4-Hydroxyisoleucine: experimental evidence of its insulinotropic and antidiabetic properties

We have recently shown in vitro that 4-hydroxyisoleucine (4-OH-Ile), an ami no acid extracted from fenugreek seeds, potentiates insulin secretion in a glucose-dependent manner. The present study was designed to investigate whe ther 4-OH-Ile could exert in vivo insulinotropic and antidiabetic propertie s. For this purpose, intravenous or oral glucose tolerance tests (IVGTTs an d OGTTs,, respectively) were performed not only in normal animals but also in a type II diabetes rat model. During IVGTT in normal rats or OGTT in nor mal dogs, 4-OH-Ile (18 mg/kg) improved glucose tolerance. The lactonic form of 4-OH-Ile was ineffective in normal rats. In non-insulin-dependent diabe tic (NIDD) rats, a single intravenous administration of 4-OH-Ile (50 mg/kg) partially restored glucose-induced insulin response without affecting gluc ose tolerance; a 6-day subchronic administration of 4-OH-Ile (50 mg/kg, dai ly) reduced basal hyperglycemia, decreased basal insulinemia, and slightly, but significantly, improved glucose tolerance. In vitro, 4-OH-Ile (200 mu M) potentiated glucose (16.7 mM)-induced insulin release from NIDD rat-isol ated islets. So, the antidiabetic effects of 4-OH-Ile on NIDD rats result, at least in part, from a direct pancreatic B cell stimulation.