title: Prevention of insulin resistance and beta-cell loss by abrogating PKCepsilon-induced serine phosphorylation of muscle IRS-1 in Psammomys obesus.
abstract: 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.
  
  
  METHODS
  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.
authors.affiliation: Diabetes Center, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Esther
authors.initials: E
authors.lastname: Mack
authors.forename: Ehud
authors.initials: E
authors.lastname: Ziv
authors.forename: Hadas
authors.initials: H
authors.lastname: Reuveni
authors.forename: Rony
authors.initials: R
authors.lastname: Kalman
authors.forename: Masha Y
authors.initials: MY
authors.lastname: Niv
authors.forename: Anne
authors.initials: A
authors.lastname: Jörns
authors.forename: Sigurd
authors.initials: S
authors.lastname: Lenzen
authors.forename: Eleazar
authors.initials: E
authors.lastname: Shafrir
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000517:prevention & control; D005260:Female; D005849:Gerbillinae; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D009842:Oligopeptides / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D051744:Protein Kinase C-epsilon / Q000037:antagonists & inhibitors*; D012694:Serine / Q000378:metabolism
chemical_list: D055504:Insulin Receptor Substrate Proteins; D009842:Oligopeptides; D012694:Serine; D051744:Protein Kinase C-epsilon