Introduction: Glucagon-like peptide-1 (GLP-1) and its mimetics have been shown to increase heart rate (HR) in both health and type 2 diabetes (T2DM). However, it remains unclear whether this effect is attributable to GLP-1 receptor signaling and, if so, whether endogenous GLP-1 modulates cardiovascular function through this pathway, particularly during the postprandial phase. Given that postprandial GLP-1 secretion is determined in part by the rate of gastric emptying, which varies substantially between individuals and is also modulated by GLP-1, we evaluated the HR and blood pressure (BP) responses to a standardised jejunal glucose infusion, with and without the GLP-1 receptor antagonist, exendin(9-39), in patients with T2DM.
Methods: 10 T2DM patients were each studied on two days, separated by ≥7 days, in a double-blind, randomised fashion. On each day, a nasal-jejunal catheter was positioned. An intravenous exendin(9-39) (600pmol/kg/min) or saline was commenced 60min before, and maintained during, a 120-min intrajejunal glucose infusion (2kcal/min). HR and BP were measured every 5min, using an automated device. On one day, autonomic function was assessed using standardised cardiovascular reflex tests.
Results: None had cardiovascular autonomic dysfunction. Prior to jejunal glucose infusion, neither HR nor BP differed between the two study days. During jejunal glucose infusion, HR increased on both days (time effect: P<0.001), and the magnitude of increase was less with exendin(9-39) compared with saline (treatment effect: P=0.009). Systolic and diastolic BP both decreased slightly (P<0.001 and =0.002 respectively) during jejunal glucose infusion, without any difference between the two study days.
Conclusion: In relatively well controlled, normotensive patients with T2DM, without autonomic dysfunction, blockade of GLP-1 receptors by exendin(9-39) attenuates the HR response to small intestinal glucose infusion. These observations are indicative of a physiological role of GLP-1 receptor signalling in the regulation of postprandial cardiovascular function in T2DM.