Effect of exendin-4 on glucose homeostasis in Suncus murinus (house musk shrew)

Abstract

Glucagon-like peptide-1 (7-36) amide (GLP-1) is regarded as an incretin hormone in the periphery, and a neurotransmitter in the brain. GLP-1 neurons and GLP-1 receptor binding sites are densely expressed in the hypothalamus, which is known to be heavily involved in mechanisms controlling food intake and energy homeostasis. In the present studies, therefore, we examined the effect of central administration of a GLP-1 receptor agonist, exendin-4, on glucose homeostasis. Female Suncus murinus were fasted 12 hour before experimentation. To elevate blood glucose levels, anaesthetized animals were administered glucose (5.55 mmol/kg, i.p.). 10 min later, they received an intracerebroventricular infusion of exendin-4 (0.3 – 3 nmol), or an intracerebral ventromedial (iVMH) or dorsomedial (iDMH) microinfusion of exendin-4 (3 – 30 pmol). In some other experiments, the GLP-1 receptor antagonist, exendin (9-39) amide (10 nmol, i.c.v.), was administered 10 min prior to exendin-4 (3 nmol, i.c.v.). Blood glucose levels were measured for 1 hour, sampling at 5-20 min intervals. Both the intracerebroventricular infusion and iVMH microinfusion of exendin-4 caused a dose-dependent reduction in bloodglucose levels (P<0.01). Conversely, iDMH microinfusion of exendin-4 had no effect (P>0.05). Exendin (9-39) amide alone failed to modify blood glucose levels but it antagonized the glucose-lowering effect of exendin-4 (P<0.05). In conclusion, centrally infused exendin-4 probably reduces blood glucose in S. murinus via GLP-1 receptors. The glucose-lowering effect of exendin-4 involves the ventromedial hypothalamus.