Effects of metformin on tyrosine kinase activity, glucose transport, and intracellular calcium in rat vascular smooth muscle.
Metformin enhances peripheral insulin action and reduces blood pressure in hypertensive rats. Our group has previously reported that insulin and insulin-like growth factor I (IGF-1) attenuate both agonist-induced vascular smooth muscle cell (VSMC) contraction and associated increases in cytosolic free calcium ([Ca]i). Thus, changes in insulin actions may explain in part metformin's vascular effects. However, metformin's mechanism of action at the vasculature had not been elucidated. Therefore, the purpose of this study was to determine whether metformin evokes alterations in VSMC insulin and IGF-I receptors, glucose transport, and/or [Ca]i. We quantitated hormone binding and tyrosine kinase (TK) activity in partially purified insulin and IGF-I receptors prepared from metformin-treated (100 microM) and control rat aortic VSMC in culture. Glucose transport was assessed by 2-deoxyglucose uptake. Metformin exposure for 24 h 1) increased basal TK activity (metformin, 3.49 +/- 0.39; control, 1.77 +/- 0.39 pmol 32P incorporated/mg protein; P < 0.01) without changes in insulin-or IGF-I stimulated TK activity, 2) increased 2-deoxyglucose transport in a dose-dependent manner, 3) decreased thrombin-induced elevation in [Ca]i (metformin, 10.3%; control, 35.3% over basal; P < 0.05), These insulin/IGF-I-like effects of metformin may help explain some of its vascular actions.
Division of Endocrinology, Metabolism and Hypertension, Wayne State University, Detroit, Michigan, USA.
L J
LJ
Dominguez
A J
AJ
Davidoff
P R
PR
Srinivas
P R
PR
Standley
M F
MF
Walsh
J R
JR
Sowers
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D009994:Osmolar Concentration; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D007328:Insulin; D007334:Insulin-Like Growth Factor I; D008687:Metformin; D011505:Protein-Tyrosine Kinases; D005947:Glucose; D002118:Calcium