scholarly journals Muscle-Specific Insulin Receptor Overexpression Protects Mice From Diet-Induced Glucose Intolerance but Leads to Postreceptor Insulin Resistance

Diabetes ◽  
2020 ◽  
Vol 69 (11) ◽  
pp. 2294-2309
Author(s):  
Guoxiao Wang ◽  
Yingying Yu ◽  
Weikang Cai ◽  
Thiago M. Batista ◽  
Sujin Suk ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Glucose Intolerance ◽  
Specific Insulin

1785-P: Mice with Muscle-Specific Insulin Receptor Overexpression Are Protected from Diet-Induced Obesity and Glucose Intolerance but Develop Post-Receptor Insulin Resistance

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 1785-P
Author(s):  
GUOXIAO WANG ◽  
WEIKANG CAI ◽  
THIAGO M. BATISTA ◽  
SAMIR SOFTIC ◽  
C. RONALD KAHN
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Glucose Intolerance ◽  
Diet Induced Obesity ◽  
Specific Insulin

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.

scholarly journals Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2

2000 ◽  
Vol 105 (2) ◽  
pp. 199-205 ◽  
Author(s):  
Yoshiaki Kido ◽  
Deborah J. Burks ◽  
Dominic Withers ◽  
Jens C. Bruning ◽  
C. Ronald Kahn ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Tissue Specific ◽  
Specific Insulin

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.

scholarly journals Brown adipose tissue–specific insulin receptor knockout shows diabetic phenotype without insulin resistance

2001 ◽  
Vol 108 (8) ◽  
pp. 1205-1213 ◽  
Author(s):  
Carmen Guerra ◽  
Paloma Navarro ◽  
Angela M. Valverde ◽  
Monica Arribas ◽  
Jens Brüning ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Insulin Receptor ◽  
Tissue Specific ◽  
Brown Adipose ◽  
Specific Insulin

scholarly journals Neuronal overexpression of insulin receptor substrate 2 leads to increased fat mass, insulin resistance, and glucose intolerance during aging

AGE ◽  
2012 ◽  
Vol 35 (5) ◽  
pp. 1881-1897 ◽  
Author(s):  
J. Zemva ◽  
M. Udelhoven ◽  
L. Moll ◽  
S. Freude ◽  
O. Stöhr ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Glucose Intolerance ◽  
Fat Mass ◽  
Insulin Receptor Substrate

scholarly journals Distinct Effects of Carrageenan and High-Fat Consumption on the Mechanisms of Insulin Resistance in Nonobese and Obese Models of Type 2 Diabetes

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Sumit Bhattacharyya ◽  
Leo Feferman ◽  
Joanne K. Tobacman
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Glucose Intolerance ◽  
Dietary Exposure ◽  
High Fat ◽  
Mediated Effects ◽  
Fat Consumption ◽  
Arylsulfatase B ◽  
Galectin 3

Exposure to low concentration of the common food additive carrageenan (10 mg/L) for only six days led to glucose intolerance and insulin resistance in the C57BL/6J mouse. Longer exposure produced fasting hyperglycemia but with no increase in weight, in contrast to the HFD. Glucose intolerance was attributable to carrageenan-induced inflammation and to increased expression of GRB10. Both HFD and carrageenan increased p(Ser32)-IκBα and p(Ser307)-IRS1, and the increases were greater following the combined exposure. The effects of carrageenan were inhibited by the combination of the free radical inhibitor Tempol and BCL10 siRNA, which had no impact on the HFD-mediated increase. In contrast, the PKC inhibitor sotrastaurin blocked the HFD-induced increases, without an effect on the carrageenan-mediated effects. HFD had no impact on the expression of GRB10. Both carrageenan and high fat increased hepatic infiltration by F4/80-positive macrophages. Serum galectin-3 and galectin-3 binding to the insulin receptor increased by carrageenan and by HFD. Tyrosine phosphorylation of the insulin receptor declined following either exposure and was further reduced by their combination. Carrageenan reduced the activity of the enzyme N-acetylgalactosamine-4-sulfatase (ARSB; arylsulfatase B), which was unchanged following HFD. Dietary exposure to both high fat and carrageenan can impair insulin signaling through both similar and distinct mechanisms.

scholarly journals Increased Hepatic Levels of the Insulin Receptor Inhibitor, PC-1/NPP1, Induce Insulin Resistance and Glucose Intolerance

Diabetes ◽  
2005 ◽  
Vol 54 (2) ◽  
pp. 367-372 ◽  
Author(s):  
H. Dong ◽  
B. A. Maddux ◽  
J. Altomonte ◽  
M. Meseck ◽  
D. Accili ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Glucose Intolerance ◽  
Induce Insulin Resistance ◽  
Receptor Inhibitor

Reduced susceptibility of muscle-specific insulin receptor knockout mice to colon carcinogenesis

2008 ◽  
Vol 294 (3) ◽  
pp. G679-G686 ◽  
Author(s):  
Kafi N. Ealey ◽  
Suying Lu ◽  
Dominic Lau ◽  
Michael C. Archer
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Insulin Receptor ◽  
Elevated Serum ◽  
Tumor Development ◽  
Colon Carcinogenesis ◽  
Aberrant Crypt Foci ◽  
Serum Triglycerides ◽  
Insulin Resistant ◽  
Specific Insulin

Insulin resistance is a risk factor for colon cancer, but it is not clear which of its metabolic sequelae are involved. The objective of this study was to determine whether increased adiposity and elevated circulating lipids commonly seen in insulin resistance promote colon carcinogenesis independent of changes in insulin. We made use of muscle-specific insulin receptor knockout (MIRKO) mice that exhibit elevated serum triglycerides (TG), free fatty acids (FFA), and fat mass but have similar body weights, circulating glucose, and insulin and insulin sensitivity to their wild-type littermates used as controls. Seven-week-old male MIRKO mice and controls received four weekly intraperitoneal injections of either 5 mg/kg azoxymethane (AOM) to induce aberrant crypt foci (ACF) or 10 mg/kg AOM to induce tumors and were killed at 24 or 40 wk of age, respectively. The MIRKO mice displayed hyperinsulinemia at 7 wk of age and reduced insulin sensitivity at 16 wk of age compared with controls. The previously reported MIRKO phenotype developed between 16 and 24 wk of age. By 40 wk of age, however, MIRKO mice were again insulin resistant. ACF development did not differ between MIRKO mice and controls, but MIRKO mice developed significantly fewer colon tumors. Our results suggest that circulating TG and FFA are not promoters of colon tumor development. Indeed, we show that the cumulative effects of the metabolic changes that occur with knockout of the insulin receptor in muscle are associated with reduced susceptibility to colon tumorigenesis.

scholarly journals Disruption of the SH2-B Gene Causes Age-Dependent Insulin Resistance and Glucose Intolerance

2004 ◽  
Vol 24 (17) ◽  
pp. 7435-7443 ◽  
Author(s):  
Chaojun Duan ◽  
Hongyan Yang ◽  
Morris F. White ◽  
Liangyou Rui
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Glucose Intolerance ◽  
Glucose Homeostasis ◽  
Adaptor Protein ◽  
Receptor Activation ◽  
Sh2 Domain ◽  
Age Dependent

ABSTRACT Insulin regulates glucose homeostasis by binding and activating the insulin receptor, and defects in insulin responses (insulin resistance) induce type 2 diabetes. SH2-B, an Src homology 2 (SH2) and pleckstrin homology domain-containing adaptor protein, binds via its SH2 domain to insulin receptor in response to insulin; however, its physiological role remains unclear. Here we show that SH2-B was expressed in the liver, skeletal muscle, and fat. Systemic deletion of SH2-B impaired insulin receptor activation and signaling in the liver, skeletal muscle, and fat, including tyrosine phosphorylation of insulin receptor substrate 1 (IRS1) and IRS2 and activation of the phosphatidylinositol 3-kinase/Akt and the Erk1/2 pathways. Consequently, SH2-B−/− knockout mice developed age-dependent hyperinsulinemia, hyperglycemia, and glucose intolerance. Moreover, SH2-B directly enhanced autophosphorylation of insulin receptor and tyrosine phosphorylation of IRS1 and IRS2 in an SH2 domain-dependent manner in cultured cells. Our data suggest that SH2-B is a physiological enhancer of insulin receptor activation and is required for maintaining normal insulin sensitivity and glucose homeostasis during aging.

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