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Research Articles
4-Hydroxyisoleucine (4-HI)
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Eur J Pharmacol
2000 Mar 3;390(3):339-45 |
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4-Hydroxyisoleucine:
effects of synthetic and natural analogues on insulin secretion.
Broca C, Manteghetti M, Gross R, Baissac Y, Jacob M, Petit P,
Sauvaire Y, Ribes G.
UMR 9921 du Centre National de la Recherche Scientifique,
Montpellier, France. broca@zeus.sc.univ-montp1.fr
4-Hydroxyisoleucine, a peculiar amino acid extracted from fenugreek
seeds and never found in mammalian tissues, exhibits interesting
insulinotropic activity. To investigate the structural requirements
for this stimulating effect, the insulinotropic activity of the
major isomer (2S,3R,4S) of 4-hydroxyisoleucine, 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 structurally related
amino acids, and (4) synthetic monomethylated analogues. In the
isolated, ex vivo, perfused rat pancreas, only the major isomer of
4-hydroxyisoleucine (200 microM) potentiated insulin release. On
incubated isolated rat islets, the threshold concentration for a
significant increase (P<0.05) in insulin release was 200 microM for
(2S,3R,4S) 4-hydroxyisoleucine, 500 microM for (2S,4R) and (2S,4S)
gamma-hydroxynorvalines as well as (2S,3S) and (2S,3R) gamma-hydroxyvalines,
and 1 mM or more for other congeners. In conclusion, the
insulinotropic properties of 4-hydroxyisoleucine, in the micromolar
range, are seen only in the presence of the linear major isoform;
they also require carbon alpha in S-configuration, full methylation
and carbon gamma-hydroxylation.
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Am J Physiol 1999
Oct;277(4 Pt 1):E617-23 |
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http://ajpendo.physiology.org/cgi/content/full/277/4/E617
4-Hydroxyisoleucine: experimental evidence of its insulinotropic and
antidiabetic properties.
Broca C, Gross R, Petit P, Sauvaire Y, Manteghetti M, Tournier M,
Masiello P, Gomis R, Ribes G.
Unite Mixte de Recherche 9921 du Centre National de la Recherche
Scientifique, Faculte de Medecine UPRES EA 1677, 34060 Montpellier,
France. broca2zeus.sc.univ-montp1.fr
We have recently shown in vitro that 4-hydroxyisoleucine (4-OH-Ile),
an amino acid extracted from fenugreek seeds, potentiates insulin
secretion in a glucose-dependent manner. The present study was
designed to investigate whether 4-OH-Ile could exert in vivo
insulinotropic and antidiabetic properties. For this purpose,
intravenous or oral glucose tolerance tests (IVGTTs and 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
normal 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 diabetic (NIDD) rats, a single intravenous
administration of 4-OH-Ile (50 mg/kg) partially restored
glucose-induced insulin response without affecting glucose
tolerance; a 6-day subchronic administration of 4-OH-Ile (50 mg/kg,
daily) reduced basal hyperglycemia, decreased basal insulinemia, and
slightly, but significantly, improved glucose tolerance. In vitro,
4-OH-Ile (200 microM) potentiated glucose (16.7 mM)-induced insulin
release from NIDD rat-isolated islets. So, the antidiabetic effects
of 4-OH-Ile on NIDD rats result, at least in part, from a direct
pancreatic B cell stimulation.
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Diabetes 1998
Feb;47(2):206-10 |
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4-Hydroxyisoleucine: a novel amino acid potentiator of insulin
secretion.
Sauvaire Y, Petit P, Broca C, Manteghetti M, Baissac Y,
Fernandez-Alvarez J, Gross R, Roye M, Leconte A, Gomis R, Ribes G.
Laboratoire de Recherche sur les Substances Naturelles Vegetales,
Universite Montpellier II, 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
micromol/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 alpha- and delta-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.
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