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Diabetologia
Published in: Diabetologia 11/2013

01-11-2013 | Article

Metformin action in human hepatocytes: coactivation of atypical protein kinase C alters 5′-AMP-activated protein kinase effects on lipogenic and gluconeogenic enzyme expression

Authors: Mini P. Sajan, Robert A. Ivey III, Robert V. Farese

Published in: Diabetologia | Issue 11/2013

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Abstract

Aims/hypothesis

Atypical protein kinase C (aPKC) levels and activity are elevated in hepatocytes of individuals with type 2 diabetes and cause excessive increases in the levels of lipogenic and gluconeogenic enzymes; aPKC inhibitors largely correct these aberrations. Metformin improves hepatic gluconeogenesis by activating 5′-AMP-activated protein kinase (AMPK). However, metformin also activates aPKC in certain tissues; in the liver, this activation could amplify diabetic aberrations and offset the positive effects of AMPK. In this study, we examined whether metformin activates aPKC in human hepatocytes and the metabolic consequences of any such activation.

Methods

We compared protein kinase activities and alterations in lipogenic and gluconeogenic enzyme levels during activity of the AMPK activators metformin and AICAR, relative to those of an aPKC-ι inhibitor, in hepatocytes from non-diabetic and type 2 diabetic human organ donors.

Results

Metformin and 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) activated aPKC at concentrations comparable with those required for AMPK activation. Moreover, both agents increased lipogenic enzyme levels by an aPKC-dependent mechanism. Thus, whereas insulin- and diabetes-dependent increases in lipogenic enzyme levels were reversed by aPKC inhibition, such levels were increased in hepatocytes from non-diabetic donors and remained elevated in hepatocytes from diabetic donors following metformin and AICAR treatment. In addition, whereas aPKC inhibition diminished gluconeogenic enzyme levels in the absence and presence of insulin in hepatocytes from both non-diabetic and diabetic donors, metformin and AICAR increased gluconeogenic enzyme levels in hepatocytes from non-diabetic individuals, but nevertheless diminished gluconeogenic enzyme levels in insulin-treated hepatocytes from diabetic donors.

Conclusions/interpretation

Metformin and AICAR activate aPKC together with AMPK in human hepatocytes. Activation of aPKC increases lipogenic enzyme levels and alters gluconeogenic enzyme levels, and therefore appears to offset the positive effects of AMPK.
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Metadata
Title
Metformin action in human hepatocytes: coactivation of atypical protein kinase C alters 5′-AMP-activated protein kinase effects on lipogenic and gluconeogenic enzyme expression
Authors
Mini P. Sajan
Robert A. Ivey III
Robert V. Farese
Publication date
01-11-2013
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 11/2013
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-013-3010-1

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