Effects of meal size and composition on incretin, α-cell, and β-cell responses

Abstract

The incretins glucagon-like peptide–1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) regulate postprandial insulin release from the β-cells. We investigated the effects of 3 standardized meals with different caloric and nutritional content in terms of postprandial glucose, insulin, glucagon, and incretin responses. In a randomized crossover study, 18 subjects with type 2 diabetes mellitus and 6 healthy volunteers underwent three 4-hour meal tolerance tests (small carbohydrate [CH]-rich meal, large CH-rich meal, and fat-rich meal). Non–model-based and model-based estimates of β-cell function and incremental areas under the curve of glucose, insulin, C-peptide, glucagon, GLP-1, and GIP were calculated. Mixed models and Friedman tests were used to test for differences in meal responses. The large CH-rich meal and fat-rich meal resulted in a slightly larger insulin response as compared with the small CH-rich meal and led to a slightly shorter period of hyperglycemia, but only in healthy subjects. Model-based insulin secretion estimates did not show pronounced differences between meals. Both in healthy individuals and in those with diabetes, more CH resulted in higher GLP-1 release. In contrast with the other meals, GIP release was still rising 2 hours after the fat-rich meal. The initial glucagon response was stimulated by the large CH-rich meal, whereas the fat-rich meal induced a late glucagon response. Fat preferentially stimulates GIP secretion, whereas CH stimulates GLP-1 secretion. Differences in meal size and composition led to differences in insulin and incretin responses but not to differences in postprandial glucose levels of the well-controlled patients with diabetes.

Introduction

The incretins glucagon-like peptide–1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are hormones released from endocrine cells in the intestinal mucosa after a meal to regulate postprandial insulin release from the pancreatic β-cell. Because incretin function is known to be reduced or absent in patients with diabetes [1], whereas the insulinotropic effect of GLP-1 is preserved, there is substantial interest in dipeptidyl peptidase-4 (DPP-IV) inhibitors and GLP-1 analogs for controlling postprandial blood glucose levels in type 2 diabetes mellitus. Augmentation of the secretion of endogenous GLP-1 could be another approach; the effect of the composition of a meal on incretin levels and subsequent insulin, glucagon, and glucose concentrations is therefore of interest.

A mixed-meal test offers the potential for assessing insulin secretion during physiologically relevant situations and for evaluating the physiologic effects of incretins. The few studies that have examined incretin responses after one or more meals are not consistent about the contributions of meal composition and size in stimulating incretin and/or insulin secretion in patients with diabetes. A recent study showed that, in both healthy subjects and type 2 diabetes mellitus patients, GIP responses were higher after mixed-meal ingestion than after an oral glucose load, but GLP-1 levels were similar during both tests [2]. In a study with 5 healthy volunteers, the time course of plasma GIP concentrations paralleled the gastric emptying of fat and protein [3]. On the other hand, it has been reported that ingestion of fat before a carbohydrate (CH) meal attenuated the postprandial rises in GIP but stimulated GLP-1 in type 2 diabetes mellitus [4]. In a study comparing 50-g vs 100-g glucose loads in healthy individuals, GLP-1 and GIP were dose-dependently increased [5]. As for meal size, one study has demonstrated higher incretin and C-peptide responses after a large as compared with a small meal [6]. β-Cell glucose sensitivity, an estimate of β-cell function, tended to increase in obese individuals during a large meal, perhaps reflecting increased incretin response. However, the meal composition of the large and small meal was similar; therefore, the influence of the macronutrients could not be derived.

It is unknown how meals with different caloric content and CH/fat load compare with one another in subjects with and without type 2 diabetes mellitus. In particular, the degree to which size of a meal (caloric load) and varying nutrient composition may influence the incretin, insulin, and glucagon responses has not been well elucidated. Furthermore, little is known about postprandial glucagon responses, which might also be influenced by meal composition.

Our objective was to investigate the effects of 3 standardized meals with different caloric and nutritional content given in randomized order to subjects with and without type 2 diabetes mellitus in terms of glucose, insulin, glucagon, and incretin postprandial response and to evaluate the potential roles of those meals for enhancing incretin function in patients with diabetes and healthy individuals.