The AMP-activated protein kinase (AMPK) is considered to be a promising target for the treatment of type 2 diabetes mellitus. It lowers blood glucose concentration by improving glucose utilization and reducing gluconeogenesis. In the present study we investigated its effects on beta cell stimulus-secretion coupling.

We found that the AMPK activator AICAR (500 mM throughout) augments glucose-induced insulin secretion of mouse islets in vitro in 10 mM glucose from 0.550.13 ng/(islet h) to 1.370.26 ng/(islet h) (n=10; P<0.05). By contrast, AICAR did not alter insulin secretion at a glucose concentration of 3 mM (n=10). Furthermore, AICAR increased the cytosolic Ca²⁺ concentration ([Ca²⁺]c) in the presence of 10 mM glucose by 6215% (n=9; P<0.01). At the threshold concentration of 6 mM glucose AICAR elicited a rise in [Ca²⁺]c in 5 out of 10 cells. We used the perforated patch configuration to examine whether these effects are caused by changes in KATP channel activity. In 15 mM glucose the KATP current in response to a 10 mV voltage step was virtually zero (holding potential -70 mV). Addition of a low concentration of diazoxide (20–40 mM) evoked a current of 5.80.7 pA. AICAR reduced this current to 4.40.9 pA (n=4; P<0.05). Under the same conditions in the current-clamp mode the membrane potential was -613 mV with diazoxide. AICAR depolarized the membrane to -572 mV (n=5; P<0.05). Likewise, AICAR enhanced glucose-induced (15 mM) electrical activity of beta cells (quantified as the fraction of plateau phase) from 495% to 759% (n=5; P<0.05). In conclusion, AICAR affects beta cell stimulus-secretion coupling. Probably, activation of the AMPK rises the cellular ATP content, which in turn decreases KATP channel activity leading to an increase in [Ca²⁺]c and finally in insulin secretion. Targeting AMPK may be beneficial in treatment of type 2 diabetes because additionally to its hepatic effects specific activation of AMPK interferes with beta cell stimulus-secretion coupling.