Cellular mechanism of nutritionally induced insulin resistance in Psammomys obesus - Overexpression of protein kinase C epsilon in skeletal muscle precedes the onset of hyperinsulinemia and hyperglycemia

The sand rat (Psammomys obesus) is an animal model of nutritionally induced diabetes. We report here that several protein kinase C (PKC) isoforms (alp ha, epsilon, and zeta, representing all three subclasses of PKC) are overex pressed in the skeletal muscle of diabetic animals of this species. This is most prominent for the epsilon isotype of PKC. Interestingly, increased ex pression of PKC epsilon could already be detected in normoinsulinemic, norm oglycemic (prediabetic) animals of the diabetes-prone (DP) line when compar ed with a diabetes-resistant (DR) line. In addition, plasma membrane (PM)-a ssociated fractions of PKC alpha and PKC epsilon were significantly increas ed 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 diacylglycer ol content in the muscle samples, Altered expression/activity of PKC epsilo n, in particular, may thus contribute to the development of diabetes in the se animals; along with other PKC isotypes, it may be involved in the progre ssion of the disease, This may possibly occur through inhibition of insulin receptor (IR) tyrosine kinase activity mediated by serine/threonine phosph orylation of the IR or insulin receptor substrate 1 (IRS-1), However, overe xpression of PKC epsilon also mediated downregulation of IR numbers in a ce ll culture model (HEK293), resulting in attenuation of insulin downstream s ignaling (reduced protein kinase B [PKB]/Akt activity). In accordance with this, we detected decreased I-125-labeled insulin binding, probably reflect ing 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 e xpression and PM-associated levels of PKC epsilon, These data suggest that overexpression of PKC epsilon may be causally related to the development of insulin resistance in these animals, possibly by increasing the degradatio n of IRs.