Glucagon-like peptide-1 induces a cAMP-dependent increase of [Na+](i) associated with insulin secretion in pancreatic beta-cells

Glucagon-like peptide-1 (GLP-1) elevates the intracellular free calcium concentration ([Ca2+](i)) and insulin secretion in a Na+-dependent manner. To investigate a possible role of Na ion in the action of GLP-1 on pancreatic islet cells, we measured the glucose- and GLP-1-induced intracellular Na+ concentration ([Na+](i)), [Ca2+](i), and insulin secretion in hamster islet cells in various concentrations of Na+. The [Na+](i) and [Ca2+](i) were monitored in islet cells loaded with sodium-binding benzofuran isophthalate and fura 2, respectively. In the presence of 135 mM Na+ and 8 mM glucose, GLP-1 (10 nM) strongly increased the [Na+](i), [Ca2+](i), and insulin secretion. In the presence of 13.5 mM Na+, both glucose and GLP-1 increased neither the [Na+](i) nor the [Ca2+](i). In a Na+-free medium, GLP-1 and glucose did not increase the [Na+](i). SQ-22536, an inhibitor of adenylate cyclase, and H-89, an inhibitor of PKA, incompletely inhibited the response. In the presence of both 8 mM glucose and H-89, 8-pCPT-2'-O-Me-cAMP, a PKA-independent cAMP analog, increased the insulin secretion and the [Na+](i). Therefore, we conclude that GLP-1 increases the cAMP level via activation of adenylate cyclase, which augments the membrane Na+ permeability through PKA-dependent and PKA-independent mechanisms, thereby increasing the [Ca2+](i) and promoting insulin secretion from hamster islet cells.