Characteristics of GLP-1 and exendins action upon glucose transport and metabolism in type 2 diabetic rat skeletal muscle.
Exendin-4, a peptide 53% structurally homologous with glucagon-like peptide 1 (GLP-1), is insulinotropic and has an antidiabetic effect even more prolonged than that of GLP-1. Exendin-9 is an antagonist of GLP-1 receptor and action in several cell systems, but shows GLP-1- and exendin-4-agonistic characteristics in human muscle cells and tissue. The action of GLP-1 upon glucose transport and metabolism in muscle is mediated by specific receptors. In this study we investigated the effect of both exendin-4 and -9, relative to that of GLP-1, upon glucose transport and metabolism in the skeletal muscle from a streptozotocin-induced type 2 diabetic rat model, compared to normal. In normal rats, exendin-4, like GLP-1 and insulin, enhanced glucose uptake. This effect, which is mediated to a certain extent by some kinases (PI3K/ PKB, p70s6k and MAPKs), may be caused by the peptide acting, at least in part, through the muscle GLP-1 receptors. Exendin-9 also stimulated the same kinases, except for PKB, but failed to modify basal glucose uptake. Type 2 diabetic rats showed lower than normal basal muscle glucose transport and oxidation value, and higher glycogen synthase alpha activity and pyruvate release; however, no modification of glucose uptake by GLP-1 or exendin-4 was detected, at variance with insulin, and basal activity of PI3K/PKB was lower than normal, while that of p70s6k and MAPKs was higher. GLP-1 failed to affect the activity of any of the kinases, while exendin-4 increased the activity of PI3K, p70s6k and MAPKs, but not PKB, suggesting that this enzyme plays a major role in exendin-4 effect upon glucose transport in muscle.
Department of Metabolism, Nutrition and Hormones, Fundación Jiménez Díaz, Avda. Reyes Católicos 2, Madrid, Spain.
Luis
L
Arnés
Nieves
N
González
Pilar
P
Tornero-Esteban
Verónica
V
Sancho
Alicia
A
Acitores
Isabel
I
Valverde
Elena
E
Delgado
María L
ML
Villanueva-Peñacarrillo
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D006006:Glycogen Synthase / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D008297:Male; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D010084:Oxidation-Reduction / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013552:Swine; D014688:Venoms / Q000494:pharmacology*
D007328:Insulin; D010455:Peptides; D047428:Protein Kinase Inhibitors; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D006006:Glycogen Synthase; D011494:Protein Kinases; D005947:Glucose