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

Esther Mack, Ehud Ziv, Hadas Reuveni, Rony Kalman, Masha Y. Niv, Anne Jörns, Sigurd Lenzen, Eleazar Shafrir*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Objective: Psammomys obesus gerbil exhibits PKĊover-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 PKC-̇induced serine phosphorylation of IRS-1 with novel PKĊabrogating peptides. Research design: PKĊabrogating 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 PKĊlevel. 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 PKĊ substrate-binding region prevented the nutritional diabetes and protected muscle IRS-1 from PKC-̇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.

Original languageAmerican English
Pages (from-to)577-584
Number of pages8
JournalDiabetes/Metabolism Research and Reviews
Volume24
Issue number7
DOIs
StatePublished - 2008

Keywords

  • Beta-cell lesion prevention
  • Diabetes prevention
  • IRS-1
  • PKCε
  • Peptides inhibiting PKCε
  • Serine phosphorylation
  • Type 2 diabetes model

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