Role of Central GLP1 in Autonomic Control

Diabetes mellitus is an expanding public health problem and current strategies for the treatment of Type 2 diabetes mellitus are not optimally effective, and even multiple drug combinations often fail to normalize glycemia in a sustained manner in the majority of treated subjects. Hence, there remains intense interest in new therapies that safely and effectively lower blood glucose in diabetic subjects. The naturally occurring regulatory peptide glucagon-like peptide 1 (GLP-1) exhibits multiple desirable actions for a potential anti-diabetic agent, and protease-resistant long-acting GLP-1 analogs are currently in clinical trials for the treatment of Type 2 diabetes. GLP-1 is also an endogenous neuropeptide that exerts actions in the central nervous system (CNS) that are less well understood.

We have recently investigated the interactions of both peripheral and central GLP-1 and CNS pathways that regulate autonomic and neuroendocrine function. Our experiments suggest that the CNS actions of GLP-1 are independent and distinct from the peripheral incretin-like actions of GLP-1 that lower blood glucose. We have found that both central and peripheral injections of GLP-1 receptor (GLP-1R) agonists increase blood pressure and heart rate, and also activate neurons in the brain known to regulate autonomic function

Given the increasing likelihood that one or more GLP-1R analogues will be used to treat diabetic patients, understanding both central and peripheral actions of GLP-1 is increasingly relevant for predicting the biological consequences of sustained GLP-1 receptor activation. Our findings suggest that peripherally administered GLP-1R agonists activate the central nervous system.

Our results suggest that the central GLP-1 system is a previously unrecognized regulator of the sympathetic outflow. Moreover, our results suggest that the CNS actions of GLP-1 are independent from peripheral actions of GLP-1 to lower blood glucose.