OBJECTIVE-Defects in glucagon-like peptide 1 (GLP-1) secretion have been reported in some patients with type 2 diabetes after meal ingestion. We addressed the following questions: 1) Is the quantitative impairment in GLP-1 levels different after mixed meal or isolated glucose ingestion? 2) Which endogenous factors are associated with the concentrations of GLP-1? In particular, do elevated fasting glucose or glucagon levels diminish GLP-1 responses?RESEARCH DESIGN AND METHODS-Seventeen patients with mild type 2 diabetes, 17 subjects with impaired glucose tolerance, and 14 matched control subjects participated in an oral glucose tolerance test (75 g) and a mixed meal challenge (820 kcal), both carried out over 240 min on separate occasions. Plasma levels of glucose, insulin, C-peptide, glucagon, triglycerides, free fatty acids (FFAs), gastric inhibitory polypeptide (GIP), and GLP-1 were determined.RESULTS-GIP and GLP-1 levels increased significantly in both experiments (P Ͻ 0.0001). In patients with type 2 diabetes, the initial GIP response was exaggerated compared with control subjects after mixed meal (P Ͻ 0.001) but not after oral glucose ingestion (P ϭ 0.98). GLP-1 levels were similar in all three groups in both experiments. GIP responses were 186 Ϯ 17% higher after mixed meal ingestion than after the oral glucose load (P Ͻ 0.0001), whereas GLP-1 levels were similar in both experiments. There was a strong negative association between fasting glucagon and integrated FFA levels and subsequent GLP-1 concentrations. In contrast, fasting FFA and integrated glucagon levels after glucose or meal ingestion and female sex were positively related to GLP-1 concentrations. Incretin levels were unrelated to measures of glucose control or insulin secretion.CONCLUSIONS-Deteriorations in glucose homeostasis can develop in the absence of any impairment in GIP or GLP-1 levels. This suggests that the defects in GLP-1 concentrations previously described in patients with long-standing type 2 diabetes are likely secondary to other hormonal and metabolic alterations, such as hyperglucagonemia. GIP and GLP-1 concentrations appear to be regulated by different factors and are independent of each other. Diabetes 57:678-687, 2008 P ostprandial glucose homeostasis is controlled not only by the direct stimulation of insulin release by the absorbed nutrients but also through the secretion of incretin hormones, namely gastric inhibitory polypeptide (GIP) and glucagonlike peptide 1 (GLP-1) (1-4). In healthy, nondiabetic subjects, the quantitative contribution of this incretin effect to the overall postprandial insulin secretion has been estimated to be 50 -70% (5,6), depending on meal size and composition. In contrast, a marked reduction of the incretin effect is characteristic of patients with type 2 diabetes (7), thereby contributing to the excess postprandial glucose excursions in such patients. Although the exact mechanisms underlying the loss of incretin activity in patients with type 2 diabetes are still not completely understood, two d...

The incretin effect denominates the phenomenon that oral glucose elicits a higher insulin response than does intravenous glucose. The two hormones responsible for the incretin effect, glucose-dependent insulinotropic hormone (GIP) and glucagon-like peptide-1 (GLP-1), are secreted after oral glucose loads and augment insulin secretion in response to hyperglycemia. In patients with type 2 diabetes, the incretin effect is reduced, and there is a moderate degree of GLP-1 hyposecretion. However, the insulinotropic response to GLP-1 is well maintained in type 2 diabetes. GIP is secreted normally or hypersecreted in type 2 diabetes; however, the responsiveness of the endocrine pancreas to GIP is greatly reduced. In ϳ50% of first-degree relatives of patients with type 2 diabetes, similarly reduced insulinotropic responses toward exogenous GIP can be observed, without significantly changed secretion of GIP or GLP-1 after oral glucose. This opens the possibility that a reduced responsiveness to GIP is an early step in the pathogenesis of type 2 diabetes. On the other hand, this provides a basis to use incretin hormones, especially GLP-1 and its derivatives, to replace a deficiency in incretin-mediated insulin secretion in the treatment of type 2 diabetes. Diabetes 53 (Suppl. 3):S190 -S196, 2004 INCRETIN HORMONESThe study of gut hormones as stimulators of secretion of the endocrine pancreas has a long history, probably starting with attempts to therapeutically administer intestinal mucosal extracts (containing putative insulinotropic hormones) in patients with diabetes (1). Due to improvements in methods to quantify plasma concentrations of potential incretins (2,3) and in the ability to estimate insulin secretion in vivo (4 -6), a clear picture of the true physiological importance of the major incretin hormones, gastric inhibitory polypeptide, also interpreted as glucose-dependent insulinotropic polypeptide (GIP), and glucagonlike peptide-1 (GLP-1), has emerged (7-11). From the beginning (1), the study of intestinal incretin hormones has been driven by the hope to better understand the pathogenesis of diabetes, especially that of type 2 diabetes, or to find new treatments based on properties of gut-derived insulinotropic agents. While the latter has been the object of several comprehensive reviews in recent years (9,12,13), the former will be the topic of the present article. QUANTIFICATION OF THE INCRETIN EFFECTThe incretin effect is a phenomenon in which oral glucose (or any other way for the administration of glucose to not bypass its absorption from the gut) elicits a much higher insulin secretory response than an intravenous infusion of glucose with similar glycemic rises (14,15) or if the same amount of glucose was given by both routes (16). In the latter case, glucose concentrations were much higher with intravenous rather than oral glucose administration (16). State of the art for exactly quantifying the incretin effect is a comparison of the insulin secretory response after oral and "isoglycemic" intravenous gluc...

Glucose levels reached after an oral glucose challenge and during real life are correlated to some extent, but the absolute levels of glycaemia greatly differ between both conditions. Therefore, 'postchallenge' glucose levels measured during an OGTT might be used as a predictor of 'postprandial hyperglycaemia', but caution should be taken when both terms are used synonymously. Furthermore, subjects with IGT during an OGTT already exhibit increased postprandial glucose levels under real-life conditions. This suggests that IGT should already be considered an overt disease condition rather than merely a high-risk situation.