Understanding the Relationship of Incretin Hormones, Gastric Emptying and the Glucoregulatory Responses to Nutrients

Abstract

Gastric emptying is a major determinant of postprandial glycaemia and varies substantially between individuals. There is a bi-directional relationship between gastric emptying and postprandial glycaemic excursions i.e. relatively more rapid gastric emptying increases postprandial glucose, but acute hyperglycaemia also slows gastric emptying. Glucose homeostasis is also mediated by the ‘incretin’ hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The release of the incretin hormones is stimulated by the arrival of nutrients in the small intestines and GLP-1, in particular, has a substantial effect to slow gastric emptying. This thesis provides novel insights into the relationships between gastric emptying, incretin hormones and glucose homeostasis. In a study of 43 individuals with type 2 diabetes (T2D), gastric emptying was evaluated using the ‘gold standard’ technique of scintigraphy following a 75 g oral glucose tolerance test. I showed that in T2D, gastric emptying correlates with the plasma glucose levels at 30, 60 and 120 minutes but not 180 minutes. In a second study of 35 individuals with an intensive care unit admission complicated by stress hyperglycaemia, 3 months after discharge, gastric emptying was evaluated using the stable isotope breath test (a method of measurement of comparable sensitivity to scintigraphy) and found to correlate to plasma glucose at 30 and 60 minutes, but not 120 minutes. Furthermore, this cohort was found to have a high 1-hour plasma glucose which has been associated with an increased risk of progression to T2D and earlier mortality. This finding highlights the need for close follow-up of survivors of critical illness who had stress hyperglycaemia for the development of T2D. In a study of 36 adults above 65 years of age without a history of diabetes, a biphasic pattern of the glucose response curve in an oral glucose tolerance test was found to correlate with GLP-1, but not GIP or gastric emptying (the latter measured by stable isotope breath test). This has provided insights into how the glucose response curve can be a marker of dysglycaemia. Liquids with greater nutrient density are known to be emptied more slowly. Therefore, in a study of 8 healthy adults, I evaluated the effect of different types of beer (low carbohydrate, low alcohol and full strength) on gastric emptying and found that there was no substantial effect. Bariatric surgery is known to be associated with markedly accelerated gastric emptying, particularly of liquids and a substantially greater GLP-1 response. To investigate if distension contributes to the GLP-1 response, I studied 8 healthy adults using the ‘gold standard’ barostat technique and I found that gastric distension was not associated with an increase in plasma GLP-1. In a metanalysis of 12 studies that have evaluated the GLP-1 response in post-bariatric surgery (Roux-en-Y gastric bypass) hypoglycaemia, I found that this response is greater in individuals that have experienced reactive hypoglycaemia, supporting GLP-1 antagonism as a rational therapeutic approach for this condition. These studies have advanced our knowledge in gastric emptying and incretin physiology with the high potential to change current clinical practice and inform future studies.