Insulin and liver disease: effect of proinsulin on hepatic carbohydrate metabolism

Abstract

The frequent occurrence of impaired glucose tolerance and diabetes mellitus in liver disease, especially liver cirrhosis, is of multifactorial origin¹. Recent findings have demonstrated that the first measurable event in patients with early idiopathic haemochromatosis in the non-cirrhotic stage of the disease is hyperinsulinaemia without hyperglycaemia². This hyperinsulinaemia was not a consequence of insulin hypersecretion because the response of serum C-peptide levels to glucose ingestion was normal, but rather it was due to a decreased insulin extraction by the liver even before shunting of portal blood. Obviously, decreased binding of insulin to the liver cell membranes results in decreased hepatic insulin extraction and decreased hepatic insulin effects, i.e. to reduced glucose uptake and, thus hyperglycaemia. Hyperinsulinaemia also induces down-regulation of insulin receptors in peripheral tissues and by this general insulin resistance, which is further enhanced by increased growth hormone and glucagon levels as frequently observed in liver cirrhotics. This, finally, leads to an exhaustion of the pancreatic B-cells (Figure 17.1).