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- Title
Prevention of insulin resistance and beta-cell loss by abrogating PKCε-induced serine phosphorylation of muscle IRS-1 in Psammomys obesus.
- Authors
Mack, Esther; Ziv, Ehud; Reuveni, Hadas; Kalman, Rony; Niv, Masha Y.; Jörns, Anne; Lenzen, Sigurd; Shafrir, Eleazar
- Abstract
Objective Psammomys obesus gerbil exhibits PKCε 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 PKCε-induced serine phosphorylation of IRS-1 with novel PKCε abrogating peptides. Research design PKCε 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 phosphoserine636, 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 PKCε 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 PKCε substrate-binding region prevented the nutritional diabetes and protected muscle IRS-1 from PKCε-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. Copyright © 2008 John Wiley & Sons, Ltd.
- Publication
Diabetes/Metabolism Research & Reviews, 2008, Vol 24, Issue 7, p577
- ISSN
1520-7552
- Publication type
Article
- DOI
10.1002/dmrr.881