Protein kinase C is increased in the liver of humans and rats with non-insulin-dependent diabetes mellitus: An alteration not due to hyperglycemia

Robert V. Considine, Mark R. Nyce, Lonnie E. Allen, Luz Marina Morales, Stuart Triester, Jose Serrano, James Colberg, Susan Lanza-Jacoby, Jose F. Caro

Research output: Contribution to journalArticle

131 Scopus citations

Abstract

We tested the hypothesis that liver protein kinase C (PKC) is increased in non-insulin-dependent diabetes mellitus (NIDDM). To this end we examined the distribution of PKC isozymes in liver biopsies from obese individuals with and without NIDDM and in lean controls. PKC isozymes α, β, ε and ζ were detected by immunoblotting in both the cytosol and membrane fractions. Isozymes γ and δ were not detected. There was a significant increase in immunodetectable PKC-α (twofold), -ε (threefold), and -ζ (twofold) in the membrane fraction isolated from obese subjects with NIDDM compared with the lean controls. In obese subjects without NIDDM, the amount of membrane PKC isozymes was not different from the other two groups. We next sought an animal model where this observation could be studied further. The Zucker diabetic fatty rat offered such a model system. Immunodetectable membrane PKC-α, -β, -ε, and -ζ were significantly increased when compared with both the lean and obese controls. The increase in immunodetectable PKC protein correlated with a 40% elevation in the activity of PKC at the membrane. Normalization of circulating glucose in the rat model by either insulin or phlorizin treatment did not result in a reduction in membrane PKC isozyme protein or kinase activity. Further, phlorizin treatment did not improve insulin receptor autophosphorylation nor did the treatment lower liver diacylglycerol. We conclude that liver PKC is increased in NIDDM, a change that is not secondary to hyperglycemia. It is possible that PKC-mediated phosphorylation of some component in the insulin signaling cascade contributes to the insulin resistance observed in NIDDM.

Original languageEnglish (US)
Pages (from-to)2938-2944
Number of pages7
JournalJournal of Clinical Investigation
Volume95
Issue number6
DOIs
StatePublished - Jun 1995

Keywords

  • Insulin resistance
  • Liver
  • PKC isozymes
  • ZDF rat

ASJC Scopus subject areas

  • Medicine(all)

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