Summary
In cirrhotic patients with normal fasting glucose levels both insulin insensitivity and a blunted early insulin response to oral glucose are important determinants of the degree of intolerance to oral glucose. It is not known whether the ability of hyperglycaemia per se to enhance glucose disposal (glucose effectiveness) is also impaired. It is also unclear whether overt diabetes is due to (1) more marked insulin insensitivity; (2) impaired insulin secretion; (3) reduced glucose effectiveness; or (4) a combination of these mechanisms. We used the “minimal model” to analyse the results of a 3-h intravenous glucose tolerance test to assess glucose effectiveness, insulin sensitivity and insulin responses in 12 non-diabetic cirrhotic patients, 8 diabetic cirrhotic patients and 10 normal control subjects. Fasting blood glucose levels were 4.8±0.2, 7.5±0.6 and 4.7±0.1 mmol/l, respectively. Fasting insulin and C-peptide levels were higher in both cirrhotic patient groups compared with control subjects. The glucose clearance between 6 and 19 min after i.v. glucose was lower in both cirrhotic groups (non-diabetic, 1.56±0.14, diabetic, 0.76±0.06, control subjects, 2.49±0.16 min−1%, both p<0.001 vs control subjects). Serum insulin peaked at 3 and 23 min in the non-diabetic cirrhotic patients and control subjects; both peaks were higher in the non-diabetic cirrhotic patients and showed a delayed return to basal levels. In the diabetic cirrhotic patients, the first phase insulin and C-peptide response to i.v. glucose was absent; their early (22–27 min) incremental insulin response to i. v. tolbutamide was however similar to that of control subjects but 43% lower than in the non-diabetic cirrhotic patients (p<0.05). Insulin sensitivity was markedly reduced in both cirrhotic groups (non-diabetic, 1.11±0.24×10−4, diabetic, 0.33±0.53×10−4, control subjects, 4.37±0.53×10−4 min−1 per mU·l−1, both p<0.001 vs controls). Glucose effectiveness was normal in the non-diabetic cirrhotic patients but 29% lower in the diabetic group. It would appear that overt diabetes develops in those cirrhotic patients who in addition to insulin insensitivity have a marked impairment of insulin secretion. An associated reduction in glucose effectiveness may be a contributory factor.
Article PDF
Similar content being viewed by others
References
Megyesi C, Samols E, Marks V (1967) Glucose tolerance and diabetes in chronic liver disease. Lancet II: 1051–1056
Conn HO, Schreiber W, Elkington SG (1971) Cirrhosis and diabetes. II. Association of impaired glucose tolerance with portal-systemic shunting in Laennec's cirrhosis. Dig Dis 16: 227–239
Kruszynska YT, Home PD, McIntyre N (1991) The relationship between insulin sensitivity, insulin secretion and glucose tolerance in cirrhosis. Hepatology 14: 103–111
Weir GC (1982) Non-insulin dependent diabetes mellitus: interplay between B cell inadequacy and insulin resistance. Am J Physiol 73: 461–464
Bergman RN (1989) Toward physiological understanding of glucose tolerance. Minimal model approach. Diabetes 38: 1512–1527
Ader M, Bergman RN (1987) Insulin sensitivity in the intact organism. In: Alberti KGMM, Home PD, Taylor R (eds) Bailliere's clinics in endocrinology and metabolism. Techniques for metabolic investigation in man, vol 1, part 1. Bailliere Tindall, London, pp 879–910
Bergman RN, Ider YZ, Bowden CR, Cobelli C (1979) Quantitative estimation of insulin sensitivity. Am J Physiol 236: E667-E677
DeFronzo RA, Tobin JD, Andres R (1979) Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237: E214-E223
Bergman RN, Prager R, Volund A, Olefsky JM (1987) Equivalence of the insulin sensitivity index in man derived by the minimal model method and the euglycaemic glucose clamp. J Clin Invest 79: 790–800
Finegood DT, Hramiak IM, Dupre J (1990) A modified protocol for estimation of insulin sensitivity with the minimal model of glucose kinetics in patients with insulin-dependent diabetes. J Clin Endocrinol Metab 70: 1538–1549
Ward GM, Weber KM, Walters IM et al. (1991) A modified minimal model analysis of insulin sensitivity and glucose mediated glucose disposal in insulin-dependent diabetes. Metabolism 40: 4–9
Petrides AS, Schulze-Berge D, Matthews D, Strohmeyer G (1991) The pathogenesis of manifest diabetes mellitus in cirrhosis. Hepatology 14: 144A (Abstract)
Yang YJ, Youn JH, Bergman RN (1987) Modified protocols insulin sensitivity estimation using the minimal model. Am J Physiol 253: E595-E602
Soeldner JS, Sloane D (1965) Critical variables in the radioimmunoassay of serum insulin using the double-antibody technique. Diabetes 14: 771–779
Heding LG (1975) Radioimmunological determination of human C-peptide in serum. Diabetologia 11: 541–548
Bergman RN, Bucolo RJ (1974) Interaction of insulin and glucose in the control of hepatic glucose balance. Am J Physiol 227: 1314–1322
Bucolo RJ, Bergman RN, Marsh DJ, Yates FE (1974) Dynamics of glucose autoregulation in the isolated, blood-perfused canine liver. Am J Physiol 227: 209–217
Kruszynska YT, Home PD, Alberti KGMM (1986) In vivo regulation of liver and skeletal muscle glycogen synthase activity by glucose and insulin. Diabetes 35: 662–667
Yki-Jarvinen H, Mott D, Young AA, Stone K, Bogardus C (1987) Regulation of glycogen synthase and phosphorylase activities by glucose and insulin in human skeletal muscle. J Clin Invest 80: 95–100
Insel PA, Liljenquist JE, Tobin JD et al. (1975) Insulin control of glucose metabolism in man. J Clin Invest 55: 1057–1066
Sherwin RS, Kramer KJ, Tobin JD et al. (1974) A model of the kinetics of insulin in man. J Clin Invest 53: 1481–1492
Cerasi E, Luft R (1967) The plasma insulin response to glucose infusion in healthy subjects and in diabetes mellitus. Acta Endocrinol 55: 278–304
Brunzell JD, Robertson RP, Lerner RL et al. (1976) Relationships between fasting plasma glucose levels and insulin secretion during intravenous glucose tolerance tests. J Clin Endocrinol Metab 42: 222–229
Nygren A, Adner N, Sundblad L, Weichel KL (1985) Insulin uptake by the human alcoholic cirrhotic liver. Metabolism 34: 48–52
Polonsky KS, Rubenstein AH (1984) C-peptide as a measure of the secretion and hepatic extraction of insulin: pitfalls and limitations. Diabetes 33: 486–494
Kruszynska YT, Munro J, Home PD; McIntyre N (1992) Twenty four hour C-peptide and insulin secretion rates and diurnal profiles of glucose, lipids and intermediary metabolites in cirrhosis. Clin Sci 83: 597–605
Tillil H, Shapiro ET, Miller MA et al. (1988) Dose-dependent effects of oral and intravenous glucose on insulin secretion and clearance in normal humans. Am J Physiol 254: E349-E357
Robertson RP (1989) Type 2 diabetes, glucose “non-sense”, and islet desensitisation. Diabetes 38: 1501–1505
Varsano-Aharon N, Echemendia E, Yalow RS, Berson SA (1970) Early insulin responses to glucose and to tolbutamide in maturity-onset diabetes. Metabolism 19: 409–417
Ward WK, Beard JC, Porte D (1986) Clinical aspects of islet B-cell function in non-insulin dependent diabetes mellitus. Diabetes Metab Rev 2: 297–313
Vetter D, Fratte S, Winiszewski P et al. (1990) Consequences de l'hyperglycemie sur le metabolisme glucidique et azote dans la cirrhose: exploration par une epreuve de clamp hyperglycemique. Gastroenterol Clin Biol 14: 483–491
Cobelli C, Pacini G, Toffolo G, Sacca L (1986) Estimation of insulin sensitivity and glucose clearance from minimal model: new insights from labelled IVGTT. Am J Physiol 250: E591-E598
Bourey RE, Koranyi L, James DE, Mueckler M, Permutt MA (1990) Effects of altered glucose homeostasis on glucose transporter expression in skeletal muscle of the rat. J Clin Invest 86: 542–547
Seltzer H, Allen W, Herron AL, Brennan MT (1967) Insulin secretion in response to glycaemic stimulus: relation of delayed initial release to carbohydrate intolerance in mild diabetes mellitus. J Clin Invest 46: 323–335
Luzi L, DeFronzo RA (1989) Effect of loss of first-phase insulin secretion on hepatic glucose production and tissue glucose disposal in humans. Am J Physiol 257: E241-E246
Bruce DG, Chisholm DJ, Storlien LH, Kraegen EW (1988) Physiological importance of deficiency in early prandial insulin secretion in non-insulin dependent diabetes. Diabetes 37: 736–744
Mitrakou A, Kelley D, Mokan M et al. (1992) Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance. N Engl J Med 326: 22–29
Lerner RL, Porte D (1972) Acute and steady-state insulin responses to glucose in non-obese diabetic subjects. J Clin Invest 51: 1624–1631
Doberne L, Greenfield MS, Schulz B, Reaven GM (1981) Enhanced glucose utilisation during prolonged glucose clamp studies. Diabetes 30: 829–835
Sacca L, Cicala M, Trimarco B, Ungaro B, Vigorito C (1982) Differential effects of insulin on splanchnic and peripheral glucose disposal after an intravenous glucose load in man. J Clin Invest 70: 117–126
DeFronzo RA (1987) The triumvirate: B-cell, muscle, liver. Diabetes 37: 667–687
Yang YJ, Hope ID, Ader M, Bergman RN (1989) Insulin transport across capillaries is rate limiting for insulin action in dogs. J Clin Invest 84: 1620–1628
Kruszynska YT, Williams N, Perry M, Home PD (1988) The relationship between insulin sensitivity and skeletal muscle enzyme activities in hepatic cirrhosis. Hepatology 8: 1615–1619
Prager R, Wallace P, Olefsky JM (1986) In vivo kinetics of insulin action on peripheral glucose disposal and hepatic glucose output in normal and obese subjects. J Clin Invest 78: 472–481
Proietto J, Alford FP, Dudley FJ (1980) The mechanism of the carbohydrate intolerance in cirrhosis. J Clin Endocrinol Metab 51: 1030–1036
Cavallo-Perin P, Cassader M, Bozzo C et al. (1985) Mechanism of insulin resistance in human liver cirrhosis: evidence of a combined receptor and postreceptor defect. J Clin Invest 75: 1659–1665
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kruszynska, Y.T., Harry, D.S., Bergman, R.N. et al. Insulin sensitivity, insulin secretion and glucose effectiveness in diabetic and non-diabetic cirrhotic patients. Diabetologia 36, 121–128 (1993). https://doi.org/10.1007/BF00400692
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00400692