Incretin Hormones and the Up-Regulation of Insulin Secretion in Insulin Resistance

Abstract

The incretin effect is the augmented insulin secretion that is elicited by oral compared with iv administration of glucose, when glucose levels during the two challenges are matched. The incretin effect has been documented in humans (1) and in experimental animals (2). The underlying reason for the incretin effect is attributed to the release of incretin hormones from the gut during oral glucose administration [mainly glucose-dependent insulinotropic polypeptide (GIP) and glucagonlike peptide-1 (GLP-1)]; these incretin hormones potentiate the glucose-stimulated insulin secretion. It has been estimated that the incretin effect is responsible for at least 60–70% of insulin secretion after oral glucose in normal humans (3). Recently, it was demonstrated that an incretin effect also exists after oral fat administration, i.e. it is not specific for glucose (4). It is now well documented that the incretin effect is reduced in type 2 diabetes (3). This impairment could be due to impaired incretin hormone secretion (i.e. incretin hormone deficiency) and/or to a defective insulinotropic action of the incretin hormones (i.e. incretin hormone resistance). Although some controversy still exists in the literature, most data support that the impaired incretin effect in type 2 diabetes is due to defective insulin secretory effects of GIP and GLP-1, rather than to defective secretion of the two incretin hormones (3, 5). Still, GLP-1 retains a high efficacy in type 2 diabetes, which is a rationale behind the incretin-based therapy (6). The defective incretin effect in type 2 diabetes has raised two fundamental questions of importance for the understanding of diabetes pathophysiology. One question is whether a defective incretin effect is involved in the pathophysiology of the disease, i.e. whether defective incretin effect participates in the development of the disease itself or is merely a consequence of the disease (7). A second question is whether the defective insulinotropic actions of GIP and GLP-1 in type 2 diabetics, compared with healthy individuals, are due to specific defects in the -cell effects of the hormones or reflect a more generalized -cell dysfunction (8). In regard to the potential pathophysiological contribution of defective incretin effect, only a few studies have explored this important question, and the results have been controversial. For example, on the one hand, it has been shown that the insulin stimulatory effect of GIP is impaired in first-degree relatives of type 2 diabetic patients (9), which would suggest a pathophysiological involvement. On the other hand, it has also been shown that the insulinotropic effect of GIP is normal in women with a history of gestational diabetes (10), which instead suggests that the defect is secondary to developed diabetes. In regard to the question of a specific defect in incretin hormone effect in type 2 diabetes vs. a generalized -cell defect, no studies have directly focused on this issue. In the present issue of the JCEM, a novel study by Hansen et al. (11) has addressed these two fundamental questions by a novel and interesting approach. The authors examined the insulin secretory responses to iv GIP and GLP-1 (given in physiological concentrations) during a hyperglycemic clamp (10 mmol/liter) in healthy subjects before and after experimental induction of insulin resistance. In insulin resistance, insulin secretion is up-regulated, and in healthy subjects, the disposition index (i.e. insulin sensitivity insulin secretion) remains normal (12). The investigators compared the up-regulated insulin secretion after glucose vs. incretin hormones. If there is a defective up-regulation of insulin secretion to insulin resistance in response to the incretin hormones, but not to