Relationships Between Gastric Emptying, Postprandial Glycemia, and Incretin Hormones

The importance of achieving tight glycemic control, usually assessed by glycated hemoglobin (HbA1c), for both the prevention and delay in the progression of diabetes-relatedmicrovascular complications, is established, and the American Diabetes Association/European Association for the Study of Diabetes joint committee has recommended an HbA1c ,7% as the goal in patients with type 2 diabetes (1). The relative contributions of preand postprandial glycemia to HbA1c have been clarified during the last decade following the seminal report by Monnier et al. (2) indicating that in type 2 diabetes, postprandial glycemic excursions account for about 70% of variability when HbA1c is ,7.3%, while the contribution of “fasting” glycemia is greater in less wellcontrolled patients. Subsequent studies have confirmed the predominance of postprandial glycemia in determining overall glycemic control in “well-controlled” type 2 diabetic patients managed by oral hypoglycemic agents or basal insulin (3). The importance of postprandial glycemia to overall glycemic control is not surprising considering that 1) humans in modern societies spend only about 3 or 4 h before breakfast in a truly fasting state because in health, gastric emptying of meals occurs at an overall rate of 1–4 kcal/min (4), and 2) postprandial hyperglycemia occurs frequently in diabetes (1). The relevance of postprandial glycemia is further increased by the recognition that it may represent an independent risk factor for adverse cardiovascular outcomes in both diabetic and nondiabetic populations (5). The determinants of postprandial glycemia include preprandial glycemic levels, meal composition, gastric emptying, insulin secretion, small intestinal glucose absorption, and hepatic and peripheral glucose metabolism. Furthermore, the relative contribution of each of these factors may vary over time during the postprandial state. Nevertheless, both the rate of gastric emptying and the secretion and action of the incretin hormones, glucagon-like peptide1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), exert amajor influence (6). The latter limit postprandial glycemia through their insulinotropic and, in the case of GLP-1, glucagonostatic actions. They account for the “incretin effect”dan augmentation of insulin secretion following oral or enteral glucose exposure when compared with an isoglycemic intravenous glucose infusiondwhich is diminished in type 2 diabetes (7). GIP and GLP-1 are released from entero-endocrine cells located most densely in the proximal small intestine and distal small intestine/colon, respectively, following nutrient exposure. Each macronutrient has the capacity to stimulate GLP-1 and GIP release, although the mechanisms underlying secretion differ, and fat and carbohydrate may be more potent stimuli than protein (8). Carbohydrates, for example, stimulate incretin secretion through a number of interrelated mechanisms that are likely to include the sodium-glucose cotransporter-1 (SGLT-1) and intestinal “sweet taste” receptors (8). Following their release, the incretin hormones are rapidly degraded to inactivemetabolites by the ubiquitous enzyme, dipeptidyl peptidase-4 (DPP-IV). While GIP may be the most important incretin hormone in health, its capacity to stimulate insulin is markedly diminished in type 2 diabetes (8). Even relatively minor variations in gastric emptying can have a major impact on the postprandial glycemic profile in health and type 2 diabetes (9–12). It is now recognized that complex, interdependent relationships exist between gastric emptying, the incretin axis, and postprandial glycemia, with the rate of gastric emptying having a major impact on the magnitude of both the glycemic excursion and incretin hormone secretion and, conversely, acute hyperglycemia and GLP-1 exerting negative feedback on gastric emptying (6). This review focuses on these interrelationships, summarized in Fig. 1, and the consequent implications for dietary and pharmacological strategies to manage postprandial glycemia in type 2 diabetes.