GLP-1 signalling and effects on glucose metabolism in myocytes from type 2 diabetic patients.
Changes in the activity of glycogen synthase a and related kinases (phosphatidylinositol-3-kinase, protein kinase B, p44/42 MAP kinases and p70s6 kinase) evoked by GLP-1 in human myocytes from normal subjects were recently implied in the effect of this hormone upon D-glucose transport and glycogen synthesis in the same cells. The major aims of the present study were i) to investigate the possible extension of this knowledge to myocytes obtained from type 2 diabetic patients, ii) to compare in these patients the response to GLP-1, insulin or the structurally related GLP-1 peptides, exendin (1-39)amide and exendin(9-39)amide, and iii) to explore possible differences in the responsiveness to these agents between normal and diabetic subjects. Apart from the much higher basal PI3K activity and impaired response to insulin of p44/42 MAP kinases in the diabetic patients, the changes in enzyme activity caused by either hormone or peptide, although not identical, were essentially comparable. Nevertheless, significant differences in glucose transport and metabolism parameters were observed in the diabetic patients vs. normal subjects: in the diabetic patients, basal 2-deoxy-glucose uptake and glycogen synthase a activity were lower, accompanied by a similar increasing effect of GLP-1 or insulin; yet, the basal value for glycogen synthesis was higher, coinciding with a lesser relative increment in response to GLP-1 or insulin.
González
Nieves
N
Department of Metabolism, Nutrition and Hormones, Fundación Jiménez Díaz, Avda. Reyes Católicos 2, 28040 Madrid, Spain.
Sancho
Verónica
V
Martín-Duce
Antonio
A
Tornero-Esteban
Pilar
P
Valverde
Isabel
I
Malaisse
Willy J
WJ
Villanueva-Peñacarrillo
María L
ML
D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000378:metabolism / Q000493:pharmacokinetics; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D000077270:Exenatide; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism; D006006:Glycogen Synthase / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007328:Insulin / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D032342:Muscle Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D014688:Venoms / Q000494:pharmacology
D007328:Insulin; D010446:Peptide Fragments; D010455:Peptides; D014688:Venoms; C083773:exendin (9-39); D006003:Glycogen; D003847:Deoxyglucose; D000077270:Exenatide; D006006:Glycogen Synthase; D019869:Phosphatidylinositol 3-Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D005947:Glucose