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. 2010 May;53(5):924-36.
doi: 10.1007/s00125-010-1692-1. Epub 2010 Mar 11.

Ablation of AMP-activated protein kinase alpha1 and alpha2 from mouse pancreatic beta cells and RIP2.Cre neurons suppresses insulin release in vivo

G Sun  1 , A I Tarasov, J McGinty, A McDonald, G da Silva Xavier, T Gorman, A Marley, P M French, H Parker, F Gribble, F Reimann, O Prendiville, R Carzaniga, B Viollet, I Leclerc, G A Rutter
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Free PMC article

Ablation of AMP-activated protein kinase alpha1 and alpha2 from mouse pancreatic beta cells and RIP2.Cre neurons suppresses insulin release in vivo

G Sun et al. Diabetologia. 2010 May.
Free PMC article

Abstract

Aims/hypothesis: AMP-activated protein kinase (AMPK) is an evolutionarily conserved enzyme and a target of glucose-lowering agents, including metformin. However, the precise role or roles of the enzyme in controlling insulin secretion remain uncertain.

Methods: The catalytic alpha1 and alpha2 subunits of AMPK were ablated selectively in mouse pancreatic beta cells and hypothalamic neurons by breeding Ampkalpha1 [also known as Prkaa1]-knockout mice, bearing floxed Ampkalpha2 [also known as Prkaa2] alleles (Ampkalpha1 ( -/- ),alpha2( fl/fl ),), with mice expressing Cre recombinase under the rat insulin promoter (RIP2). RIP2 was used to express constitutively activated AMPK selectively in beta cells in transgenic mice. Food intake, body weight and urinary catecholamines were measured using metabolic cages. Glucose and insulin tolerance were determined after intraperitoneal injection. Beta cell mass and morphology were analysed by optical projection tomography and confocal immunofluorescence microscopy, respectively. Granule docking, insulin secretion, membrane potential and intracellular free Ca(2+) were measured with standard techniques.

Results: Trigenic Ampkalpha1 ( -/- ),alpha2( fl/fl ) expressing Cre recombinase and lacking both AMPKalpha subunits in the beta cell, displayed normal body weight and increased insulin sensitivity, but were profoundly insulin-deficient. Secreted catecholamine levels were unchanged. Total beta cell mass was unaltered, while mean islet and beta cell volume were reduced. AMPK-deficient beta cells displayed normal glucose-induced changes in membrane potential and intracellular free Ca(2+), while granule docking and insulin secretion were enhanced. Conversely, betaAMPK transgenic mice were glucose-intolerant and displayed defective insulin secretion.

Conclusions/interpretation: Inhibition of AMPK activity within the beta cell is necessary, but not sufficient for stimulation of insulin secretion by glucose to occur. AMPK activation in extrapancreatic RIP2.Cre-expressing cells might also influence insulin secretion in vivo.

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References

    1. Shaw RJ, Lamia KA, Vasquez D, et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 2005;310:1642–1646. - PMC - PubMed
    1. Towler MC, Hardie DG. AMP-activated protein kinase in metabolic control and insulin signaling. Circ.Res. 2007;100:328–341. - PubMed
    1. KurthKraczek EJ, Hirshman MF, Goodyear LJ, Winder WW. 5 ′ AMP-activated protein kinase activation causes GLUT4 translocation in skeletal muscle. Diabetes. 1999;48:1667–1671. - PubMed
    1. Salt IP, Johnson G, Ashcroft SJ, Hardie DG. AMP-activated protein kinase is activated by low glucose in cell lines derived from pancreatic beta cells, and may regulate insulin release. Biochem J. 1998;335:533–539. - PMC - PubMed
    1. daSilvaXavier G, Leclerc I, Salt IP, et al. Role of AMP-activated protein kinase in the regulation by glucose of islet beta-cell gene expression. Proc Natl Acad Sci U S A. 2000;97:4023–4028. - PMC - PubMed

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