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.
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.
Authors: E D Targonsky; F Dai; V Koshkin; G T Karaman; A V Gyulkhandanyan; Y Zhang; C B Chan; M B Wheeler Journal: Diabetologia Date: 2006-05-13 Impact factor: 10.122
Authors: Debra D Canabal; Zhentao Song; Joseph G Potian; Annie Beuve; Joseph J McArdle; Vanessa H Routh Journal: Am J Physiol Regul Integr Comp Physiol Date: 2006-12-14 Impact factor: 3.619
Authors: Russell G Jones; David R Plas; Sara Kubek; Monica Buzzai; James Mu; Yang Xu; Morris J Birnbaum; Craig B Thompson Journal: Mol Cell Date: 2005-04-29 Impact factor: 17.970
Authors: Catherine E Gleason; Danhong Lu; Lee A Witters; Christopher B Newgard; Morris J Birnbaum Journal: J Biol Chem Date: 2007-02-07 Impact factor: 5.157
Authors: B Viollet; F Andreelli; S B Jørgensen; C Perrin; D Flamez; J Mu; J F P Wojtaszewski; F C Schuit; M Birnbaum; E Richter; R Burcelin; S Vaulont Journal: Biochem Soc Trans Date: 2003-02 Impact factor: 5.407
Authors: Gabriela da Silva Xavier; Isabelle Leclerc; Aniko Varadi; Takashi Tsuboi; S Kelly Moule; Guy A Rutter Journal: Biochem J Date: 2003-05-01 Impact factor: 3.857
Authors: Isabelle Leclerc; Wolfram W Woltersdorf; Gabriela da Silva Xavier; Rebecca L Rowe; Sarah E Cross; Greg S Korbutt; Ray V Rajotte; Richard Smith; Guy A Rutter Journal: Am J Physiol Endocrinol Metab Date: 2004-02-10 Impact factor: 4.310
Authors: Pär Steneberg; Emma Lindahl; Ulf Dahl; Emmelie Lidh; Jurate Straseviciene; Fredrik Backlund; Elisabet Kjellkvist; Eva Berggren; Ingela Lundberg; Ingela Bergqvist; Madelene Ericsson; Björn Eriksson; Kajsa Linde; Jacob Westman; Thomas Edlund; Helena Edlund Journal: JCI Insight Date: 2018-06-21
Authors: Gao Sun; Andrei I Tarasov; James A McGinty; Paul M French; Angela McDonald; Isabelle Leclerc; Guy A Rutter Journal: Am J Physiol Endocrinol Metab Date: 2010-03-30 Impact factor: 4.310