The action of GLP-1 and exendins upon glucose transport in normal human adipocytes, and on kinase activity as compared to morbidly obese patients.
A role of GLP-1 (glucagon-like peptide-1) in the recovery of the metabolic conditions of morbidly obese patients after bariatric surgery has been proposed. Exendin 4 (Ex-4) and exendin 9 (Ex-9) both have GLP-1-like effects upon glucose metabolism in human myocytes. We investigated in normal human adipocytes the effect of GLP-1, Ex-4 and Ex-9, compared with insulin upon the activity of PI3K, PKB, MAPKs and p70s6 kinases, and the participation of these enzymes in their action upon 2-deoxy-D-glucose transport by using potential inhibitors. The study was extended to morbidly obese patients. In normal subjects, GLP-1, Ex-4 and insulin, but not Ex-9, increased glucose uptake. In addition, GLP-1 and Ex-4 stimulated PI3K and MAPKs, similar to insulin, but not PKB. Ex-9 only enhanced PI3K, while none affected p70s6k. Inhibition of both PI3K and MAPKs blocked the stimulatory action of GLP-1, Ex-4 and insulin upon glucose transport. In obese patients, basal PI3K, PKB and MAPK activity was, as a rule, lower than that in normal subjects, while cells maintained their normal incremental response to GLP-1, Ex-4 or insulin; Ex-9 induced a clear stimulation of p42 MAPK. In summary, in normal human adipocytes, GLP-1 and Ex-4 have a protein kinase-dependent increasing effect upon glucose transport, which is impaired in obese patients. The participation of GLP-1 in the normalization of the metabolic conditions of the obese may occur through its effects on lipid metabolism or through effects upon glucose transport and/or metabolism in the liver and muscle, which in human obesity remain to be investigated.
Sancho
Verónica
V
Department of Metabolism, Nutrition and Hormones, Fundación Jiménez Díaz, 28040 Madrid, Spain.
Nuche
Bernardo
B
Arnés
Luis
L
Cancelas
Jesús
J
González
Nieves
N
Díaz-Miguel
Mariano
M
Martín-Duce
Antonio
A
Valverde
Isabel
I
Villanueva-Peñacarrillo
María L
ML
D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000328:Adult; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000493:pharmacokinetics; D000077270:Exenatide; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009767:Obesity, Morbid / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D010770:Phosphotransferases / Q000378:metabolism*; D014688:Venoms / Q000494:pharmacology*
D010446:Peptide Fragments; D010455:Peptides; D014688:Venoms; C083773:exendin (9-39); D052216:Glucagon-Like Peptide 1; D003847:Deoxyglucose; D000077270:Exenatide; D010770:Phosphotransferases; D005947:Glucose