4-Hydroxyisoleucine: effects of synthetic and natural analogues on insulinsecretion

4-Hydroxyisoleucine, a peculiar amino acid extracted from fenugreek seeds a nd never found in mammalian tissues, exhibits interesting insulinotropic ac tivity. To investigate the structural requirements for this stimulating eff ect, the insulinotropic activity of the major isomer (2S,3R,4S) of 4-hydrox yisoleucine in the presence of 8.3 mM glucose, was compared to that of (1) its minor isomer (2R,3R,4S) (2) its lactone form, (3) classical structurall y related amino acids, and (4) synthetic monomethylated analogues. In the i solated, ex vivo, perfused rat pancreas, only the major isomer of 4-hydroxy isoleucine (200 mu M) potentiated insulin release. On incubated isolated ra t islets, the threshold concentration for a significant increase (P < 0.05) in insulin release was 200 mu M for (2S,3R,4S) 4-hydroxyisoleucine 500 mu M for (2S,4R) and (2S,4S) gamma-hydroxynorvalines as well as (2S,3S) and (2 S,3R) gamma-hydroxyvalines, and 1 mM or more for other congeners. In conclu sion, the insulinotropic properties of 4-hydroxyisoleucine, in the micromol ar range, are seen only in the presence of the Linear major isoform; they a lso require carbon a in S-configuration, full methylation and carbon gamma- hydroxylation. (C) 2000 Elsevier Science B.V. All rights reserved.