Relationship between insulin sensitivity, insulin secretion and glucose tolerance in cirrhosis

Abstract

Hepatic insulin extraction is difficult to measure in humans; as a result, the interrelationship between defective insulin secretion and insulin insensitivity in the pathogenesis of glucose intolerance in cirrhosis remains unclear. To reassess this we used recombinant human C-peptide to measure C-peptide clearance in cirrhotic patients and controls and thus derive C-peptide and insulin secretion rates after a 75-gm oral glucose load and during a 10 mmol/L hyperglycemic clamp. Cirrhotic patients were confirmed as insulin-insensitive during a euglycemic clamp (glucose requirement: 4.1 +/- 0.1 mg/kg/min vs. 8.1 +/- 0.5 mg/kg/min; p less than 0.001), which also demonstrated a low insulin metabolic clearance rate (p less than 0.001). Although intolerant after oral glucose, the cirrhotic patients had glucose requirements identical to those of controls during the hyperglycemic clamp (cirrhotic patients: 6.1 +/- 1.0 mg/kg/min; controls: 6.3 +/- 0.7 mg/kg/min), suggesting normal intravenous glucose tolerance. C-peptide MCR was identical in cirrhotic patients (2.93 +/- 0.16 ml/min/kg) and controls (2.96 +/- 0.24 ml/min/kg). Insulin secretion was higher in cirrhotic patients, both fasting (2.13 +/- 0.26 U/hr vs. 1.09 +/- 0.10 U/hr; p less than 0.001) and from min 30 to 90 of the hyperglycemic clamp (5.22 +/- 0.70 U/hr vs. 2.85 +/- 0.22 U/hr; p less than 0.001). However, with oral glucose the rise in serum C-peptide concentration was relatively delayed, and the insulin secretion index (secretion/area under 3-hr glucose curve) was not elevated. Hepatic insulin extraction was reduced both in fasting and during the hyperglycemic clamp (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin sensitivity, insulin secretion and glucose effectiveness in diabetic and non-diabetic cirrhotic patients

“…However, their incremental C-peptide responses to glucose and tolbutamide were not significantly different. Our previous studies [3,26] and that of Tillil et al [27] suggested that first pass hepatic extraction of insulin falls at high rates of insulin secretion. Thus, the greater insulin response to tolbutamide compared to i.v.…”

“…In both groups there was a strong relationship between these two estimates of insulin sensitivity (cirrhotic patients, r = 0.902,p < 0.001; control subjects r = 0.750,p < 0.02) Fasting insulin levels were increased five-fold in the non-diabetic cirrhotic patients and nine-fold in the diabetic cirrhotic patients. Interpretation of peripheral insulin levels in cirrhosis is complicated by their reduced hepatic insulin extraction [3,24]. C-peptide which is co-secreted with insulin in equimotar amounts but not extracted by the liver provides a much better index of insulin secretion [25].…”

“…S~ was normal in the non-diabetic cirrhotic patients, which helps to explain their relatively good i.v. glucose tolerance and their normal rates of glucose disposal under hyperglycaemic clamp conditions [3,31], although in the latter situation interpretation is complicated by the striking increase in plasma insulin levels [3]. SG depends on the inhibitory effect of the plasma glucose level on HGO as well as on its mass action effect on peripheral glucose uptake [32].…”

“…The non-diabetic cirrhotic patients and the control subjects also were studied during a hyperinsulinaemic euglycaemic clamp. The euglycaemic clamp data on seven of the cirrhotic patients and eight of the control subjects have been published previously [3]; their data is included in this study for comparison of the euglycaemic clamp and "minimal model" as measures of insulin sensitivity in cirrhosis. Euglycaemic clamp studies were not performed in the diabetic cirrhotic patients.…”

“…Overt diabetes mellitus is common. We recently showed, in cirrhotic patients with normal fasting blood glucose levels, that both insulin resistance and a relative impairment of insulin secretion are important determinants of the degree of oral glucose intolerance [3], as they are in Type 2 (non-insulin-dependent) diabetes [4,5]. In Type 2 diabetes, there is also an impairment of the ability of hyperglycaemia per se to promote tissue glucose utilisation and to inhibit hepatic glucose production [5,6]; this decrease in "glucose effectiveness" interacts synergistically with tissue insulin insensitivity and impaired islet beta-cell function to reduce glucose tolerance [5,6].…”