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Diabetes 50:584-592, 2001
© 2001 by the American Diabetes Association, Inc.

Cellular Mechanism of Nutritionally Induced Insulin Resistance in Psammomys Obesus

Overexpression of Protein Kinase C{varepsilon} in Skeletal Muscle Precedes the Onset of Hyperinsulinemia and Hyperglycemia

Yukio Ikeda1, Grith S. Olsen1, Ehud Ziv2, Lone L. Hansen1, Anna K. Busch1, Bo F. Hansen3, Eleazar Shafrir2, and Luitgard Mosthaf-Seedorf1

1 Department of Molecular Signaling, Hagedorn Research Institute, Gentofte, Denmark
2 Diabetes Research Unit, Hadassah University Hospital, Jerusalem, Israel
3 Novo Nordisk A/S, Bagsværd, Denmark

The sand rat (Psammomys obesus) is an animal model of nutritionally induced diabetes. We report here that several protein kinase C (PKC) isoforms ({alpha}, {varepsilon}, and {zeta}, representing all three subclasses of PKC) are overexpressed in the skeletal muscle of diabetic animals of this species. This is most prominent for the {varepsilon} isotype of PKC. Interestingly, increased expression of PKC{varepsilon} could already be detected in normoinsulinemic, normoglycemic (prediabetic) animals of the diabetes-prone (DP) line when compared with a diabetes-resistant (DR) line. In addition, plasma membrane (PM)–associated fractions of PKC{alpha} and PKC{varepsilon} were significantly increased in skeletal muscle of diabetic animals, suggesting chronic activation of these PKC isotypes in the diabetic state. The increased PM association of these PKC isotypes revealed a significant correlation with the diacylglycerol content in the muscle samples. Altered expression/activity of PKC{varepsilon}, in particular, may thus contribute to the development of diabetes in these animals; along with other PKC isotypes, it may be involved in the progression of the disease. This may possibly occur through inhibition of insulin receptor (IR) tyrosine kinase activity mediated by serine/threonine phosphorylation of the IR or insulin receptor substrate 1 (IRS-1). However, overexpression of PKC{varepsilon} also mediated downregulation of IR numbers in a cell culture model (HEK293), resulting in attenuation of insulin downstream signaling (reduced protein kinase B [PKB]/Akt activity). In accordance with this, we detected decreased 125I-labeled insulin binding, probably reflecting a downregulation of IR numbers, in skeletal muscle of Psammomys animals from the DP line. The number of IRs was inversely correlated to both the expression and PM-associated levels of PKC{varepsilon}. These data suggest that overexpression of PKC{varepsilon} may be causally related to the development of insulin resistance in these animals, possibly by increasing the degradation of IRs.

Abbreviations: DAG, diacylglycerol; DP, diabetes-prone; DP/A, diabetes-prone stage A; DP/C, diabetes-prone stage C; DR, diabetes-resistant; ELISA, enzyme-linked immunosorbent assay; GST, glutathione S-transferase; HE, high energy; IR, insulin receptor; IRK, insulin receptor kinase; IRS-1, insulin receptor substrate 1; LE, low energy; PKB, protein kinase B; PKC, protein kinase C; PM, plasma membrane; TPA, tetradecanoylphorbol acetate


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