Endocrine Abstracts

Gastric inhibitory polypeptide (GIP) is a physiologically important incretin hormone secreted from K cell of the upper small intestine. Glucagon-like peptide 1 (GLP-1) is secreted from L cells in the lower small and large intestine. Both hormones are released after nutrient (especially carbohydrate and fat) ingestion and glucose-dependently augment insulin secretion. An involvement of either incretin hormone in the pathogenesis of diabetes may, in principle, be related to abnormalities of either secretion or action. While some studies suggest reduced GLP-1 secretion after oral glucose or meal ingestion in patients with type 2 diabetes, more recent data do not support any systematic difference to healthy subjects. There is, however, a large inter-individual variation. GIP secretion is also not impaired in type 2 diabetic versus healthy subjects. Nevertheless, type 2 diabetes is associated with a reduced incretin effect. This means that oral glucose has only little more stimulatory effect on insulin secretion than has an isoglycaemic intravenous glucose infusion (i.e. at the same glycaemic profile). In healthy subjects, marked differences are typical, with two thirds of the secretory response being due to factors other than hyperglycaemia, pointing to mechanisms related to the absorption of nutrients from the gut. Insulinotropic GIP effects, in contrast to unchanged secretion, are markedly reduced in patients with type 2 diabetes compared to healthy subjects. Therefore, defective GIP action on β-cells explains impaired insulin secretory responses in patients with type 2 diabetes. This may be pathophysiologically relevant in the case of nurtrient-stimulated insulin secretion, i.e. after meals. A similarly reduced insulinotropic activity of GIP has been described with a variety of other forms of diabetes, whenever there is fasting hyperglycemia. Whether or not such defects are central to the pathophysiology of type 2 diabetes is still unclear. Two hypothesis have been derived: i) there is a specific insensitivity to GIP in type 2 diabetes, so that the type 2-diabetic endocrine pancreas is particularly insensitive to endogenous and exogenous GIP, more than, for example, in response to glucose or other insulinotropic stimuli. The alternative explanation is that ii) there is a generalized functional defect in the endocrine pancreas of patients with type 2 diabetes, which pertains for glucose- as well as GIP-stimulated insulin secretion to a similar degree. Current evidence supports the latter hypothesis. In contrast to markedly reduced insulinotropic GIP effects in type 2 diabetes, GLP-1 actions are much less impaired. If not at physiological concentrations, at pharmacological GLP-1 concentrations, a normalization of plasma glucose can be achieved in most type 2 diabetic patients examined so far. In conclusion, the major abnormality with respect to incretin (GIP and GLP-1) secretion and action in type 2 diabetes is a reduced responsiveness of β cells to GIP. This may partly explain impaired insulin secretion in type 2 diabetes. On the other hand, GLP-1 retains its insulinotropic activity even in advanced type 2 diabetes, why it has become the parent compound for incretin-based medications like GLP-1 receptor agonists and inhibitors of dipeptidyl peptidase-4 (DPP-4).