scholarly journals Metformin improves hepatic IRS2/PI3K/Akt signaling in insulin-resistant rats of NASH and cirrhosis

2016 ◽  
Vol 229 (2) ◽  
pp. 133-144 ◽  
Author(s):  
Hong Xu ◽  
Yang Zhou ◽  
Yongxia Liu ◽  
Jian Ping ◽  
Qiyang Shou ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Function ◽  
Insulin Receptor ◽  
Glucose Intolerance ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Akt Signaling ◽  
Hepatic Glycogen ◽  
Impaired Liver Function ◽  
Insulin Resistant

Nonalcoholic fatty liver disease and cirrhosis are strongly associated with insulin resistance and glucose intolerance. To date, the influence of metformin on glycogen synthesis in the liver is controversial. Limited studies have evaluated the effect of metformin on hepatic insulin signaling pathwayin vivo. In this study, an insulin-resistant rat model of nonalcoholic steatohepatitis and cirrhosis was developed by high-fat and high-sucrose diet feeding in combination with subcutaneous injection of carbon tetrachloride. Liver tissues of the model rats were featured with severe steatosis and cirrhosis, accompanied by impaired liver function and antioxidant capacity. The glucose tolerance was impaired, and the index of insulin resistance was increased significantly compared with the control. The content of hepatic glycogen was dramatically decreased. The expression of insulin receptor β (IRβ); phosphorylations of IRβ, insulin receptor substrate 2 (IRS2), and Akt; and activities of phosphatidylinositol 3-kinase (PI3K) and glycogen synthase (GS) in the liver were significantly decreased, whereas the activities of glycogen synthase kinase 3α (GSK3α) and glycogen phosphorylase a (GPa) were increased. Metformin treatment remarkably improved liver function, alleviated lipid peroxidation and histological damages of the liver, and ameliorated glucose intolerance and insulin resistance. Metfromin also significantly upregulated the expression of IRβ; increased the phosphorylations of IRβ, IRS2, and Akt; increased the activities of PI3K and GS; and decreased GSK3α and GPa activities. In conclusion, our study suggests that metformin upregulates IRβ expression and the downstream IRS2/PI3K/Akt signaling transduction, therefore, to increase hepatic glycogen storage and improve insulin resistance. These actions may be attributed to the improved liver histological alterations by metformin.

Selective in vitro reversal of the insulin resistance of glucose transport in denervated rat skeletal muscle

1989 ◽  
Vol 257 (3) ◽  
pp. E418-E425 ◽  
Author(s):  
M. O. Sowell ◽  
S. L. Dutton ◽  
M. G. Buse
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Glucose Transport ◽  
Glycogen Synthesis ◽  
Insulin Response ◽  
Medium Composition ◽  
Insulin Resistant ◽  
Denervated Muscles

Denervation (24 h) of skeletal muscle causes severe postreceptor insulin resistance of glucose transport and glycogen synthesis that is demonstrable in isolated muscles after short (30 min) preincubations. After longer preincubations (2-4 h), the insulin response of glucose transport increased to normal, whereas glycogen synthesis remained insulin resistant. Basal and insulin-stimulated amino acid transport were significantly lower in denervated muscles than in controls after short or long incubations, although the percentage stimulation of transport by insulin was not significantly different. The development of glucose transport insulin resistance after denervation was not attributable to increased sensitivity to glucocorticoids or adenosine. The selective in vitro reversal of glucose transport insulin resistance was not dependent on medium composition, did not require protein or prostaglandin synthesis, and could not be attributed to release of a positive regulator into the medium. The data suggest 1) the insulin receptor in muscle stimulates glucose transport by a signaling pathway that is not shared by other insulin-sensitive effector systems, and 2) denervation may affect insulin receptor signal transduction at more than one site.

Lack of defect in insulin action on hepatic glycogen synthase and phosphorylase in insulin-resistant monkeys

1998 ◽  
Vol 274 (6) ◽  
pp. G1005-G1010
Author(s):  
Heidi K. Ortmeyer ◽  
Noni L. Bodkin
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Muscle Glycogen ◽  
Rhesus Monkeys ◽  
Insulin Action ◽  
Glycogen Phosphorylase ◽  
Glycogen Synthase ◽  
Liver Glycogen ◽  
Hepatic Glycogen ◽  
Insulin Resistant

It is well known that an alteration in insulin activation of skeletal muscle glycogen synthase is associated with insulin resistance. To determine whether this defect in insulin action is specific to skeletal muscle, or also present in liver, simultaneous biopsies of these tissues were obtained before and during a euglycemic hyperinsulinemic clamp in spontaneously obese insulin-resistant male rhesus monkeys. The activities of glycogen synthase and glycogen phosphorylase and the concentrations of glucose 6-phosphate and glycogen were measured. There were no differences between basal and insulin-stimulated glycogen synthase and glycogen phosphorylase activities or in glucose 6-phosphate and glycogen contents in muscle. Insulin increased the activities of liver glycogen synthase ( P < 0.05) and decreased the activities of liver glycogen phosphorylase ( P ≤ 0.001). Insulin also caused a reduction in liver glucose 6-phosphate ( P = 0.05). We conclude that insulin-resistant monkeys do not have a defect in insulin action on liver glycogen synthase, although a defect in insulin action on muscle glycogen synthase is present. Therefore, tissue-specific alterations in insulin action on glycogen synthase are present in the development of insulin resistance in rhesus monkeys.

scholarly journals Skeletal Muscle Insulin Resistance in Endocrine Disease

2010 ◽  
Vol 2010 ◽  
pp. 1-13 ◽  
Author(s):  
Melpomeni Peppa ◽  
Chrysi Koliaki ◽  
Panagiotis Nikolopoulos ◽  
Sotirios A. Raptis
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Polycystic Ovary ◽  
Glycogen Synthesis ◽  
Whole Body ◽  
Endocrine Disorders ◽  
Peripheral Tissues ◽  
Insulin Resistant ◽  
Skeletal Muscle Insulin Resistance

We summarize the existing literature data concerning the involvement of skeletal muscle (SM) in whole body glucose homeostasis and the contribution of SM insulin resistance (IR) to the metabolic derangements observed in several endocrine disorders, including polycystic ovary syndrome (PCOS), adrenal disorders and thyroid function abnormalities. IR in PCOS is associated with a unique postbinding defect in insulin receptor signaling in general and in SM in particular, due to a complex interaction between genetic and environmental factors. Adrenal hormone excess is also associated with disrupted insulin action in peripheral tissues, such as SM. Furthermore, both hyper- and hypothyroidism are thought to be insulin resistant states, due to insulin receptor and postreceptor defects. Further studies are definitely needed in order to unravel the underlying pathogenetic mechanisms. In summary, the principal mechanisms involved in muscle IR in the endocrine diseases reviewed herein include abnormal phosphorylation of insulin signaling proteins, altered muscle fiber composition, reduced transcapillary insulin delivery, decreased glycogen synthesis, and impaired mitochondrial oxidative metabolism.

Egg oil from Portunus trituberculatus alleviates insulin resistance through activation of insulin signaling in mice

2019 ◽  
Vol 44 (10) ◽  
pp. 1081-1088 ◽  
Author(s):  
Shiwei Hu ◽  
Jingfeng Wang ◽  
Xiaojun Yan ◽  
Huicheng Yang ◽  
Shijie Li ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Transporter ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Animal Experiments ◽  
Portunus Trituberculatus ◽  
Hepatic Glycogen ◽  
Transcriptional Level ◽  
Protective Effects ◽  
Bioactive Lipids

Marine bioactive lipids have been utilized to overcome insulin resistance. However, oil from swimming crab has never been studied. Here, we analyzed the constituents of egg oil from Portunus trituberculatus (Pt-egg oil) and investigated its protective effects against insulin resistance in mice on a high-fat diet. The results showed that Pt-egg oil contained 52.05% phospholipids, 8.61% free fatty acids (especially eicosapentaenoic acid and docosahexaenoic acid), 32.38% triglyceride, 4.79% total cholesterol, and ditissimus astaxanthin. Animal experiments showed that Pt-egg oil significantly mitigated insulin resistance and was associated with reductions in blood glucose, insulin, glucose tolerance, insulin tolerance, serum lipids, and hepatic glycogen. Pt-egg oil activated the phosphatidylinositol 3-hydroxy kinase (PI3K)/protein kinase B (Akt)/glucose transporter 4 pathway in skeletal muscle both at the transcriptional level and at the translational level. Pt-egg oil also promoted hepatic glycogen synthesis through activation of the PI3K/Akt/glycogen synthase kinase-3 beta pathway. These indicate that Pt-egg oil can be used as an alternative to marine bioactive lipids to improve insulin resistance.

scholarly journals Catestatin reduces hyperglycemia in insulin-resistant mice by redirecting glucose-6-phosphate from the gluconeogenic to the glycogenic pathway

2020 ◽  
Author(s):  
Gautam Bandyopadhyay ◽  
Kechun Tang ◽  
Nicholas J.G. Webster ◽  
Geert van den Bogaart ◽  
Sushil K. Mahata
Keyword(s):  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Glucose Production ◽  
Liver Glycogen ◽  
Hepatic Glycogen ◽  
Cultured Hepatocytes ◽  
Glycogen Accumulation ◽  
Insulin Resistant ◽  
Glucose Levels ◽  
Gsk 3Β

AbstractObjectiveDefects in hepatic glycogen synthesis contribute to postprandial hyperglycemia in type 2 diabetic (T2D) patients. Chromogranin A (CgA) peptide Catestatin (CST: hCgA352-372) inhibits dephosphorylation of glucose 6-phosphate (G6P) and improves glucose tolerance in insulin-resistant mice. Here, we seek to determine whether CST also reduces hyperglycemia by increasing hepatic glycogen synthesis.MethodsWe determined liver glycogen, G6P, and UDP glucose (UDPG); plasma insulin, glucagon, norepinephrine (NE), and epinephrine (EPI) levels, and glycogen synthase (GYS) activities in fed and fasted liver of lean and obese wild-type and genetically obese CST knockout (KO) mice after treatments with saline, CST or insulin. We determined glycogen synthesis and glycogenolysis in cultured hepatocytes. We analyzed phosphorylation signals of GYS2 and GSK-3β by immunoblotting.ResultsCST stimulated glycogen accumulation in fed and fasted liver and in cultured hepatocytes. CST reduced plasma NE and EPI levels, suggesting that CST promotes glycogenesis by inhibiting catecholamine-induced glycogenolysis. CST also directly stimulated glycogenesis and inhibited NE and EPI-induced glycogenolysis in hepatocytes. CST elevated the levels of G6P and UDPG and increased GYS activity, thus redirecting G6P to the glycogenic pathway. CST-KO mice had decreased liver glycogen that was restored by treatment with CST, reinforcing the crucial role that CST plays in hepatic glycogenesis.ConclusionsWe conclude that CST directly promotes the glycogenic pathway and reduces plasma glucose levels in insulin-resistant mice by (i) reducing glucose production from G6P, (ii) increasing glycogen synthesis from G6P via formation of UDPG, and (iii) reducing glycogenolysis.

Contraction activates glucose uptake and glycogen synthase normally in muscles from dexamethasone-treated rats

2005 ◽  
Vol 289 (2) ◽  
pp. E241-E250 ◽  
Author(s):  
Jérôme Ruzzin ◽  
Jørgen Jensen
Keyword(s):  
Insulin Resistance ◽  
Glucose Uptake ◽  
Insulin Signaling ◽  
Skeletal Muscles ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Glycogen Synthase Kinase 3 ◽  
Dexamethasone Treatment ◽  
Insulin Resistant ◽  
Gsk 3Β

Glucocorticoids cause insulin resistance in skeletal muscle. The aims of the present study were to investigate the effects of contraction on glucose uptake, insulin signaling, and regulation of glycogen synthesis in skeletal muscles from rats treated with the glucocorticoid analog dexamethasone (1 mg·kg−1·day−1 ip for 12 days). Insulin resistance in dexamethasone-treated rats was confirmed by reduced insulin-stimulated glucose uptake (∼35%), glycogen synthesis (∼70%), glycogen synthase activation (∼80%), and PKB Ser473 phosphorylation (∼40%). Chronic dexamethasone treatment did not impair glucose uptake during contraction in soleus or epitrochlearis muscles. In epitrochlearis (but not in soleus), the presence of insulin during contraction enhanced glucose uptake to similar levels in control and dexamethasone-treated rats. Contraction also increased glycogen synthase fractional activity and dephosphorylated glycogen synthase at Ser645, Ser649, Ser653, and Ser657 normally in muscles from dexamethasone-treated rats. After contraction, insulin-stimulated glycogen synthesis was completely restored in epitrochlearis and improved in soleus from dexamethasone-treated rats. Contraction did not increase insulin-stimulated PKB Ser473 or glycogen synthase kinase-3 (GSK-3) phosphorylation. Instead, contraction increased GSK-3β Ser9 phosphorylation in epitrochlearis (but not in soleus) in muscles from control and dexamethasone-treated rats. In conclusion, contraction stimulates glucose uptake normally in dexamethasone-induced insulin resistant muscles. After contraction, insulin's ability to stimulate glycogen synthesis was completely restored in epitrochlearis and improved in soleus from dexamethasone-treated rats.

scholarly journals Insulin-Like Growth Factor 2 and the Insulin Receptor, But Not Insulin, Regulate Fetal Hepatic Glycogen Synthesis

Endocrinology ◽  
2010 ◽  
Vol 151 (2) ◽  
pp. 741-747 ◽  
Author(s):  
Li Liang ◽  
Wei Hui Guo ◽  
Diego R. Esquiliano ◽  
Masato Asai ◽  
Susana Rodriguez ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Kinase Inhibitor ◽  
Glycogen Synthase ◽  
Fetal Liver ◽  
Glycogen Synthesis ◽  
Mouse Strains ◽  
Hepatic Glycogen ◽  
Insulin Receptor Isoforms ◽  
Phosphoinositide 3 Kinase

Whether insulin or IGFs regulate glycogen synthesis in the fetal liver remains to be determined. In this study, we used several knockout mouse strains, including those lacking Pdx-1 (pancreatic duodenal homeobox-1), Insr (insulin receptor), and Igf2 (IGF-II) to determine the role of these genes in the regulation of fetal hepatic glycogen synthesis. Our data show that insulin deficiency does not alter hepatic glycogen stores, whereas Insr and Igf2 deficiency do. We found that both insulin receptor isoforms (IR-A and IR-B) are present in the fetal liver, and their expression is gestationally regulated. IR-B is highly expressed in the fetal liver; nonetheless, the percentage of hepatic IR-A isoform, which binds Igf2, was significantly higher in the fetus than the adult. In vitro experiments demonstrate that Igf2 increases phosphorylation of hepatic Insr, insulin receptor substrate-2, and Akt proteins and also the activity of glycogen synthase. Igf2 ultimately increased glycogen synthesis in fetal hepatocytes. This increase could be blocked by the phosphoinositide 3-kinase inhibitor LY294008. Taken together, we propose Igf2 as a major regulator of fetal hepatic glycogen metabolism, the insulin receptor as its target receptor, and phosphoinositide 3-kinase as the signaling pathway leading to glycogen formation in the fetal liver.

Reduced insulin receptor signaling in the obese spontaneously hypertensive Koletsky rat

1997 ◽  
Vol 273 (5) ◽  
pp. E1014-E1023 ◽  
Author(s):  
Jacob E. Friedman ◽  
Tatsuya Ishizuka ◽  
Sha Liu ◽  
Craig J. Farrell ◽  
David Bedol ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Glucose Intolerance ◽  
Leptin Receptor ◽  
Spontaneously Hypertensive Rat ◽  
Regulatory Subunit ◽  
Oral Glucose ◽  
Spontaneously Hypertensive

Insulin resistance is associated with both obesity and hypertension. However, the cellular mechanisms of insulin resistance in genetic models of obese-hypertension have not been identified. The objective of the present study was to investigate the effects of genetic obesity on a background of inherited hypertension on initial components of the insulin signal transduction pathway and glucose transport in skeletal muscle and liver. Oral glucose tolerance testing in SHROB demonstrated a sustained postchallenge elevation in plasma glucose at 180 and 240 min compared with lean spontaneously hypertensive rat (SHR) littermates, which is suggestive of glucose intolerance. Fasting plasma insulin levels were elevated 18-fold in SHROB. The rate of insulin-stimulated 3- O-methylglucose transport was reduced 68% in isolated epitrochlearis muscles from the SHROB compared with SHR. Insulin-stimulated tyrosine phosphorylation of the insulin receptor β-subunit and insulin receptor substrate-1 (IRS-1) in intact skeletal muscle of SHROB was reduced by 36 and 23%, respectively, compared with SHR, due primarily to 32 and 60% decreases in insulin receptor and IRS-1 protein expression, respectively. The amounts of p85α regulatory subunit of phosphatidylinositol-3-kinase and GLUT-4 protein were reduced by 28 and 25% in SHROB muscle compared with SHR. In the liver of SHROB, the effect of insulin on tyrosine phosphorylation of IRS-1 was not changed, but insulin receptor phosphorylation was decreased by 41%, compared with SHR, due to a 30% reduction in insulin receptor levels. Our observations suggest that the leptin receptor mutation fak imposed on a hypertensive background results in extreme hyperinsulinemia, glucose intolerance, and decreased expression of postreceptor insulin signaling proteins in skeletal muscle. Despite these changes, hypertension is not exacerbated in SHROB compared with SHR, suggesting these metabolic abnormalities may not contribute to hypertension in this model of Syndrome X.

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