LKB1 and AMPK differentially regulate pancreatic β-cell identity.
Bottom Line: These changes were partially recapitulated by the loss of AMPK, which also up-regulated β-cell "disallowed" genes (Slc16a1, Ldha, Mgst1, Pdgfra) 1.8- to 3.4-fold (E < 0.01).Correspondingly, targeted promoters were enriched for neuronal (Zfp206; P = 1.3 × 10(-33)) and hypoxia-regulated (HIF1; P = 2.5 × 10(-16)) transcription factors.In summary, LKB1 and AMPK, through only partly overlapping mechanisms, maintain β-cell identity by suppressing alternate pathways leading to neuronal, hepatic, and other characteristics.
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Mentions: Ins1AMPKdKO mice displayed a more minor phenotype compared to that observed in the RIP2AMPKdKO model (23, 24). Thus, glucose tolerance was only slightly impaired in Ins1AMPKdKO animals (Fig. 1D), with blood glucose significantly elevated only at 30 min during intraperitoneal glucose tests (IPGTTs). Moreover, whereas insulin sensitivity was markedly improved in RIP2AMPKdKO mice vs. heterozygous controls (23), no alterations in this parameter were seen in Ins1AMPKdKO animals (Fig. 1E). Finally, whereas the first phase of glucose-stimulated insulin release in vivo was completely abolished in RIP2AMPKdKO mice (23), release of the hormone was diminished by only ∼50% in Ins1AMPKdKO mice vs. controls (Fig. 1F). No evident changes in β-cell mass were observed in Ins1AMPKdKO mice vs. littermate controls (pancreatic β-cell area: 0.31±0.06 vs. 0.39±0.5%, respectively, n=5–6 mice/genotype), though the ratio of β:α cells was significantly reduced in these mice (Fig. 3). In common with RIP2AMPKdKO mice (23), a dramatic improvement in glucose-stimulated insulin secretion was observed in vitro with islets isolated from Ins1AMPKdKO mice (Supplemental Fig. S1B).