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Prevention of insulin resistance and beta‐cell loss by abrogating PKCε‐induced serine phosphorylation of muscle IRS‐1 in Psammomys obesus
Author(s) -
Mack Esther,
Ziv Ehud,
Reuveni Hadas,
Kalman Rony,
Niv Masha Y.,
Jörns Anne,
Lenzen Sigurd,
Shafrir Eleazar
Publication year - 2008
Publication title -
diabetes/metabolism research and reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.307
H-Index - 110
eISSN - 1520-7560
pISSN - 1520-7552
DOI - 10.1002/dmrr.881
Subject(s) - medicine , insulin resistance , endocrinology , hyperinsulinemia , diabetes mellitus , insulin , glut4 , insulin receptor , protein kinase c , protein kinase b , phosphorylation , biology , biochemistry
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 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 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.