Prevention of insulin resistance and beta‐cell loss by abrogating PKCε‐induced serine phosphorylation of muscle IRS‐1 in Psammomys obesus

OBJECTIVE: Psammomys obesus gerbil exhibits PKCepsilon over-expression on high-energy (HE) diet. Muscle insulin receptor (IR) signalling and tyrosine kinase activity are inhibited eliciting insulin resistance. We aimed at preventing diabetes by inhibiting PKCepsilon-induced serine phosphorylation of IRS-1 with novel PKCepsilon abrogating peptides. RESEARCH DESIGN: PKCepsilon abrogating peptides were copied from catalytic domain of PKC molecule (PCT patent IL2006/000755). Psammomys fed a diabetogenic HE diet received i.p. peptides KCe-12 and KCe-16 (18 mg/kg) on days 0, 7 and 14 controls received peptide solvent. RESULTS: Food consumption and animal weight remained unchanged. On day 16, non-fasting blood glucose levels returned to normal (90 +/- 5 versus 347 +/- 16 mg/dL in untreated controls). Hyperinsulinemia fell from 584 +/- 55 to 180 +/- 22 mU/L. Western blot analysis showed that the increased phosphoserine(636, 639) content on IRS-1 in gastrocnemius muscle of diabetic animals was reduced three fold, the PKB/AKT activity increased two fold and muscle GLUT4 tended to increase, compared with controls. Likewise, administration of KCe-12 prior to placing the HE diet prevented the onset of diabetes. KCe-12 treatment did not reduce muscle PKCepsilon level. Damage and loss of insulin in pancreatic beta cells on HE diet were prevented by KCe-12, as shown in micrographs of islet hematoxylin-eosin staining and insulin immunostaining. The preserved secretory function enabled Psammomys to normalize glucose homeostasis. CONCLUSIONS: KCe-16 and KCe-12 peptides derived from PKCepsilon substrate-binding region prevented the nutritional diabetes and protected muscle IRS-1 from PKCepsilon-induced serine phosphorylation, abrogating the insulin-signalling impediment in the Psammomys model of type 2 diabetes. Anti-diabetic peptides may lead to novel modalities preventing human overnutrition-induced insulin resistance and diabetes.