Central nervous system effects of glucagon-like peptide 1

At a symposium on nonislet effects of glucagon-like peptide 1 (GLP-1) at the American Diabetes Association (ADA) Scientific Sessions, Remy Burcelin (Toulouse, France) reviewed the controversy as to the extent of GLP-1 action mediated in the central nervous system versus peripheral effects, advancing the concept that a central effect of GLP-1 may be to induce insulin secretion, but showing studies suggesting that central administration of GLP-1 decreases muscle glycogen—an effect blocked with a GLP-1 receptor antagonist (1). If the central effect of GLP-1 is to increase insulin secretion and to reduce peripheral glucose utilization, it would be expected to increase hepatic glycogen stores, which could be useful in preparation for situations of decreased nutrient availability. The nature of the signal sent to muscle may be understood by recognizing that muscle glucose utilization is controlled by muscle blood flow (2). In his group's study of muscle blood flow, central GLP-1 administration blocked the increase in muscle blood flow seen with insulin and glucose. Mice not expressing the GLP-1 receptor do not show this inhibition of vasodilation and therefore have greater insulin sensitivity with administration of GLP-1. Addressing central GLP-1 signaling mechanisms, Burcelin noted that hypothalamic protein kinase C (PKC) is increased with central GLP-1, whereas the central administration of the PKC inhibitor calphostin C prevented the inhibitory effect of GLP-1 on muscle glucose uptake. In contrast, activation of brain PKC by phorbol-12-myristate, 13-acetate infusion induced insulin resistance and inhibited vasodilation. Although there are more than 12 PKCs, anti-PKC ε appears to block this GLP-1 effect. High-fat diet–induced diabetes is associated with insulin resistance (not seen in …