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. 1985 May;75(5):1659–1665. doi: 10.1172/JCI111873

Mechanism of insulin resistance in human liver cirrhosis. Evidence of a combined receptor and postreceptor defect.

P Cavallo-Perin, M Cassader, C Bozzo, A Bruno, P Nuccio, A M Dall'Omo, M Marucci, G Pagano
PMCID: PMC425508  PMID: 3889056

Abstract

Insulin resistance in liver cirrhosis may depend on either reduced sensitivity (receptor defect) and/or reduced response to insulin (postreceptor defect). To clarify the mechanism of such resistance, a [3H]glucose infusion (0.2 microCi/min) was performed for 120 min before and during a euglycemic clamp at approximately 100, 1,000, and 10,000 microU/ml steady state plasma insulin concentration in 18 compensated cirrhotics with portal hypertension and impaired glucose tolerance, and 18 healthy volunteers with no family history of diabetes, matched for sex, age, and weight. Mean fasting plasma insulin (29.2 +/- 3.4 SEM vs. 14.8 +/- 1.1 microU/ml) was significantly higher (P less than 0.001) in cirrhotics, while fasting plasma glucose was much the same in the two groups. Glucose use (milligrams per kilogram per minute) was significantly lower in cirrhotics at all three steady state plasma insulin levels: 3.04 +/- 0.34 vs. 7.72 +/- 0.61 (P less than 0.001) at approximately 100; 6.05 +/- 1.07 vs. 11.45 +/- 1.24 (P less than 0.001) at approximately 1,000; and 11.69 +/- 0.69 vs. 14.13 +/- 0.74 (P less than 0.05) at approximately 10,000 microU/ml. Mean plasma C-peptide was significantly higher in cirrhotics both basally and during the steady states (P less than 0.001); it was completely suppressed at approximately 10,000 microU/ml in controls and only 57.5% of the baseline in cirrhotics. Endogenous glucose production (milligrams per kilogram per minute) was much the same in the two groups in the fasting state and almost entirely suppressed in the controls (0.10 +/- 0.05 vs. 0.48 +/- 0.11, P less than 0.001) at approximately 100 microU/ml; at approximately 1,000 microU/ml a residual glucose production, 0.07 +/- 0.05, was observed in the cirrhotics only. In addition, insulin binding and 3-ortho-methyl-glucose transport were studied in vitro in six cirrhotics and six controls. Insulin binding to circulating monocytes and isolated adipocytes was significantly lower (P less than 0.025) in cirrhotics in all insulin concentration studies. Glucose transport values on isolated adipocytes were significantly lower in cirrhotics both basally (P less than 0.001) and at maximal insulin concentration (P less than 0.05). These results suggest that insulin resistance in human cirrhosis is more dependent on depressed peripheral glucose use than on increased endogenous glucose production, and that a combined receptor and postreceptor defect in insulin action on target cells seems to be present.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Beck-Nielsen H., Pedersen O. Insulin receptors on monocytes of young healthy persons correlated with glucose tolerance and insulin sensitivity. Diabetologia. 1978 Mar;14(3):159–163. doi: 10.1007/BF00429775. [DOI] [PubMed] [Google Scholar]
  2. Berkowitz D. Glucose tolerance, free fatty acid, and serum insulin responses in patients with cirrhosis. Am J Dig Dis. 1969 Oct;14(10):691–699. doi: 10.1007/BF02233575. [DOI] [PubMed] [Google Scholar]
  3. Blei A. T., Robbins D. C., Drobny E., Baumann G., Rubenstein A. H. Insulin resistance and insulin receptors in hepatic cirrhosis. Gastroenterology. 1982 Dec;83(6):1191–1199. [PubMed] [Google Scholar]
  4. Ciaraldi T. P., Kolterman O. G., Siegel J. A., Olefsky J. M. Insulin-stimulated glucose transport in human adipocytes. Am J Physiol. 1979 Jun;236(6):E621–E625. doi: 10.1152/ajpendo.1979.236.6.E621. [DOI] [PubMed] [Google Scholar]
  5. Coller F. A., Troost F. L. GLUCOSE TOLERANCE AND HEPATIC DAMAGE. Ann Surg. 1929 Oct;90(4):781–793. [PMC free article] [PubMed] [Google Scholar]
  6. Czech M. P. Insulin action and the regulation of hexose transport. Diabetes. 1980 May;29(5):399–409. doi: 10.2337/diab.29.5.399. [DOI] [PubMed] [Google Scholar]
  7. DeFronzo R. A., Tobin J. D., Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979 Sep;237(3):E214–E223. doi: 10.1152/ajpendo.1979.237.3.E214. [DOI] [PubMed] [Google Scholar]
  8. Fujita S., Takimoto T., Kobayashi M., Shigeta Y., Hoshi M. Erythrocyte insulin receptors in patients with chronic liver diseases. Horm Metab Res. 1982 Jan;14(1):51–52. doi: 10.1055/s-2007-1018918. [DOI] [PubMed] [Google Scholar]
  9. Greco A. V., Bentoli A., Caputo S., Altomonte L., Manna R., Ghirlanda G. Decreased insulin binding to red blood cells in liver cirrhosis. Acta Diabetol Lat. 1983 Jul-Sep;20(3):251–256. doi: 10.1007/BF02581269. [DOI] [PubMed] [Google Scholar]
  10. Greco A. V., Rebuzzi A. G., Altomonte L., Manna R., Bertoli A., Ghirlanda G. Glucose, insulin and somatostatin infusion for the determination of insulin resistance in liver cirrhosis. Horm Metab Res. 1979 Oct;11(10):547–549. doi: 10.1055/s-0028-1092777. [DOI] [PubMed] [Google Scholar]
  11. Greenfield M. S., Doberne L., Rosenthal M., Schulz B., Widstrom A., Reaven G. M. Effect of sulfonylurea treatment on in vivo insulin secretion and action in patients with non-insulin-dependent diabetes mellitus. Diabetes. 1982 Apr;31(4 Pt 1):307–312. doi: 10.2337/diab.31.4.307. [DOI] [PubMed] [Google Scholar]
  12. Gunnlaugsson O., Berkowitz D. Individual free fatty acids in patients with liver disease. Am J Dig Dis. 1977 Nov;22(11):1005–1009. doi: 10.1007/BF01076201. [DOI] [PubMed] [Google Scholar]
  13. HED R. Clinical studies in chronic alcoholism. II. Carbohydrate metabolism in chronic alcoholism with particular reference to glucose and insulin tolerances. Acta Med Scand. 1958 Oct 22;162(3):195–202. [PubMed] [Google Scholar]
  14. Harewood M. S., Proietto J., Dudley F., Alford F. P. Insulin action and cirrhosis: insulin binding and lipogenesis in isolated adipocytes. Metabolism. 1982 Dec;31(12):1241–1246. doi: 10.1016/0026-0495(82)90011-7. [DOI] [PubMed] [Google Scholar]
  15. Hernandez A., Zorrilla E., Gershberg H. Decreased insulin production, elevated growth hormone levels, and glucose intolerance in liver disease. J Lab Clin Med. 1969 Jan;73(1):25–33. [PubMed] [Google Scholar]
  16. Horwitz D. L., Starr J. I., Mako M. E., Blackard W. G., Rubenstein A. H. Proinsulin, insulin, and C-peptide concentrations in human portal and peripheral blood. J Clin Invest. 1975 Jun;55(6):1278–1283. doi: 10.1172/JCI108047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Issekutz B., Jr, Allen M., Borkow I. Estimation of glucose turnover in the dog with glucose-2-T and glucose-U- 14 C. Am J Physiol. 1972 Mar;222(3):710–712. doi: 10.1152/ajplegacy.1972.222.3.710. [DOI] [PubMed] [Google Scholar]
  18. Iwasaki Y., Ohkubo A., Kajinuma H., Akanuma Y., Kosaka K. Degradation and secretion of insulin in hepatic cirrhosis. J Clin Endocrinol Metab. 1978 Oct;47(4):774–779. doi: 10.1210/jcem-47-4-774. [DOI] [PubMed] [Google Scholar]
  19. Johnson D. G., Alberti K. G., Faber O. K., Binder C. Hyperinsulinism of hepatic cirrhosis: Diminished degradation or hypersecretion? Lancet. 1977 Jan 1;1(8001):10–13. doi: 10.1016/s0140-6736(77)91652-x. [DOI] [PubMed] [Google Scholar]
  20. Johnston D. G., Alberti G. M., Wright R., Smith-Laing G., Stewart A. M., Sherlock S., Faber O., Binder C. C-peptide and insulin in liver disease. Diabetes. 1978;27 (Suppl 1):201–206. doi: 10.2337/diab.27.1.s201. [DOI] [PubMed] [Google Scholar]
  21. Johnston D. G., Alberti K. G., Binder C., Faber O. K., Wright R., Orskov H. Hormonal and metabolic changes in hepatic cirrhosis. Horm Metab Res. 1982 Jan;14(1):34–39. doi: 10.1055/s-2007-1018914. [DOI] [PubMed] [Google Scholar]
  22. Kahn C. R. Insulin resistance, insulin insensitivity, and insulin unresponsiveness: a necessary distinction. Metabolism. 1978 Dec;27(12 Suppl 2):1893–1902. doi: 10.1016/s0026-0495(78)80007-9. [DOI] [PubMed] [Google Scholar]
  23. Kato K., Kikuchi S., Ito M., Hidano S., Oya T. Clinical investigation on glucose tolerance in liver cirrhosis. Nagoya J Med Sci. 1973 Mar;35(2):91–101. [PubMed] [Google Scholar]
  24. Katz A. I., Rubenstein A. H. Metabolism of proinsulin, insulin, and C-peptide in the rat. J Clin Invest. 1973 May;52(5):1113–1121. doi: 10.1172/JCI107277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kolterman O. G., Gray R. S., Griffin J., Burstein P., Insel J., Scarlett J. A., Olefsky J. M. Receptor and postreceptor defects contribute to the insulin resistance in noninsulin-dependent diabetes mellitus. J Clin Invest. 1981 Oct;68(4):957–969. doi: 10.1172/JCI110350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kühl C., Faber O. K., Hornnes P., Jensen S. L. C-peptide metabolism and the liver. Diabetes. 1978;27 (Suppl 1):197–200. doi: 10.2337/diab.27.1.s197. [DOI] [PubMed] [Google Scholar]
  27. Megyesi C., Samols E., Marks V. Glucose tolerance and diabetes in chronic liver disease. Lancet. 1967 Nov 18;2(7525):1051–1056. doi: 10.1016/s0140-6736(67)90334-0. [DOI] [PubMed] [Google Scholar]
  28. Olefsky J. M. Insulin resistance in humans. Gastroenterology. 1982 Dec;83(6):1313–1318. [PubMed] [Google Scholar]
  29. Pagano G., Cassader M., Lenti G. Insulin receptors in adipocytes of non-diabetic and diabetic subjects. Preliminary report. Acta Diabetol Lat. 1977 May-Aug;14(3-4):164–169. doi: 10.1007/BF02581404. [DOI] [PubMed] [Google Scholar]
  30. Pagano G., Cavallo-Perin P., Cassader M., Bruno A., Ozzello A., Masciola P., Dall'omo A. M., Imbimbo B. An in vivo and in vitro study of the mechanism of prednisone-induced insulin resistance in healthy subjects. J Clin Invest. 1983 Nov;72(5):1814–1820. doi: 10.1172/JCI111141. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Riggio O., Merli M., Cangiano C., Capocaccia R., Cascino A., Lala A., Leonetti F., Mauceri M., Pepe M., Rossi Fanelli F. Glucose intolerance in liver cirrhosis. Metabolism. 1982 Jun;31(6):627–634. doi: 10.1016/0026-0495(82)90103-2. [DOI] [PubMed] [Google Scholar]
  32. Riley W. J., McCann V. J. Impaired glucose tolerance and growth hormone in chronic liver disease. Gut. 1981 Apr;22(4):301–305. doi: 10.1136/gut.22.4.301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Rizza R. A., Mandarino L. J., Gerich J. E. Cortisol-induced insulin resistance in man: impaired suppression of glucose production and stimulation of glucose utilization due to a postreceptor detect of insulin action. J Clin Endocrinol Metab. 1982 Jan;54(1):131–138. doi: 10.1210/jcem-54-1-131. [DOI] [PubMed] [Google Scholar]
  34. Rowe J. W., Minaker K. L., Pallotta J. A., Flier J. S. Characterization of the insulin resistance of aging. J Clin Invest. 1983 Jun;71(6):1581–1587. doi: 10.1172/JCI110914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. STEELE R., WALL J. S., DE BODO R. C., ALTSZULER N. Measurement of size and turnover rate of body glucose pool by the isotope dilution method. Am J Physiol. 1956 Sep;187(1):15–24. doi: 10.1152/ajplegacy.1956.187.1.15. [DOI] [PubMed] [Google Scholar]
  36. Sherwin R. S., Fisher M., Bessoff J., Snyder N., Hendler R., Conn H. O., Felig P. Hyperglucagonemia in cirrhosis: altered secretion and sensitivity to glucagon. Gastroenterology. 1978 Jun;74(6):1224–1228. [PubMed] [Google Scholar]
  37. Sherwin R., Joshi P., Hendler R., Felig P., Conn H. O. Hyperglucagonemia in Laennec's cirrhosis. The role of portal-systemic shunting. N Engl J Med. 1974 Jan 31;290(5):239–242. doi: 10.1056/NEJM197401312900502. [DOI] [PubMed] [Google Scholar]
  38. Shurberg J. L., Resnick R. H., Koff R. S., Ros E., Baum R. A., Pallotta J. A. Serum lipids, insulin, and glucagon after portacaval shunt in cirrhosis. Gastroenterology. 1977 Feb;72(2):301–304. [PubMed] [Google Scholar]
  39. Smith-Laing G., Sherlock S., Faber O. K. Effects of spontaneous portal-systemic shunting on insulin metabolism. Gastroenterology. 1979 Apr;76(4):685–690. [PubMed] [Google Scholar]
  40. Teng C. S., Ho P. W., Yeung R. T. Down-regulation of insulin receptors in postnecrotic cirrhosis of liver. J Clin Endocrinol Metab. 1982 Sep;55(3):524–530. doi: 10.1210/jcem-55-3-524. [DOI] [PubMed] [Google Scholar]

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