Insulinotropic agent ID-1101 (4-hydroxyisoleucine) activates insulin signaling in rat.
ID-1101 (4-hydroxyisoleucine), an amino acid extracted from fenugreek seeds, exhibits an interesting glucose-dependent insulin-stimulating activity. The present study was undertaken to investigate a possible extrapancreatic effect of ID-1101 on insulin signaling and action besides its previously described insulinotropic action. Insulin-sensitizing effects of ID-1101 were investigated in rat in vivo by three different approaches: 1) using euglycemic hyperinsulinemic clamps in two different rat models of insulin resistance, i.e., Zucker fa/fa rats and rats fed a sucrose-lipid diet; 2) measuring liver and muscle phosphatidylinositol (PI) 3-kinase activity after an acute injection of ID-1101 in normal and insulin-resistant diabetic rats; and 3) after chronic treatment in two rat models of insulin resistance. Euglycemic hyperinsulinemic clamp experiments revealed that ID-1101 can improve insulin resistance through an increase of peripheral glucose utilization rate in sucrose-lipid-fed rats and by decreasing hepatic glucose production in Zucker fa/fa rats. Moreover, we demonstrated that a single injection of ID-1101 activates the PI 3-kinase activity in liver and muscle from normal rats but also in muscle from diabetic rats. Finally, chronic ID-1101 treatment significantly reduced insulinemia in type 2 diabetic rats and reduced the progression of hyperinsulinemia in insulin-resistant obese Zucker fa/fa rats. These findings clearly demonstrate that ID-1101 can reduce insulin resistance through activation of the early steps of insulin signaling in peripheral tissues and in liver. In summary, ID-1101, besides its insulinotropic effect, directly improves insulin sensitivity, making it a potentially very valuable therapeutic agent for diabetes treatment.
Broca
Christophe
C
Laboratoire de Pharmacologie, Centre de Pharmacologie et Biotechnologies pour la Santé-Unite Mixte de Recherche 5160 Centre National de la Recherche Scientifique, Faculté de Médecine, 34060 Montpellier, France. christophe.broca@univ-montp1.fr
Breil
Vincent
V
Cruciani-Guglielmacci
Céline
C
Manteghetti
Michèle
M
Rouault
Christine
C
Derouet
Michel
M
Rizkalla
Salwa
S
Pau
Bernard
B
Petit
Pierre
P
Ribes
Gérard
G
Ktorza
Alain
A
Gross
René
R
Reach
Gérard
G
Taouis
Mohammed
M
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000503:physiopathology; D004032:Diet; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000037:antagonists & inhibitors; D015309:Glucose Clamp Technique; D006946:Hyperinsulinism / Q000150:complications / Q000503:physiopathology; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D007333:Insulin Resistance; D007532:Isoleucine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008055:Lipids / Q000009:adverse effects; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000201:enzymology; D009536:Niacinamide; D009765:Obesity / Q000150:complications / Q000503:physiopathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D015398:Signal Transduction / Q000187:drug effects*; D013395:Sucrose / Q000008:administration & dosage
C104672:4-hydroxyisoleucine; D007328:Insulin; D008055:Lipids; D007532:Isoleucine; D009536:Niacinamide; D013395:Sucrose; D019869:Phosphatidylinositol 3-Kinases; D005947:Glucose