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LKB1 and AMPK differentially regulate pancreatic β-cell identity.

Kone M, Pullen TJ, Sun G, Ibberson M, Martinez-Sanchez A, Sayers S, Nguyen-Tu MS, Kantor C, Swisa A, Dor Y, Gorman T, Ferrer J, Thorens B, Reimann F, Gribble F, McGinty JA, Chen L, French PM, Birzele F, Hildebrandt T, Uphues I, Rutter GA - FASEB J. (2014)

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.

View Article: PubMed Central - PubMed

Affiliation: Section of Cell Biology and.

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Deletion of AMPK catalytic subunits with Ins1Cre alters islet β:α cell ratio. Pancreata from Ins1AMPKdKO mice and controls were fixed, sectioned, and subjected to immunocytochemical analysis for insulin and GCG as given in Materials and Methods. n = 3 mice/genotype in each case. *P < 0.05; paired Student's t test.
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Figure 3: Deletion of AMPK catalytic subunits with Ins1Cre alters islet β:α cell ratio. Pancreata from Ins1AMPKdKO mice and controls were fixed, sectioned, and subjected to immunocytochemical analysis for insulin and GCG as given in Materials and Methods. n = 3 mice/genotype in each case. *P < 0.05; paired Student's t test.

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).


LKB1 and AMPK differentially regulate pancreatic β-cell identity.

Kone M, Pullen TJ, Sun G, Ibberson M, Martinez-Sanchez A, Sayers S, Nguyen-Tu MS, Kantor C, Swisa A, Dor Y, Gorman T, Ferrer J, Thorens B, Reimann F, Gribble F, McGinty JA, Chen L, French PM, Birzele F, Hildebrandt T, Uphues I, Rutter GA - FASEB J. (2014)

Deletion of AMPK catalytic subunits with Ins1Cre alters islet β:α cell ratio. Pancreata from Ins1AMPKdKO mice and controls were fixed, sectioned, and subjected to immunocytochemical analysis for insulin and GCG as given in Materials and Methods. n = 3 mice/genotype in each case. *P < 0.05; paired Student's t test.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4377859&req=5

Figure 3: Deletion of AMPK catalytic subunits with Ins1Cre alters islet β:α cell ratio. Pancreata from Ins1AMPKdKO mice and controls were fixed, sectioned, and subjected to immunocytochemical analysis for insulin and GCG as given in Materials and Methods. n = 3 mice/genotype in each case. *P < 0.05; paired Student's t test.
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).

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.

View Article: PubMed Central - PubMed

Affiliation: Section of Cell Biology and.

Show MeSH
Related in: MedlinePlus