Insulin signalling in hepatocytes of humans with type 2 diabetes: excessive production and activity of protein kinase C-ι (PKC-ι) and dependent processes and reversal by PKC-ι inhibitors.

Diabetologia
Mini Sajan, Robert V Farese

Abstract

We examined the role of protein kinase C-ι (PKC-ι) in mediating alterations in the abundance of enzymes in hepatocytes of type 2 diabetic humans that contribute importantly to the development of lipid and carbohydrate abnormalities in type 2 diabetes. We examined (1) insulin signalling in isolated hepatocytes of non-diabetic and type 2 diabetic humans and (2) the effects of two newly developed small molecule PKC-ι inhibitors on aberrant signalling and downstream processes. In contrast with PKC-ι deficiency in diabetic muscle, which diminishes glucose transport, PKC-ι in diabetic hepatocytes was overproduced and overactive, basally and after insulin treatment, and, moreover, was accompanied by increased abundance of PKC-ι-dependent lipogenic, proinflammatory and gluconeogenic enzymes. Heightened PKC-ι activity most likely reflected heightened activity of IRS-2-dependent phosphatidylinositol 3-kinase (PI3K), as IRS-1 levels and IRS-1/PI3K activity were markedly diminished. Importantly, insulin-stimulated PKC-ι abundance and its overabundance in diabetic hepatocytes was reversed in vitro by both insulin deprivation and PKC-ι inhibitors; this suggested operation of an insulin-driven, feed-forward/positive-feedback mechanism. In con...Continue Reading

References

May 17, 2000·The Journal of Clinical Investigation·K UekiT Kadowaki
Aug 28, 2003·Diabetes·Angela M ValverdeManuel Benito
Jul 25, 2006·The Journal of Biological Chemistry·Eda ErdoganAlan P Fields
Jul 21, 2007·The Journal of Clinical Investigation·Robert V FareseMichael Leitges
Oct 25, 2007·Biochemical Society Transactions·A P FieldsR P Regala
Feb 10, 2009·Journal of Lipid Research·Mini P SajanRobert V Farese
Jul 15, 2009·Molecular and Cellular Biology·Shaodong GuoMorris F White
Nov 6, 2009·American Journal of Physiology. Endocrinology and Metabolism·M P SajanR V Farese
Dec 10, 2009·American Journal of Physiology. Endocrinology and Metabolism·Robert V Farese, Mini P Sajan
Feb 6, 2010·Proceedings of the National Academy of Sciences of the United States of America·Shijie LiJoseph L Goldstein
Feb 15, 2011·The International Journal of Biochemistry & Cell Biology·Prajit PillaiMildred Acevedo-Duncan

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Citations

Mar 28, 2012·Current Opinion in Lipidology·Robert V Farese, Mini P Sajan
Sep 4, 2012·Trends in Endocrinology and Metabolism : TEM·Barbara E Corkey, Orian Shirihai
Nov 22, 2014·Frontiers in Endocrinology·Beina TengMario Schiffer
Oct 2, 2013·Indian Journal of Endocrinology and Metabolism·Ambika Gopalakrishnan UnnikrishnanPaturi V Rao

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