Dataset Information

LNK deficiency decreases obesity-induced insulin resistance by regulating GLUT4 through the PI3K-Akt-AS160 pathway in adipose tissue.

ABSTRACT: In recent years, LNK, an adapter protein, has been found to be associated with metabolic diseases, including hypertension and diabetes. We found that the expression of LNK in human adipose tissue was positively correlated with serum glucose and insulin in obese people. We examined the role of LNK in insulin resistance and systemic energy metabolism using LNK-deficient mice (LNK-/-). With consumption of a high-fat diet, wild type (WT) mice accumulated more intrahepatic triglyceride, higher serum triglyceride (TG), free fatty acid (FFA) and high sensitivity C-reactive protein (hsCRP) compared with LNK-/- mice. However, there was no significant difference between LNK-/- and WT mice under normal chow diet. Meanwhile, glucose transporter 4 (GLUT4) expression in adipose tissue and insulin-stimulated glucose uptake in adipocytes were increased in LNK-/- mice. LNK-/- adipose tissue showed activated reactivity for IRS1/PI3K/Akt/AS160 signaling, and administration of a PI3K inhibitor impaired glucose uptake. In conclusion, LNK plays a pivotal role in adipose glucose transport by regulating insulin-mediated IRS1/PI3K/Akt/AS160 signaling.

SUBMITTER: Zhong X

PROVIDER: S-EPMC7521507 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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LNK deficiency decreases obesity-induced insulin resistance by regulating GLUT4 through the PI3K-Akt-AS160 pathway in adipose tissue.

Zhong Xiaozhu X Ke Chuanfeng C Cai Zhaoxi Z Wu Hao H Ye Yang Y Liang Xiaolin X Yu Liqun L Jiang Sushi S Shen Jun J Wang Laiyou L Xie Meiqing M Wang Guanlei G Zhao Xiaomiao X

Aging 20200910 17

In recent years, LNK, an adapter protein, has been found to be associated with metabolic diseases, including hypertension and diabetes. We found that the expression of LNK in human adipose tissue was positively correlated with serum glucose and insulin in obese people. We examined the role of LNK in insulin resistance and systemic energy metabolism using LNK-deficient mice (<i>LNK<sup>-/-</sup></i>). With consumption of a high-fat diet, wild type (WT) mice accumulated more intrahepatic triglycer ...[more]

PMID: 32911464

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Project description:Panax notoginseng saponins (PNS) are a commonly used traditional medicine to treat diabetes in China. Recent studies have confirmed their anti-diabetic effects, but the underlying mechanisms have remained unclear. The present study was designed to explore whether PNS decrease hyperglycemia by improving insulin sensitivity in skeletal muscle and to elucidate the molecular mechanisms. The anti-diabetic effects of PNS were analyzed in a skeletal myoblast cell line, C2C12, and in high fat diet-induced diabetic KKAy mice. C2C12 cells were treated with PNS (50, 100, and 200 μg·L-1 ) and examined for glucose uptake, cell viability and expression of components of the phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway. KKAy mice were intraperitoneally injected with PNS (200 mg·kg-1 ) for 6 weeks. Body weight, blood glucose, serum insulin, serum lipid, glucose and insulin tolerance were measured to evaluate the anti-diabetic effects of PNS. Pathological changes, apoptosis and the PI3K-AKT signaling pathway were analyzed in KKAy skeletal muscle. PNS significantly increased insulin-induced glucose uptake, but did not affect the cell viability of C2C12 cells. In addition, PNS reduced blood glucose and serum insulin levels and improved glucose tolerance and insulin tolerance of KKAy mice. Pathological changes and apoptosis of skeletal muscle were relieved by PNS treatment. Moreover, PNS treatment enhanced expression of mRNA encoding IRS1 and GLUT4, as well as the protein expression of phosphorylated (p) -insulin receptor substrate 1 (IRS1), p-PI3K, p-AKT and glucose transporter type 4 (GLUT4) in C2C12 and KKAy mouse muscle. Collectively, these data indicate that PNS reduces hyperglycemia and insulin resistance through up-regulating GLUT4 expression and the IRS1-PI3K-AKT signaling pathway. Furthermore, PNS alleviated diabetes skeletal muscle pathological damage. Thus, our data suggest that PNS may be promising anti-diabetic compounds.

Project description:Impaired insulin-mediated glucose uptake characterizes cardiac muscle in humans and animals with insulin resistance and diabetes, despite preserved or enhanced phosphatidylinositol 3-kinase (PI3K) and the serine-threonine kinase, Akt-signaling, via mechanisms that are incompletely understood. One potential mechanism is PI3K- and Akt-mediated activation of mechanistic target of rapamycin (mTOR) and ribosomal protein S6 kinase (S6K), which may impair insulin-mediated activation of insulin receptor substrate (IRS)1/2 via inhibitory serine phosphorylation or proteasomal degradation. To gain mechanistic insights by which constitutive activation of PI3K or Akt may desensitize insulin-mediated glucose uptake in cardiomyocytes, we examined mice with cardiomyocyte-restricted, constitutive or inducible overexpression of a constitutively activated PI3K or a myristoylated Akt1 (myrAkt1) transgene that also expressed a myc-epitope-tagged glucose transporter type 4 protein (GLUT4). Although short-term activation of PI3K and myrAkt1 increased mTOR and S6 signaling, there was no impairment in insulin-mediated activation of IRS1/2. However, insulin-mediated glucose uptake was reduced by 50-80%. Although longer-term activation of Akt reduced IRS2 protein content via an mTORC1-mediated mechanism, treatment of transgenic mice with rapamycin failed to restore insulin-mediated glucose uptake, despite restoring IRS2. Transgenic activation of Akt and insulin-stimulation of myrAkt1 transgenic cardiomyocytes increased sarcolemmal insertion of myc-GLUT4 to levels equivalent to that observed in insulin-stimulated wild-type controls. Despite preserved GLUT4 translocation, glucose uptake was not elevated by the presence of constitutive activation of PI3K and Akt. Hexokinase II activity was preserved in myrAkt1 hearts. Thus, constitutive activation of PI3K and Akt in cardiomyocytes impairs GLUT4-mediated glucose uptake via mechanisms that impair the function of GLUT4 after its plasma-membrane insertion.

Dataset Information

LNK deficiency decreases obesity-induced insulin resistance by regulating GLUT4 through the PI3K-Akt-AS160 pathway in adipose tissue.

Publications

LNK deficiency decreases obesity-induced insulin resistance by regulating GLUT4 through the PI3K-Akt-AS160 pathway in adipose tissue.

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