AMP-activated protein kinase (AMPK) is an important cellular energy sensor in regulation of metabolic activity. AMPK activation improves glucose homeostasis by increasing muscle glucose uptake and reducing hepatic glucose production. Although the effects on glucose-stimulated insulin secretion in the pancreatic β cells are still controversial. Our aim was to investigate the regulation of insulin secretion in pancreatic β cells using specific pharmacological AMPK activators and in mouse models of constitutive activation. We used a chronic global AMPK (γ1D316A) and a pancreatic β cell specific (β-D316A) activation mouse model that express the AMPK γamma1 isoform with a D316A mutation under the control of β-actin and ins1 promoter respectively. We tested how chronic AMPK activation impacted insulin secretion on C57BL6 mouse isolated islets using direct activators PF-06409577 (β1 isoform-selective) and RA089 (binds both β1 and β2 isoforms). Global activation of AMPK reduced insulin secretion from islets isolated from γ1D316A mice on chow and high-fat diet (2.4-fold, p<0.05 and 1.9-fold p<0.01, respectively). Dual AMPK activation of β1 and β2 (RA089) on control mouse islets enhanced in a dose-response manner insulin secretion in response to high glucose (17mM) and KCl after 30 minutes of incubation (1.7-fold p<0.005 and 1.7-fold p<0.005, respectively). The same effects were observed by activating AMPK β1 isoform with PF-06409577, increasing insulin release in response to high glucose and KCl (2-fold, p<0.005 and 1.7-fold, p<0.05). These findings suggest that the effects of AMPK on insulin secretion depends on its mode of activation. Acute pharmacological activation targetting β1 and/or β2 subunit increased insulin secretion whereas chronic global activation in mice reduced insulin release. Investigating our second model of chronic activation β-D316A and further studies of our models will help us decipher the role of AMPK in the pancreas.


M. Nguyen-Tu: None. J.P. Harris: None. A. Martinez-Sanchez: None. I. Leclerc: None. G.A. Rutter: Consultant; Self; Sun Pharma.

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