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

• Published in: American journal of physiology: endocrinology and metabolism Vol. 287; no. 3; pp. E463 - E471
• Main Authors: Broca, Christophe, Breil, Vincent, Cruciani-Guglielmacci, Celine, Manteghetti, Michele, Rouault, Christine, Derouet, Michel, Rizkalla, Salwa, Pau, Bernard, Petit, Pierre, Ribes, Gerard, Ktorza, Alain, Gross, Rene, Reach, Gerard, Taouis, Mohammed
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.09.2004
• Subjects: Animals; Diabetes Mellitus, Experimental - chemically induced; Diabetes Mellitus, Experimental - physiopathology; Diet; Enzyme Activation - drug effects; Glucose - antagonists & inhibitors; Glucose Clamp Technique; Hyperinsulinism - complications; Hyperinsulinism - physiopathology; Insulin - blood; Insulin - metabolism; Insulin Resistance; Isoleucine - analogs & derivatives; Isoleucine - pharmacology; Lipids - adverse effects; Liver - enzymology; Liver - metabolism; Male; Muscle, Skeletal - enzymology; Niacinamide; Obesity - complications; Obesity - physiopathology; Phosphatidylinositol 3-Kinases - metabolism; Rats; Rats, Sprague-Dawley; Rats, Zucker; Signal Transduction - drug effects; Sucrose - administration & dosage
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00163.2003

1 Laboratoire 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; 2 INNODIA S.A., 34000 Montpellier; 3 Institut National de la Santé et de la Recherche Médicale U341, Service de Diabétologie, 75004 Paris; 4 Laboratoire de Biologie Cellulaire et Moléculaire, bÂtiment des Biotechnologies, Institut National de la Recherche Agronomique, 78352 Jouy-en-Josas; and 5 Laboratoire 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 Address for reprint requests and other correspondence: C. Broca, Laboratoire de Pharmacologie, CPBS-UMR 5160 CNRS, Faculté de Médecine, Institut de Biologie, Boulevard Henri IV, 34060 Montpellier cedex 1, France (E-mail: christophe.broca{at}univ-montp1.fr ).