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

Department of Hygiene, Dokkyo University School of Medicine, Tochigi 321-0293, Japan

Submitted 6 January 2003 ; accepted in final form 17 July 2003

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.

cytosolic Na⁺; cytosolic Ca²⁺; pancreatic islet cells; cyclic adenosine 5'-monophosphate; hamster

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