Role for AMP-activated protein kinase in glucose-stimulated insulin secretion and preproinsulin gene expression

摘要: AMP-activated protein kinase (AMPK) has recently been implicated in the control of preproinsulin gene expression pancreatic islet beta-cells [da Silva Xavier, Leclerc, Salt, Doiron, Hardie, Kahn and Rutter (2000) Proc. Natl. Acad. Sci. U.S.A. 97, 4023-4028]. Using pharmacological molecular strategies to regulate AMPK activity rat islets clonal MIN6 beta-cells, we show here that effects are exerted largely upstream insulin release. Thus forced increases achieved pharmacologically with 5-amino-4-imidazolecarboxamide riboside (AICAR), or by adenoviral overexpression a truncated, constitutively active form enzyme (AMPK alpha 1.T(172)D), blocked glucose-stimulated secretion. In cells, activation suppressed glucose metabolism, as assessed changes total, cytosolic mitochondrial [ATP] NAD(P)H, reduced intracellular [Ca(2+)] caused either tolbutamide. By contrast, inactivation dominant-negative mutated catalytic site 1.D(157)A) did not affect [ATP], NAD(P)H [Ca(2+)], but led unregulated release insulin. These results indicate inhibition is essential for secretion sugar, may contribute transcriptional stimulation gene. Modulation beta-cell thus represent novel therapeutic strategy treatment type 2 diabetes mellitus.