The liver is the primary organ of insulin clearance; thus, hyperinsulinism in peripheral blood may result from diminished insulin degradation rather than hypersecution. Proinsulin is cleaved in the pancreatic β-cell to insulin and C-peptide, which are released into the circulation in equimolar quantities. Unlike insulin, C-peptide is not degraded by liver, and in liver disease the peripheral C-peptide concentration is a better index of insulin secretion than is peripheral insulin concentration.

Fasting plasma insulin concentration was raised in 21 cirrhotic patients (0.13 ± 0.02 vs. 0.06 ± 0.01 nmol per liter) despite normal fasting blood glucose concentrations. C-peptide concentrations and, therefore, insulin secretion did not differ from controls', and the C-peptide:insulin ratio was decreased in cirrhotic subjects (4.0 ± 0.5 vs 7.0 ± 1.1). After oral glucose, hyperinsulinemic cirrhotic subjects had similar C-peptide concentrations to those of cirrhotics with a normal insulin response in whom glucose values were similar. Hyperinsulinism (both fasting and after glucose) appears to result from diminished insulin degradation, therefore.

To distinguish the roles of liver damage and of portal-systemic shunting, similar studies were performed in patients with ostensibly normal liver function but long-standing portal venous block. Despite mild hyperglycemia, hyperinsulinism was not found in these subjects, either fasting or after oral glucose. The fasting C-peptide:insulin ratio was normal, and only after stimulation of insulin secretion by glucose was a mild impairment of insulin degradation seen.

The hyperinsulinism of hepatic cirrhosis is due to impaired insulin degradation; this is more likely to result from liver damage per se than from portal-systemic shunting.

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