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Diabetologia

Published in:

01-01-2011 | Article

AMP-activated protein kinase regulates glucagon secretion from mouse pancreatic alpha cells

Authors: I. Leclerc, G. Sun, C. Morris, E. Fernandez-Millan, M. Nyirenda, G. A. Rutter

Published in: Diabetologia | Issue 1/2011

Abstract

Aim/hypothesis

AMP-activated protein kinase (AMPK), encoded by Prkaa genes, is emerging as a key regulator of overall energy homeostasis and the control of insulin secretion and action. We sought here to investigate the role of AMPK in controlling glucagon secretion from pancreatic islet alpha cells.

Methods

AMPK activity was modulated in vitro in clonal alphaTC1-9 cells and isolated mouse pancreatic islets using pharmacological agents and adenoviruses encoding constitutively active or dominant negative forms of AMPK. Glucagon secretion was measured during static incubation by radioimmunoassay. AMPK activity was assessed by both direct phosphotransfer assay and by western (immuno-)blotting of the phosphorylated AMPK α subunits and the downstream target acetyl-CoA carboxylase 1. Intracellular free [Ca²⁺] was measured using Fura-Red.

Results

Increasing glucose concentrations strongly inhibited AMPK activity in clonal pancreatic alpha cells. Forced increases in AMPK activity in alphaTC1-9 cells, achieved through the use of pharmacological agents including metformin, phenformin and A-769662, or via adenoviral transduction, resulted in stimulation of glucagon secretion at both low and high glucose concentrations, whereas AMPK inactivation inhibited both [Ca²⁺]_i increases and glucagon secretion at low glucose. Transduction of isolated mouse islets with an adenovirus encoding AMPK-CA under the control of the preproglucagon promoter increased glucagon secretion selectively at elevated glucose concentrations.

Conclusions/interpretation

AMPK is strongly regulated by glucose in pancreatic alpha cells, and increases in AMPK activity are sufficient and necessary for the stimulation of glucagon release in vitro. Modulation of AMPK activity in alpha cells may therefore provide a novel approach to controlling blood glucose concentrations.

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Title: AMP-activated protein kinase regulates glucagon secretion from mouse pancreatic alpha cells
Authors: I. Leclerc
G. Sun
C. Morris
E. Fernandez-Millan
M. Nyirenda
G. A. Rutter
Publication date: 01-01-2011
Publisher: Springer-Verlag
Published in: Diabetologia / Issue 1/2011
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-010-1929-z

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