Activation of the AMP-activated protein kinase enhances glucose-stimulated insulin secretion in mouse beta-cells

作者：Duefer Martina; Noack Katja; Krippeit Drews Peter; Drews Gisela^*

来源：Islets, 2010, 2(3): 156-163.

DOI：10.4161/isl.2.3.11412

• AICAR
• metformin
• AMPK
• [Ca2+](c)
• mitochondrial membrane potential
• insulin secretion
• K-ATP channel
• electrical activity

The AMP-activated protein kinase (AMPK) is one of the key players in cellular energy regulation adapting cellular demands to nutritional and metabolic variations. Oral antidiabetic drugs like metformin and glitazones (thiazolidinediones) are known to stimulate this enzyme. Besides their established action on peripheral organs including liver and muscles, it has been claimed that these drugs may affect beta-cell function. However, it is still a matter of debate whether pharmacological AMPK stimulation increases or decreases insulin secretion. To study this point and to reveal mechanisms underlying changes in insulin secretion we used the specific AMPK activator AICA R and investigated its effects on stimulus-secretion coupling. Membrane potential and currents were measured by the patch-clamp technique, [Ca2+](c), mitochondrial membrane potential, and NAD(P) H by fluorescence techniques and insulin secretion by a radioimmunoassay. AICA R enhanced glucose-stimulated insulin release, an effect that can be attributed to the augmentation of electrical activity and [Ca2+](c) resulting from an AICAR-evoked inhibition of the K-ATP current. This latter effect was not due to a direct interaction of AICAR with the K-ATP channels but was dependent on cell metabolism. AICA R did not affect mitochondrial membrane potential or NAD(P) H autofluorescence. Metformin mimicked the action of AICA R on electrical activity, [Ca2+](c) and K-ATP current. However, compared to AICA R the effects were less pronounced and not sufficient to stimulate insulin secretion. In conclusion, activation of AMPK augments nutrient-induced insulin secretion. Thus, targeting AMPK of beta-cells may be an appropriate strategy for the treatment of disturbed glucose homeostasis.

• 出版日期2010-6