The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2018

Glucagon-like peptide-1 (GLP-1) - incretin or enterogastrone? (#164)

Michael Horowitz 1
  1. University of Adelaide, Discipline of Medicine, Adelaide, SA, Australia

The rate of gastric emptying, which exhibits a wide inter-, but low intra-individual, variation is a critical determinant of postprandial glycaemic excursions. Because nutrients empty from the stomach at 1-4 kcal/min, humans are predominantly in the ‘postprandial’, rather than ‘fasting’, state. In type 2 diabetes ‘fasting’ glucose has the greatest impact on glycated haemoglobin (HbA1c) in patients with poor glycaemic control (HbA1c >8.0%), while in better-controlled patients (HbA1c ≤8.0%) postprandial glucose predominates. Agonists of glucagon-like-peptide (GLP-1 RAs) which may be ‘short’ or ‘long-acting’ based on their plasma half-lives, are prescribed widely for the management of type 2 diabetes. Their use is empirical despite the recognition that the lowering of HbA1c is highly variable. GLP-1 RAs have been ‘sold’ on the basis of their ‘pancreatic’ actions (ie glucose-dependent insulin stimulation and glucagon suppression). This is despite the recognition that the GLP-1 antagonist, exendin 9-39, accelerates gastric emptying and when pharmacological doses of GLP-1 are given intravenously with a meal the reduction in glycaemia is associated with a decrease, rather than an increase, in plasma insulin.  The effect of exogenous GLP-1 to slow gastric emptying is, however, attenuated markedly with continuous, rather than acute, or intermittent, exposure. This ‘tachyphylaxis’ suggests that sustained stimulation of the GLP-1 receptor by ‘long-acting’ GLP-1 RAs will diminish, and potentially abolish, their effect to slow gastric emptying, which would account for them being less effective than ‘short-acting’ GLP-1 RAs for targeting postprandial glucose.  There is clearly a differential effect of ‘short’- and ‘long-acting’ GLP-1RAs on gastric emptying -  ‘short-acting’ GLP-1 RAs , exenatide BID and lixisenatide, delay gastric emptying in type 2 diabetes and the reduction in postprandial glucose can be predicted by the magnitude of this slowing,  which is greater in patients with normal, or rapid, gastric emptying . These insights provide a rationale for the personalised use of ‘short’- or ‘long-acting’ GLP-1 RAs in type 2 diabetes.