The role of insulin and proinsulin in the regulation of triglyceride metabolism

Summary

The mechanisms underlying the associations between abnormal glucose tolerance and myocardial infarction are poorly understood. It has often been suggested that an increased plasma insulin concentration is causally linked to many of the metabolic abnormalities that are associated with abnormal glucose tolerance, although this suggestion remains controversial. Recently it has been proposed that proinsulin and proinsulin-like molecules may also be involved in the atherogenic process. Both hyperinsulinaemia and insulin resistance are associated with fasting hypertriglyceridaemia and both increased VLDL production and increased plasma triglyceride concentrations commonly occur in association with abnormal glucose tolerance and atheromatous vascular disease. In order to study the effects of insulin, proinsulin and proinsulin-like molecules on hepatic triglyceride secretion we have undertaken experiments in vitro using the liver cell line Hep G2. In conjunction with these in vitro experiments we have also studied, in vivo, the associations between insulin, proinsulin, proinsulin-like molecules and plasma triglyceride concentrations in subjects with both normal and abnormal glucose tolerance. Our results in vitro show that proinsulin and proinsulin-like molecules have similar and not different effects to insulin but are less biologically active. In vivo, our results show that concentrations of insulin, proinsulin and proinsulin-like molecules per se are not an important determinant of plasma triglyceride concentrations. Both abnormal NEFA suppression during an oral glucose tolerance test and increased central adiposity are closely linked to poor glucose tolerance and are the most important determinants of plasma triglyceride concentrations. Taken together these results suggest that it is not insulin nor proinsulin concentrations per se that are causally linked to hypertriglyceridaemia. We suggest that abnormal NEFA suppression plays an important part in the increase in risk of vascular disease associated with insulin resistance.

Key words

Insulin - proinsulin - proinsulin-like molecules and triglycerides