein-4, or intraabdominal fat volume. These data demonstrate that insulin resistance in skeletal muscle, due to decreased muscle glycogen synthesis, can promote atherogenic dyslipidemia by changing the pattern of ingested carbohydrate away from skeletal muscle glycogen synthesis into hepatic de novo lipogenesis, resulting in an increase in plasma triglyceride concentrations and a reduction in plasma high-density lipoprotein concentrations. Furthermore, insulin resistance in these subjects was independent of changes in the plasma concentrations of TNF-alpha, IL-6, high-molecular-weight adiponectin, resistin, retinol binding protein-4, or intraabdominal obesity, suggesting that these factors do not play a primary role in causing insulin resistance in the early stages of the metabolic syndrome.

Topics: Cytokines; Fasting; Glycogen; Hormones; Humans; Insulin Resistance; Magnetic Resonance Imaging; Metabolic Syndrome; Muscle, Skeletal

Epidemiological studies have shown a clear link between fetal growth retardation and an increased propensity for later cardiovascular disease in adults. It has been hypothesized that such early fetal deprivation "programs" individuals toward a life-long metabolical "thrifty phenotype" that predisposes adults to such diseases. Here we test this hypothesis, and its possible genetic basis, in rat recombinant inbred (RI) strains that uniquely allow the longitudinal studies necessary for its testing. Placental and fetal weights were determined on day 20 of pregnancy in (at least) 6 litters from each of 25 available BXH/HXB RI strains and from their SHR and BN-Lx progenitors and were correlated with metabolic traits determined in adult rats from the same inbred lines. Quantitative trait loci (QTLs) associated with placental and fetal weights were identified by total genome scanning of RI strains using the Map Manager QTX program. Heritabilities of placental and fetal weights were 56% and 62%, respectively, and total genome scanning of RI strains revealed QTLs near the D1Rat266 marker on chromosome 1 and near the D15Rat101 marker on chromosome 15 that were significantly associated with fetal and placental weights respectively. Placental weights correlated with fetal weights (r = 0.60, P = 0.001), while reduced fetal weights correlated with increased insulin concentrations during glucose tolerance test (r = -0.71, P = 0.0001) and with increased serum triglycerides (r = -0.54, P = 0.006) in adult rats. Our results suggest that predisposition toward a thrifty phenotype associated with decreased placental weight and restricted fetal growth is in part genetically determined.

Topics: Analysis of Variance; Animals; Biomarkers; Blood Glucose; Chromosome Mapping; Chromosomes, Mammalian; Female; Fetal Weight; Glycogen; Inbreeding; Liver; Male; Metabolic Syndrome; Muscle, Skeletal; Organ Size; Phenotype; Placentation; Pregnancy; Quantitative Trait Loci; Rats; Rats, Inbred BN; Rats, Inbred SHR; Recombination, Genetic; Triglycerides

RSG is a member of the TZD group of drugs widely used in treatment of type 2 diabetes. The underlying mechanism of TZD action in insulin-sensitive tissues is not fully understood. In this study we show that 14-day RSG administration in a new rodent model of metabolic syndrome X, polydactylous rat strain (PD/Cub), substantially improves its lipid profile (serum TGs 4.20 +/- 0.23 vs 2.34 +/- 0.14 mmol/l, P < 0.0001; FFA 0.46 +/- 0.05 vs 0.33 +/- 0.02 mmol/l, P = 0.017), diminishes the liver TG depots (15.76 +/- 0.60 vs 8.44 +/- 0.55 micromol/g, P < 0.0001), serum insulin concentrations (1.10 +/- 0.08 vs 0.63 +/- 0.02 nmol/l, P < 0.0001) and promotes visceral adiposity (adiposity index 1.28 +/- 0.03 vs 1.85 +/- 0.07, P < 0.0001). No changes were observed in serum or liver concentrations of cholesterol. Concomitantly, both basal and insulin-stimulated glycogen synthesis in red-fibre type muscle (m. soleus) was enhanced, as well as glucose uptake into adipose tissue. However, glucose oxidation in soleus (basal and insulin-stimulated) remained unchanged. In consent with previously published data we suggest the current pharmacogenetic study as a further proof of substantial influence of genetic background on the physiological outcome of TZD therapy.

Topics: Adipose Tissue; Animals; Disease Models, Animal; Glucose; Glucose Tolerance Test; Glycogen; Hypoglycemic Agents; Insulin; Insulin Resistance; Lipids; Male; Metabolic Syndrome; Rats; Rats, Inbred Strains; Rosiglitazone; Thiazoles; Thiazolidinediones