4-Hydroxyisoleucine: A Novel Amino Acid Potentiator of Insulin Secretion

  1. Gèrard Ribes
  1. Laboratoire de Recherche sur les Substances Naturelles Végétales, Université Montpellier II, Unité Propre de Recherche Enseignement Superieur EA 1677, Université Montpellier II Montpellier, France
  2. Laboratoire de Pharmacologie, Faculty de Médecine, Unité Propre de Recherche Enseignement Supérieur EA 1677, Faculty de Médecine Montpellier, France
  3. Unité Mixte de Recherche, Centre National de la Recherche Scientifique, UMR 9921, Université Montpellier I Montpellier, France
  4. Endocrinology Unit, Hospital Clinic Barcelona, Spain
  1. Address correspondence and reprint requests to Yves Sauvaire, Laboratoire de Recherche sur les Substances Naturelles Végétales, Université Montpellier II, Place Eugène Bataillon, 34095 Montpellier Cedex 05, France.


We report the characterization of a new insulinotropic compound, 4-hydroxyisoleucine. This amino acid has been extracted and purified from fenugreek seeds, which are known in traditional medicine for their antidiabetic properties. 4-Hydroxyisoleucine increases glucose-induced insulin release, in the concentration range of 100 μmol/l to 1 mmol/l, through a direct effect on isolated islets of Langerhans from both rats and humans. The stimulating effect of 4-hydroxyisoleucine was strictly glucose dependent; indeed, ineffective at low (3 mmol/l) or basal (5 mmol/l) glucose concentrations, the amino acid potentiated the insulin secretion induced by supranormal (6.6–16.7 mmol/l) concentrations of glucose. In addition, in the isolated perfused rat pancreas, we could show 1) that the pattern of insulin secretion induced by 4-hydroxyisoleucine was biphasic, 2) that this effect occurred in the absence of any change in pancreatic α-and δ-cell activity, and 3) that the more glucose concentration was increased, the more insulin response was amplified. Moreover, 4-hydroxyisoleucine did not interact with other agonists of insulin secretion (leucine, arginine, tolbutamide, glyceraldehyde). Therefore, we conclude that 4-hydroxyisoleucine insulinotropic activity might, at least in part, account for fenugreek seeds' antidiabetic properties. This secretagogue may be considered as a novel drug with potential interest for the treatment of NIDDM.

  • Received January 2, 1997.
  • Revision received October 22, 1997.
  • Accepted October 22, 1997.
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