Insulin secretion and plasma levels of glucose-dependent insulinotropic peptide and glucagon-like peptide 1 [7–36 amide] after oral glucose in cirrhosis

Abstract

A blunted initial insulin secretory response may contribute to oral glucose intolerance in cirrhosis. Oral glucose is a better stimulant to insulin secretion than intravenous (IV) glucose in part because of release of gut peptides, notably glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 [7–36 amide] (GLP-1 [7–36 amide]). Because impaired release of or resistance to these gut peptides could explain impaired insulin secretion after oral glucose, we measured insulin secretion, plasma GIP, and GLP-1 [7–36 amide] levels, basally and after 75 g oral glucose, in 10 cirrhotics and 10 controls. Insulin secretion was calculated from a two-compartment analysis of serum C-peptide levels using kinetic parameters derived from IV injection of recombinant human C-peptide. C-peptide metabolic clearance rate, and the fractional rate constants for C-peptide (using the two-compartment model) were not significantly different, but the volume of the central compartment was 15% greater in cirrhotics ( P < .01). Fasting blood glucose levels were similar (cirrhotics, 4.9 ± 0.2; controls, 4.6 ± 0.1 mmol/L) but serum insulin was six times higher in cirrhotics ( P < .001). Cirrhotics had higher fasting GIP (215 ± 72 vs. 42 ± 18 pmol/L) and GLP-1 [7–36 amide] levels (25 ± 3 vs. 16 ± 1 pmol/L) (both P < .05). After oral glucose, blood glucose levels were significantly higher in cirrhotics. The timing of the gut peptide response to oral glucose was similar in the two groups, but peak levels of both peptides were ∼x2 higher in the cirrhotics. For the 1st 30 minutes, C-peptide levels and insulin secretion were similar in the two groups. In controls, insulin secretion peaked at 20 to 25 minutes and coincided with the GLP-1 [7–36 amide] peak; insulin secretion then decreased despite a persistent elevation in plasma GIP and glucose levels. In cirrhotics, peak insulin secretion was delayed until 50 to 55 minutes (coincident with the glucose peak). Total insulin secretion during the 4 hours after glucose ingestion was 55% higher in the cirrhotics, but peak insulin secretion rates were similar despite higher gut peptide and glucose levels in cirrhotics. The study shows that, after oral glucose, cirrhotics have a blunted serum C-peptide response and insulin secretion rate. This is not attributable to reduced levels of GIP or GLP-1 [7–36 amide] but could be attributable to resistance to their action.