4-HYDROXYISOLEUCINE - A NOVEL AMINO-ACID POTENTIATOR OF INSULIN-SECRETION

We report the characterization of a new insulinotropic compound, 4-hyd roxyisoleucine. This amino acid has been extracted and purified from f enugreek seeds, which are known in traditional medicine for their anti diabetic properties. 4-Hydroxyisoleucine increases glucose-induced ins ulin release, in the concentration range of 100 mu mol/l to 1 mmol/l, through a direct effect on isolated islets of Langerhans from both rat s and humans. The stimulating effect of 4-hydroxyisoleucine was strict ly glucose dependent; indeed, ineffective at low (3 mmol/l) or basal ( 5 mmol/l) glucose concentrations, the amino acid potentiated the insul in secretion induced by supranormal (6.6-16.7 mmol/l) concentrations o f glucose. In addition, in the isolated perfused rat pancreas, we coul d show 1) that the pattern of insulin secretion induced by 4-hydroxyis oleucine was biphasic, 2) that this effect occurred in the absence of any change in pancreatic alpha- and delta-cell activity, and 3) that t he more glucose concentration was increased, the more insulin response was amplified. Moreover, 4-hydroxyisoleucine did not interact with ot her agonists of insulin secretion (leucine, arginine, tolbutamide, gly ceraldehyde). Therefore, we conclude that 4-hydroxyisoleucine insulino tropic activity might, at least in part, account for fenugreek seeds' antidiabetic properties. This secretagogue may be considered as a nove l drug with potential interest for the treatment of NIDDM.