Cellular Cyclic AMP Levels Modulate Insulin Sensitivity and Responsiveness - Evidence Against a Significant Role of Gi in Insulin Signal Transduction

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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The regulatory role of protein kinase C in insulin signal transduction via adenylyl cyclase signalling system

Relaxin 2000 ◽

10.1007/978-94-017-2877-5_53 ◽

2001 ◽

pp. 321-323

Author(s):

Svetlana Plesneva ◽

Alexander Shpakov ◽

Ludmila Kuznetsova ◽

Marianna Pertseva

Keyword(s):

Signal Transduction ◽

Protein Kinase C ◽

Protein Kinase ◽

Adenylyl Cyclase ◽

Regulatory Role ◽

Signalling System ◽

Insulin Signal Transduction ◽

Insulin Signal ◽

Kinase C

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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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