Alterations in G-protein expression, Gi function and stimulatory receptor-mediated regulation of adipocyte adenylyl cyclase in a model of insulin-resistant diabetes with obesity.
The stimulatory effect of Mn2+ (1.5-fold), forskolin (1.6-fold) and low (1 microM) concentrations of GTP (1.9-fold) on the adenylyl cyclase of adipocyte membranes from obese, diabetic CBA/Ca mice was markedly enhanced compared to that seen using membranes prepared from their lean littermates. In contrast, receptor-mediated stimulation, achieved with either isoprenaline or secretin was reduced and that by glucagon abolished in membranes from diabetic animals. The levels of expression of alpha-subunits of Gi-1, Gi-2 and Gi-3 were reduced to some 49, 76 and 54%, respectively, in membranes from diabetic animals compared with those from normal animals. Levels of G-protein beta-subunits and Gs alpha-subunits were similar. Receptor-mediated inhibition of adenylate activity elicited by either nicotinic acid or prostaglandin E1 (PGE1) was of a similar magnitude in membranes from normal and diabetic animals but the inhibitory action of N6-(L-2-phenylisopropyl)adenosine (PIA) was greater in membranes from diabetic animals by about 30%. Gi function was similarly evident in membranes from both lean and diabetic animals, as assessed using low concentrations of guanylyl 5'-imidodiphosphate to inhibit forskolin-stimulated adenylyl cyclase activity. However, assessing Gi function using GTP showed marked dissimilarities in that the elevated GTP concentrations expected to occur physiologically were incapable of reversing the stimulation achieved at low concentrations of GTP in membranes from diabetic but not normal animals. The adipocytes of CBA/Ca mice, as do other animal models of insulin resistance, show lesions in adenylyl cyclase regulation, Gi function and G-protein expression.
Palmer
T M
TM
Department of Biochemistry, University of Glasgow, U.K.
Taberner
P V
PV
Houslay
M D
MD
D000262:Adenylyl Cyclases / Q000187:drug effects / Q000378:metabolism*; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D003920:Diabetes Mellitus / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004195:Disease Models, Animal; D019204:GTP-Binding Proteins / Q000096:biosynthesis* / Q000502:physiology; D005934:Glucagon / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008274:Magnesium / Q000494:pharmacology; D051379:Mice; D008808:Mice, Inbred CBA; D009765:Obesity; D012633:Secretin / Q000494:pharmacology
D012633:Secretin; D005576:Colforsin; D005934:Glucagon; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D008274:Magnesium; D007545:Isoproterenol