Summary
Acute hyperinsulinaemias induced by insulin and stimulants of insulin secretion have been shown to cause a translocation of liver insulin receptors from the cell surface to the intracellular compartment, with little or no change in total receptor number. To determine whether a similar phenomenon occurs in chronic hyperinsulinaemic states, we have carried out a longitudinal study of total, cell surface and intracellular liver insulin receptors in genetically obese Zucker rats, with spontaneously develop hyperinsulinaemia. Liver plasma membranes, Golgi-endosomal fractions, a microsomal fraction and a total particulate fraction were isolated in 2–14-week old obese (fa/fa) rats and examined for specific insulin binding relative to lean (Fa/?) age-matched animals. In 16-day old rats, which were still normoinsulinaemic, insulin binding was unchanged. Later on, as hyperinsulinaemia developed, three sequential changes in insulin binding activity were observed: first, a 25–30% increase in Golgiendosomal fractions (20 days); then, a 50–60% decrease in Golgi-endosomal fractions (4–5 weeks); and finally, a 50% decrease in plasma membranes (11 weeks), microsomal fraction and total particulate fraction (14 weeks), accompanied by restoration in Golgi-endosomal fractions (8–11 weeks). Unlike insulin receptors, insulin extractable from Golgiendosomal fractions at 4–5 weeks was unchanged or increased. We conclude that, although an early increase in the endocytosis of liver insulin receptors may occur in hyperinsulinaemic Zucker rats, this mechanism does not account for the later decrease in cell surface receptors observed in these animals.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Forgue ME, Freychet P (1975) Insulin receptors in the heart muscle. Demonstration of specific binding sites and impairment of insulin binding in the plasma membrane of the obese hyperglycemic mouse. Diabetes 24: 715–723
Kahn CR, Neville DM, Roth J (1973) Insulin-receptor interaction in the obese-hyperglycemic mouse. A model of insulin resistance. J Biol Chem 248: 244–250
Posner BI, Raquidan D, Josefsberg Z, Bergeron JJM (1978) Different regulation of insulin receptors in intracellular (Golgi) and plasma membranes from livers of obese and lean mice. Proc Natl Acad Sci USA 75: 3302–3306
Soll AH, Goldfine ID, Roth J, Kahn CR (1974) Thymic lymphocytes in obese (ob/ob) mice. A mirror of the insulin receptor defect in liver and fat. J Biol Chem 249: 4127–4131
Soll AH, Kahn CR (1975) Insulin binding to liver plasma membranes in the obese hyperglycemic (ob/ob) mouse. J Biol Chem 250: 4702–4707
Soll AH, Kahn CR, Neville DM, Roth J (1975) Insulin receptor deficiency in genetic and acquired obesity. J Clin Invest 56: 769–780
Freychet P, Laudat MH, Laudat P, Rosselin G, Kahn CR, Gorden P, Roth J (1972) Impairment of insulin binding to fat cell plasma membrane in the obese hyperglycemic mouse. FEBS Lett 25: 339–342
Kern P, Picard J, Caron M, Veissière D (1975) Decreased binding of insulin to liver plasma membrane receptors in hereditary diabetic mice. Biochim Biophys Acta 389: 281–289
Clark JB, Clark CM (1982) Age-related changes in insulin receptor regulation in liver membranes from Zucker fatty rats. Endocrinology 111: 964–969
Crettaz M, Prentki M, Zaninetti D, Jeanrenaud B (1980) Insulin resistance in soleus muscle from obese Zucker rats. Involvement of several defective sites. Biochem J 186: 525–534
Figlewicz DP, Dorsa DM, Stein LJ, Baskin DG, Paquette T, Greenwood MRC, Woods SC, Porte D (1985) Brain and liver insulin binding is decreased in Zucker rats carrying the “fa” gene. Endocrinology 117: 1537–1543
Karakash C, Jeanrenaud B (1983) Insulin binding and removal by livers of genetically obese rats. Diabetes 32: 605–609
Mahmood HA, Wood PJ, Marks V (1978) The effect of induced hyperglucagonaemia on the Zucker fatty rat. Diabetologia 14: 405–412
Steele NC, Martin RJ, Baile CA (1979) Insulin receptor characteristics and insulin degradation by Zucker lean and obese rats. Horm Metab Res 11: 525–526
Le Marchand Y, Freychet P, Jeanrenaud B (1978) Longitudinal study on the stablishment of insulin resistance in hypothalamic obese mice. Endocrinology 102: 74–85
Kobayashi M, Olefsky JM (1978) Effect of experimental hyperinsulinaemia on insulin binding and glucose transport in isolated rat adipocytes. Am J Physiol 235: E53-E62
Vigneri R, Pliam NB, Cohen DC, Pezzino V, Wong KY, Goldfine ID (1978) In vivo regulation of cell surface and intracellular insulin binding sites by insulin. J Biol Chem 253: 8192–8197
Gavin JR, Roth J, Neville DM, De Meyts P, Buell DN (1974) Insulin-dependent regulation of insulin receptor concentration: a direct demonstration in cell culture. Proc Natl Acad Sci USA 71: 84–88
Kasuga M, Kahn CR, Hedo JA, Van Obberghen E, Yamada KM (1981) Insulin-induced receptor loss in cultured human lymphocytes is due to accelerated receptor degradation. Proc Natl Acad Sci USA 78: 6917–6921
Ronnet GV, Knutson VP, Lane MD (1982) Insulin-induced down regulation of insulin receptors in 3T3-L1 adipocytes. Altered rate of receptor inactivation. J Biol Chem 257: 4285–4291
Krupp M, Lane MD (1981) On the mechanism of ligand-induced down-regulation of insulin receptor level in the liver cell. J Biol Chem 256: 1689–1694
Knutson VP, Ronnet GV, Lane MD (1983) Rapid, reversible internalization of cell surface insulin receptors. Correlation with insulin-induced down-regulation. J Biol Chem 258: 12139–12142
Desbuquois B, López S, Burlet H (1982) Ligand-induced translocation of insulin receptors in intact rat liver. J Biol Chem 257: 10852–10860
López S, Desbuquois B (1983) Changes in the subcellular distribution of insulin receptors in rat liver induced by acute endogenous hyperinsulinemia. Endocrinology 113: 783–789
Lavau M, Bazin R (1982) Inguinal fat pad weight plotted versus body weight as a method of genotype identification in 16-day-old Zucker rats. J Lipid Res 23: 941–943
Neville DM (1968) Isolation of an organ specific protein antigen from cell surface membrane of rat liver. Biochim Biophys Acta 154: 540–552
Ehrenreich JH, Bergeron JJM, Siekevitz P, Palade GE (1973) Golgi fractions prepared from rat liver homogenates. I. Isolation procedure and morphological characterization. J Cell Biol 59: 45–72
López S, Desbuquois B (1987) Insulin-related changes in the subcellular distribution of insulin receptors in intact rat liver: effects of acute hypoinsulinemia induced by diazoxide, somatostatin, and xylazine. Endocrinology 120: 1695–1702
Clark JB, Stacey K, Clark CM (1982) Studies on the regulation of insulin binding by liver plasma membranes from Zucker fatty rats. Diabetes 31: 867–873
Broer Y, Freychet P, Rosselin G (1977) Insulin and glucagon-receptor interactions in the genetically obese Zucker rat: studies of hormone binding and glucagon-stimulated cyclic AMP levels in isolated hepatocytes. Endocrinology 101: 236–249
Sodoyez JC, Sodoyez-Goffaux F, Treves S, Kahn CR, von Frenckell R (1984) In vivo imaging and quantitative analysis of insulin-receptor interaction in lean and obese Zucker rats. Diabetologia 26: 229–233
Bazin R, Lavau M (1982) Development of hepatic and adipose tissue lipogenic enzymes and insulinemia during suckling and weaning on to a high-fat diet in Zucker rats. J Lipid Res 23: 839–849
Zucker LM, Antoniades HN (1972) Insulin and obesity in the genetically obese rat “Fatty”. Endocrinology 90: 1320–1330
Quintart J, Courtoy PJ, Baudhuin P (1984) Receptor-mediated endocytosis in rat liver: purification and enzymic characterization of low density organelles involved in uptake of galactose-exposing proteins. J Cell Biol 98: 877–884
Kay DG, Khan MN, Posner BI, Bergeron JJM (1984) In vivo uptake of insulin into hepatic Golgi fractions: application of the diaminobenzidine-shift protocol. Biochem Biophys Res Commun 123: 1144–1148
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
López, S., Desbuquois, B., Postel-Vinay, M.C. et al. Insulin-dependent changes in subcellular distribution of liver insulin receptors in obese Zucker rats. Diabetologia 31, 922–927 (1988). https://doi.org/10.1007/BF00265378
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00265378