Compensatory alterations for insulin signal transduction and glucose transport in insulin-resistant diabetes

Insulin binding activates the receptor tyrosine kinase toward the insulin receptor substrate-1 (IRS-1). Phosphorylated IRS-1 then interacts with the p85 alpha subunit of phosphatidylinositol 3-kinase (PI3K), Nck, growth factor receptor-bound protein 2 (GRB2), and Syp, thus branching insulin's signal for both mitogenic and metabolic responses. To determine whether the expression of these proteins is altered in insulin resistance, the levels of these proteins were compared in adipose and liver tissues of nondiabetic mice and obese insulin-resistant diabetic KKAy mice. IR and PI3K p85 alpha protein levels were significantly lower in KKAy mice than in control nondiabetic mice, whereas IRS-1 protein levels were not altered. In contrast, the protein levels of GRB2, Nck, Syp, and GLUT-1 were dramatically elevated in KKAy fat, with less striking changes in liver. Treatment of diabetic animals with pioglitazone, an insulin-sensitizing antihyperglycemic agent, partially corrected the expression of some of these proteins. Taken together, these findings suggest that the insulin-resistant diabetic condition is characterized by changes in expression of insulin signal transduction components that may be associated with altered glucose metabolism.

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Invited Review: Exercise training-induced changes in insulin signaling in skeletal muscle

Journal of Applied Physiology ◽

10.1152/japplphysiol.00126.2002 ◽

2002 ◽

Vol 93 (2) ◽

pp. 773-781 ◽

Cited By ~ 113

Author(s):

Juleen R. Zierath

Keyword(s):

Skeletal Muscle ◽

Signal Transduction ◽

Protein Kinase ◽

Glucose Metabolism ◽

Exercise Training ◽

Molecular Mechanism ◽

Insulin Signaling ◽

Insulin Signal Transduction ◽

Insulin Signal ◽

Insulin Resistant

This review will provide insight on the current understanding of the intracellular signaling mechanisms by which exercise training increases glucose metabolism and gene expression in skeletal muscle. Participation in regular exercise programs can have important clinical implications, leading to improved health in insulin-resistant persons. Evidence is emerging that insulin signal transduction at the level of insulin receptor substrates 1 and 2, as well as phosphatidylinositol 3-kinase, is enhanced in skeletal muscle after exercise training. This is clinically relevant because insulin signaling is impaired in skeletal muscle from insulin-resistant Type 2 diabetic and obese humans. The molecular mechanism for enhanced insulin-stimulated glucose uptake after exercise training may be partly related to increased expression and activity of key proteins known to regulate glucose metabolism in skeletal muscle. Exercise also leads to an insulin-independent increase in glucose transport, mediated in part by AMP-activated protein kinase. Changes in protein expression may be related to increased signal transduction through the mitogen-activated protein kinase signaling cascades, a pathway known to regulate transcriptional activity. Understanding the molecular mechanism for the activation of insulin signal transduction pathways after exercise training may provide novel entry points for new strategies to enhance glucose metabolism and for improved health in the general population.

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BMP7 improves insulin signal transduction in the liver via inhibition of mitogen-activated protein kinases

Journal of Endocrinology ◽

10.1530/joe-18-0693 ◽

2019 ◽

Vol 243 (2) ◽

pp. 97-110 ◽

Cited By ~ 1

Author(s):

Hong Ma ◽

Jin Yuan ◽

Jinyu Ma ◽

Jie Ding ◽

Weiwei Lin ◽

...

Keyword(s):

Signal Transduction ◽

Insulin Sensitivity ◽

Protein Kinases ◽

Transforming Growth Factor ◽

Mitogen Activated Protein Kinases ◽

Insulin Signal Transduction ◽

Insulin Signal ◽

Insulin Resistant ◽

Mitogen Activated Protein

Bone morphogenetic protein 7 (BMP7), a member of the transforming growth factor-β (TGF-β) family, plays pivotal roles in energy expenditure. However, whether and how BMP7 regulates hepatic insulin sensitivity is still poorly understood. Here, we show that hepatic BMP7 expression is reduced in high-fat diet (HFD)-induced diabetic mice and palmitate (PA)-induced insulin-resistant HepG2 and AML12 cells. BMP7 improves insulin signaling pathway in insulin resistant hepatocytes. On the contrary, knockdown of BMP7 further impairs insulin signal transduction in PA-treated cells. Increased expression of BMP7 by adenovirus expressing BMP7 improves hyperglycemia, insulin sensitivity and insulin signal transduction. Furthermore, BMP7 inhibits mitogen-activated protein kinases (MAPKs) in both the liver of obese mice and PA-treated cells. In addition, inhibition of MAPKs recapitulates the effects of BMP7 on insulin signal transduction in cultured hepatocytes treated with PA. Activation of p38 MAPK abolishes the BMP7-mediated upregulation of insulin signal transduction both in vitro and in vivo. Together, our results show that hepatic BMP7 has a novel function in regulating insulin sensitivity through inhibition of MAPKs, thus providing new insights into treating insulin resistance-related disorders such as type 2 diabetes.

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Cellular consequences for insulin signal transduction of the naturally occurring AKT2 p.Glu17Lys mutation

Endocrine Abstracts ◽

10.1530/endoabs.31.p196 ◽

2013 ◽

pp. 1-1

Author(s):

Marina Minic ◽

Nuno Rocha ◽

Ben Challis ◽

Matthijs Groeneveld ◽

Stephen O Rahilly ◽

...

Keyword(s):

Signal Transduction ◽

Insulin Signal Transduction ◽

Insulin Signal ◽

Naturally Occurring

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Signal Transducer and Activator of Transcription (Stat)-Induced Stat Inhibitor 1 (Ssi-1)/Suppressor of Cytokine Signaling 1 (Socs1) Inhibits Insulin Signal Transduction Pathway through Modulating Insulin Receptor Substrate 1 (Irs-1) Phosphorylation

Journal of Experimental Medicine ◽

10.1084/jem.193.2.263 ◽

2001 ◽

Vol 193 (2) ◽

pp. 263-270 ◽

Cited By ~ 111

Author(s):

Yoshinori Kawazoe ◽

Tetsuji Naka ◽

Minoru Fujimoto ◽

Hidetsugu Kohzaki ◽

Yoshiaki Morita ◽

...

Keyword(s):

Signal Transduction ◽

Negative Feedback ◽

Signal Transduction Pathway ◽

Cytokine Signaling ◽

Insulin Receptor Substrate ◽

Signal Transducer ◽

Transduction Pathway ◽

Insulin Signal Transduction ◽

Insulin Signal ◽

Insulin Signal Transduction Pathway

Signal transducer and activator of transcription (STAT)-induced STAT inhibitor 1 (SSI-1) is known to function as a negative feedback regulator of cytokine signaling, but it is unclear whether it is involved in other biological events. Here, we show that SSI-1 participates and plays an important role in the insulin signal transduction pathway. SSI-1–deficient mice showed a significantly low level of blood sugar. While the forced expression of SSI-1 reduced the phosphorylation level of insulin receptor substrate 1 (IRS-1), SSI-1 deficiency resulted in sustained phosphorylation of IRS-1 in response to insulin. Furthermore, SSI-1 achieves this inhibition both by binding directly to IRS-1 and by suppressing Janus kinases. These findings suggest that SSI-1 acts as a negative feedback factor also in the insulin signal transduction pathway through the suppression of IRS-1 phosphorylation.

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