Hyper- and hypoinsulinemia in type-2 diabetes: what may be wrong in the secretory mechanism of the B-cell.

Abstract

Type-2 diabetes frequently is the consequence of overnutrition causing overweight, which then produces insulin resistance. The following hyperglycemia induces permanent overstimulation of the insulin secretory machinery of the B-cell, which results in hyperinsulinemia and/or hypoinsulinemia. The mechanisms, however, of these disturbances are not understood so far. Animal models, which can be used to solve these questions, are, among others, long-term incubation of pancreatic islets in culture in the presence of high glucose and/or long-term infusion of rats with glucose. Using these models sensitization [Bedoya and Jeanrenaud, 1991; Leahy et al., 1987; Purrello et al., 1992; Thams, 1991; Thibault et al., 1993; Timmers et al., 1990] and/or desensitization of insulin release [Bedoya and Jeanrenaud, 1991; Leahy et al., 1987; Davalli et al., 1992; Eizirik et al., 1992; Bolaffi et al., 1988; Timmers et al., 1990] have been reported. Whether or not there is sensitization or desensitization depends on the glucose concentration [Eizirik et al., 1992; Leahy et al., 1986; Sako and Grill, 1990] and the duration of glucose action [Bedoya and Jeanrenaud, 1991; Bolaffi et al., 1988]. Both, sensitization and desensitization, appear to be reversible on return to normal glucose or mild hypoglycemia [Leahy and Weir, 1991; Svenson and Hellerström, 1991]. It seems, however, that there is a fluent change from the first occurring hyperinsulinemia to hypoinsulinemia. In this lecture I first want to talk about the possible mechanism of sensitization of insulin secretion discussing previous results we have obtained from rat islets isolated after a 48 hours period of i.v. infusion with 50% glucose. In the second part I will discuss some of the findings coming from the respective literature concerning desensitization of insulin secretion.