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 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.

Naringin improves zidovudine- and stavudine-induced skeletal muscle complications in rats

2016 ◽  
Vol 36 (1) ◽  
pp. 93-105 ◽  
Author(s):  
OO Adebiyi ◽  
OA Adebiyi ◽  
PMO Owira
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Vitamin E ◽  
Protein Expression ◽  
Hiv Infection ◽  
Glucose Intolerance ◽  
B Cell Lymphoma ◽  
Oral Glucose ◽  
Management Options ◽  
Carbonyl Protein

Chronic use of nucleoside reverse transcriptase inhibitors (NRTIs) in managing human immunodeficiency virus (HIV) infection has been associated with several complications. Available management options for these complications have yielded controversial results, thus the need to urgently find newer alternatives. Naringin, a plant-derived flavonoid, has been shown to possess antioxidant and antiapoptotic properties which can be exploited in managing NRTI-induced complications. This study therefore investigated the effects of naringin on some NRTI-induced complications. Forty-nine rats (200–250 g) were divided into seven groups and were orally treated with stavudine (d4T)-only, d4T + naringin, d4T + vitamin E, zidovudine (AZT)-only, AZT + naringin, AZT + vitamin E, and distilled water, respectively. Drugs were administered once daily for 56 days, and oral glucose tolerance tests conducted on day 54 of the experiments and rats were thereafter sacrificed on day 56 by halothane overdose. Plasma samples and the left gastrocnemius muscles were stored at −80°C for further analysis. There was significant glucose intolerance, insulin resistance, oxidative stress, and apoptosis in the skeletal muscles of AZT- or d4T-only–treated rats. Naringin, however, significantly reduced fasting blood glucose and fasting plasma insulin concentrations, mitigated glucose intolerance, and insulin resistance in addition to reducing malondialdehyde and carbonyl protein concentrations when coadministered with either NRTIs. Furthermore, naringin improved antioxidant enzyme activities, reduced skeletal muscle BCL-2-associated X protein expression, and improved B-cell lymphoma-2 protein expression compared to AZT- or d4T-only–treated rats. Naringin ameliorated AZT- and d4T-induced complications and therefore should be further investigated as a possible nutritional supplement in managing HIV infection.

Immobilization depresses insulin signaling in skeletal muscle

2000 ◽  
Vol 279 (6) ◽  
pp. E1235-E1241 ◽  
Author(s):  
Munetaka Hirose ◽  
Masao Kaneki ◽  
Hiroki Sugita ◽  
Shingo Yasuhara ◽  
J. A. Jeevendra Martyn
Keyword(s):  
Skeletal Muscle ◽  
Protein Expression ◽  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Glucose Transport ◽  
Insulin Signaling ◽  
Regulatory Subunit ◽  
Protein Levels ◽  
Essential Components ◽  
Prolonged Immobilization

Prolonged immobilization depresses insulin-induced glucose transport in skeletal muscle and leads to a catabolic state in the affected areas, with resultant muscle wasting. To elucidate the altered intracellular mechanisms involved in the insulin resistance, we examined insulin-stimulated tyrosine phosphorylation of the insulin receptor β-subunit (IR-β) and insulin receptor substrate (IRS)-1 and activation of its further downstream molecule, phosphatidylinositol 3-kinase (PI 3-K), after unilateral hindlimb immobilization in the rat. The contralateral hindlimb served as control. After 7 days of immobilization of the rat, insulin was injected into the portal vein, and tibialis anterior muscles on both sides were extracted. Immobilization reduced insulin-stimulated tyrosine phosphorylation of IR-β and IRS-1. Insulin-stimulated binding of IRS-1 to p85, the regulatory subunit of PI 3-K, and IRS-1-associated PI 3-K activity were also decreased in the immobilized hindlimb. Although IR-β and p85 protein levels were unchanged, IRS-1 protein expression was downregulated by immobilization. Thus prolonged immobilization may cause depression of insulin-stimulated glucose transport in skeletal muscle by altering insulin action at multiple points, including the tyrosine phosphorylation, protein expression, and activation of essential components of insulin signaling pathways.

scholarly journals Bitter gourd (Momordica charantia) improves insulin sensitivity by increasing skeletal muscle insulin-stimulated IRS-1 tyrosine phosphorylation in high-fat-fed rats

2007 ◽  
Vol 99 (4) ◽  
pp. 806-812 ◽  
Author(s):  
M. G. Sridhar ◽  
R. Vinayagamoorthi ◽  
V. Arul Suyambunathan ◽  
Z. Bobby ◽  
N. Selvaraj
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Insulin Signalling ◽  
Bitter Gourd ◽  
High Fat ◽  
Fat Feeding

The aim of this present study was to investigate the effect of bitter gourd extract on insulin sensitivity and proximal insulin signalling pathways in high-fat-fed rats. High-fat feeding of male Wistar rats for 10 weeks decreased the glucose tolerance and insulin sensitivity compared to chow-fed control rats. Bitter gourd extract supplementation for 2 weeks (9th and 10th) of high-fat feeding improved the glucose tolerance and insulin sensitivity. In addition bitter gourd extract reduced the fasting insulin (43 (se 4·4) v. 23 (se 5·2) μU/ml, P < 0·05), TAG (134 (se 12) v. 96 (se 5·5) mg/dl, P < 0·05), cholesterol (97 (se 6·3) v. 72 (se 5·2) mg/dl, P < 0·05) and epidydimal fat (4·8 (se 0·29) v. 3·6 (se 0·24) g, P < 0·05), which were increased by high-fat diet (HFD). High-fat feeding and bitter gourd supplementation did not have any effect on skeletal muscle insulin receptor, insulin receptor subtrate-1 (IRS-1) and insulin- stimulated insulin receptor tyrosine phosphorylation compared to chow-fed control rats. However high-fat feeding for 10 weeks reduced the insulin-stimulated IRS-1 tyrosine phosphorylation compared to control rats. Bitter gourd supplementation together with HFD for 2 weeks improved the insulin-stimulated IRS-1 tyrosine phosphorylation compared to rats fed with HFD alone. Our results show that bitter gourd extract improves insulin sensitivity, glucose tolerance and insulin signalling in HFD-induced insulin resistance. Identification of potential mechanism(s) by which bitter gourd improves insulin sensitivity and insulin signalling in high-fat-fed rats may open new therapeutic targets for the treatment of obesity/dyslipidemia-induced insulin resistance.

scholarly journals Hepatokine ERAP1 impairs skeletal muscle insulin sensitivity via ADRB2/PKA pathway

2020 ◽  
Author(s):  
Feifan Guo ◽  
Yuguo Niu ◽  
Haizhou Jiang ◽  
Hanrui Yin ◽  
Fenfen Wang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Neutralizing Antibodies ◽  
Leptin Receptor ◽  
Whole Body ◽  
C2c12 Myotubes ◽  
Insulin Resistant ◽  
Skeletal Muscle Insulin Sensitivity ◽  
Pka Pathway

Abstract The current study aimed to investigate the role of endoplasmic reticulum aminopeptidase 1 (ERAP1), a novel hepatokine, in whole-body glucose metabolism. Here, we found that hepatic ERAP1 levels were increased in insulin-resistant leptin-receptor-mutated (db/db) and high-fat diet (HFD)-fed mice. Consistently, hepatic ERAP1 overexpression attenuated skeletal muscle (SM) insulin sensitivity, whereas knockdown ameliorated SM insulin resistance. Furthermore, serum and hepatic ERAP1 levels were positively correlated, and recombinant mouse ERAP1 or conditioned medium with high ERAP1 content (CM-ERAP1) attenuated insulin signaling in C2C12 myotubes, and CM-ERAP1 or HFD-induced insulin resistance was blocked by ERAP1 neutralizing antibodies. Mechanistically, ERAP1 reduced ADRB2 expression and interrupted ADRB2-dependent signaling in C2C12 myotubes. Finally, ERAP1 inhibition via global knockout or the inhibitor thimerosal improved insulin sensitivity. Together, ERAP1 is a hepatokine that impairs SM and whole-body insulin sensitivity, and its inhibition might provide a therapeutic strategy for diabetes, particularly for those with SM insulin resistance.

Gliclazide increases insulin receptor tyrosine phosphorylation but not p38 phosphorylation in insulin-resistant skeletal muscle cells

2002 ◽  
Vol 205 (23) ◽  
pp. 3739-3746 ◽  
Author(s):  
Naresh Kumar ◽  
Chinmoy S. Dey
Keyword(s):  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Tyrosine Phosphorylation ◽  
Insulin Signaling ◽  
Mapk Pathway ◽  
Muscle Cells ◽  
Skeletal Muscle Cells ◽  
Insulin Resistant ◽  
Resistant Cells

SUMMARY Sulfonylurea drugs are used in the treatment of type 2 diabetes. The mechanism of action of sulfonylureas is to release insulin from pancreatic cells and they have been proposed to act on insulin-sensitive tissues to enhance glucose uptake. The goal of the present study was to test the hypothesis that gliclazide, a second-generation sulfonylurea, could enhance insulin signaling in insulin-resistant skeletal muscle cells. We demonstrated that gliclazide enhanced insulin-stimulated insulin receptor tyrosine phosphorylation in insulin-resistant skeletal muscle cells. Although insulin receptor substrate-1 tyrosine phosphorylation was unaffected by gliclazide treatment, phosphatidylinositol 3-kinase activity was partially restored by treatment with gliclazide. No increase in 2-deoxyglucose uptake in insulin-resistant cells by treatment with gliclazide was observed. Further investigations into the mitogen-activated protein kinase (MAPK) pathway revealed that insulin-stimulated p38 phosphorylation was impaired, as compared with extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal kinase(JNK), which were phosphorylated normally in insulin-resistant cells. Treatment with gliclazide could not restore p38 phosphorylation in insulin-resistant cells. We propose that gliclazide can regulate part of the insulin signaling in insulin-resistant skeletal muscle, and p38 could be a potential therapeutic target for glucose uptake to treat insulin resistance.

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