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This Article Full Text Full Text (PDF) All Versions of this Article: 287/3/E463    most recent 00163.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Broca, C. Articles by Taouis, M. Search for Related Content PubMed PubMed Citation Articles by Broca, C. Articles by Taouis, M.

Insulinotropic agent ID-1101 (4-hydroxyisoleucine) activates insulin signaling in rat

¹Laboratoire de Pharmacologie, Centre de Pharmacologie et Biotechnologies pour la Santé-Unite Mixte de Recherche 5160 Centre National de la Recherche Scientifique, Faculté de Médecine, 34060 Montpellier; ²INNODIA S.A., 34000 Montpellier; ³Institut National de la Santé et de la Recherche Médicale U341, Service de Diabétologie, 75004 Paris; ⁴Laboratoire de Biologie Cellulaire et Moléculaire, bÂtiment des Biotechnologies, Institut National de la Recherche Agronomique, 78352 Jouy-en-Josas; and ⁵Laboratoire de Physiopathologie de la Nutrition, Centre National de la Recherche Scientifique UMR 7059, Université Paris 7, 75005 Paris, France

Submitted 11 April 2003 ; accepted in final form 2 March 2004

ID-1101 (4-hydroxyisoleucine), an amino acid extracted from fenugreek seeds, exhibits an interesting glucose-dependent insulin-stimulating activity. The present study was undertaken to investigate a possible extrapancreatic effect of ID-1101 on insulin signaling and action besides its previously described insulinotropic action. Insulin-sensitizing effects of ID-1101 were investigated in rat in vivo by three different approaches: 1) using euglycemic hyperinsulinemic clamps in two different rat models of insulin resistance, i.e., Zucker fa/fa rats and rats fed a sucrose-lipid diet; 2) measuring liver and muscle phosphatidylinositol (PI) 3-kinase activity after an acute injection of ID-1101 in normal and insulin-resistant diabetic rats; and 3) after chronic treatment in two rat models of insulin resistance. Euglycemic hyperinsulinemic clamp experiments revealed that ID-1101 can improve insulin resistance through an increase of peripheral glucose utilization rate in sucrose-lipid-fed rats and by decreasing hepatic glucose production in Zucker fa/fa rats. Moreover, we demonstrated that a single injection of ID-1101 activates the PI 3-kinase activity in liver and muscle from normal rats but also in muscle from diabetic rats. Finally, chronic ID-1101 treatment significantly reduced insulinemia in type 2 diabetic rats and reduced the progression of hyperinsulinemia in insulin-resistant obese Zucker fa/fa rats. These findings clearly demonstrate that ID-1101 can reduce insulin resistance through activation of the early steps of insulin signaling in peripheral tissues and in liver. In summary, ID-1101, besides its insulinotropic effect, directly improves insulin sensitivity, making it a potentially very valuable therapeutic agent for diabetes treatment.

insulin resistance; phosphatidylinositol 3-kinase; euglycemic hyperinsulinemic clamp; diabetes; obesity