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Ablation of AMP-activated protein kinase α1 and α2 from mouse pancreatic beta cells and RIP2.Cre neurons suppresses insulin release in vivo
Ist Teil von
Diabetologia, 2010-05, Vol.53 (5), p.924-936
Ort / Verlag
Berlin/Heidelberg: Springer-Verlag
Erscheinungsjahr
2010
Quelle
Alma/SFX Local Collection
Beschreibungen/Notizen
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 α1 and α2 subunits of AMPK were ablated selectively in mouse pancreatic beta cells and hypothalamic neurons by breeding
Ampkα1
[also known as
Prkaa1
]-knockout mice, bearing floxed
Ampkα2
[also known as
Prkaa2
] alleles (
Ampkα1
−/−
,α2
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
Ampkα1
−/−
,α2
fl/fl
expressing
Cre
recombinase and lacking both AMPKα 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, βAMPK 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.