Summary
Previous studies have shown that hepatocyte and liver membranes from insulin resistant animals exhibit an impairment of inhibitory guanine nucleotide binding regulatory protein, Gi function, such that a Gi defect may contribute towards the diabetic syndrome. In the current studies, it is shown that the demonstration of Gi activity in liver and hepatocyte membranes is dependent critically on the membrane preparation technique. A technique is defined that allows functional Gi activity to be demonstrated in liver and hepatocyte membranes from both lean (Fa/?) and obese (fa/fa) Zucker rats. Consequently, previous reports on the loss of Gi function in insulin resistant states require revaluation.
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DeFronzo RA (1988) The triumvirate: β-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 37: 667–687
Exton JH (1980) Cyclic nucleotides in diabetes mellitus and obesity. In: Hamlet P, Sands H (eds) Advances in cyclic nucleotide research, vol 12. Raven Press, New York, pp 319–327
Gawler D, Milligan G, Spiegel AM, Unson CG, Houslay MD (1987) Abolition of the expression of inhibitory guanine nucleotide regulatory protein Gi activity in diabetes. Nature 327: 229–232
Gawler D, Milligan G, Houslay MD (1988) Treatment of streptozotocin-diabetic rats with metformin restores the ability of insulin to inhibit adenylate cyclase activity and demonstrates that insulin does not exert this action through the inhibitory guanine nucleotide regulatory protein Gi. Biochem J 249: 537–542
Begin-Heick N, Welsh J (1988) The regulation of adenylate cyclase in liver membranes of lean and obese mice. Mol Cell Endocrinol 59: 187–194
Houslay MD, Gawler DJ, Milligan G, Wilson A (1988) Multiple defects occur in the guanine nucleotide regulatory protein system in liver plasma membranes of obese (fa/fa) but not lean (Fa/Fa) Zucker rats: loss of functional Gi and abnormal Gs function. Cell Signal 1: 9–22
Lynch CJ, Blackmore PF, Johnson EH, Wange RL, Krone PK, Exton JH (1989) Guanine nucleotide binding regulatory proteins and adenylate cyclase in livers of streptozotocin-and BB/Wor-diabetic rats. J Clin Invest 83: 2050–2062
Elliott KRF, Ash R, Pogson CI, Smith SA, Crisp DM (1976) Comparative aspects of the preparation and biochemistry of liver cells from various species. In: Tager JM. Soling HD, Williamson JR (eds) Use of isolated liver cells and kidney tubules in metabolic studies. Amsterdam, pp 139–153
Smith SA, Elliott KRF, Pogson CI (1978) Differential effects of tryptophan on glucose synthesis in rats and guinea pigs. Biochem J 176: 817–825
Itoh H, Okajima F, Ui M (1984) Conversion of adrenergic mechanism from an α-to a β-type during primary culture of rat hepatocytes. J Biol Chem 259: 15464–15473
Houslay MD, Metcalfe JC, Warren GB, Hesketh TR, Smith GA (1976) The glucagon receptor of rat liver plasma membrane can couple to adenylate cyclase without activating it. Biochem BiophysActa 436: 489–494
Salomon Y, Londos C, Rodbell M (1974) A highly sensitive adenylate cyclase assay. Anal Biochem 58: 541–548
Black MA, Heick HM, Begin-Heick N (1988) Abnormal regulation of cAMP accumulation in the pancreatic islets of obese mice. Am J Physiol 255: E833-E838
Seamon KB, Daly JW (1982) Guanosine 5′-(β,γ-imido)triphosphate inhibition of forskolin-activated adenylate cyclase is mediated by the putative inhibitory guanine nucleotide regulatory protein. J Biol Chem 257: 11591–11596
Van Berkel TJC (1979) The role of non-parenchymal cells in liver metabolism. Trends. Biochem Sci 4: 202–205
Proietto J, Rohner-Jeanrenaud F, Ionescu E, Jeanrenaud B (1989) The effects of islet activating protein on oral glucose tolerance in the genetically obese fa/fa rat. Metabolism 38: 338–342
Begin-Heick N (1985) Absence of the inhibitory effect of guanine nucleotides on adenylate cyclase activity in white adipocyte membranes of the ob/ob mouse. J Biol Chem 260: 6187–6193
Hadjiconstantinou M, Qu Z-X, Moroi-Fetters SE, Neff NH (1988) Apparent loss of Gi protein activity in the diabetic retina. Eur J Pharmacol 149: 193–194
Pyne NJ, Murphy GJ, Milligan G, Houslay MD (1989) Treatment of intact hepatocytes with either the phorbol ester TPA or glucagon elicits the phosphorylation and functional inactivation of the inhibitory guanine nucleotide regulatory protein, Gi. FEBS Lett 243: 77–82
Okajima F, Tokumitsu Y, Kondo Y, Ui M (1987) P2-purinergic receptors are coupled to two signal transduction systems leading to inhibition of cAMP generation and to production of inositol trisphosphate in rat hepatocytes. J Biol Chem 262: 13483–13490
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Young, P., Kirkham, D.M., Murphy, G.J. et al. Evaluation of inhibitory guanine nucleotide regulatory protein Gi function in hepatocyte and liver membranes from obese Zucker (fa/fa) rats and their lean (Fa/?) littermates. Diabetologia 34, 565–569 (1991). https://doi.org/10.1007/BF00400274
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DOI: https://doi.org/10.1007/BF00400274