Is the Diminished Incretin Effect in Type 2 Diabetes Just an Epi-Phenomenon of Impaired β-Cell Function?

Type 2 diabetes is characterized by a deficit in β-cell mass, impaired insulin secretion in response to various stimuli (1–3), as well as a variable extent of insulin resistance (4). More specifically, regarding β-cell function, a significant reduction of the incretin effect, i.e., the postprandial augmentation of insulin secretion by gut hormones, has been described in patients with type 2 diabetes (5). Thus, while the two incretin hormones gastric inhibitory polypeptide (glucose-dependent insulinotopic polypeptide [GIP]) and glucagon-like peptide 1 (GLP-1) are held responsible for ∼50–70% of the postprandial insulin responses in healthy individuals (6), their contribution to the overall insulin responses after oral glucose ingestion may amount to <20% in patients with type 2 diabetes (5,7). The reasons underlying the loss of incretin activity in type 2 diabetes are still incompletely understood. The present article reviews the available evidence regarding disturbances in the enteroinsular axis in patients with type 2 diabetes and provides possible explanations for their etiologies, focusing on the personal experience of the authors. ### Secretion of incretin hormones in patients with type 2 diabetes. Because the incretin effect has been related to the secretion and insulinotropic action of GIP and GLP-1 (8,9), it was obvious to compare these parameters between patients with type 2 diabetes and healthy control subjects: Regarding the secretion of GIP, elevated, normal, and reduced plasma levels have been described in patients with type 2 diabetes (10–15). However, taking together all the evidence available, the secretion of GIP appears to be relatively unchanged in type 2 diabetic patients. For GLP-1 release, the case is even more complex. Several studies have reported significant reductions in GLP-1 levels after mixed meal ingestion in patients with type 2 diabetes (10,16,17). In addition, one study has found minor impairments in GLP-1 levels in individuals with impaired glucose …