2020
DOI: 10.1101/2020.02.13.947630
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Pharmacologic activation of the mitochondrial phosphoenolpyruvate cycle enhances islet function in vivo

Abstract: Highlights:• Loss of mitochondrial phosphoenolpyruvate (PEP) impairs insulin release in vivo.• Pyruvate kinase (PK) activators stimulate beta-cells in preclinical diabetes models.• PEP cycling in vivo depends on PK and mitochondrial PEPCK (PCK2) for insulin release. • Acute and 3-week oral PK activator amplifies insulin release during hyperglycemia. eTOC Blurb:Abudukadier et al. show that small molecule pyruvate kinase activation in vivo and in vitro increases insulin secretion in rodent and human models of di… Show more

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Cited by 5 publications
(11 citation statements)
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“…For SAME to be responsive to PKa, it must enhance the supply of PEP. This fits with the observation, shown in the companion paper, that SAME requires PCK2 to increase insulin secretion (Abulizi et al, 2020), and confirms in human islets that, like glycolysis, mitochondrial anaplerosis-cataplerosis can provide a source of PEP to PK that, in turn, is responsive to PK activation.…”
Section: The Gk-independent Actions Of Pk Are Powered By Mitochondrial Anaplerosissupporting
confidence: 90%
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“…For SAME to be responsive to PKa, it must enhance the supply of PEP. This fits with the observation, shown in the companion paper, that SAME requires PCK2 to increase insulin secretion (Abulizi et al, 2020), and confirms in human islets that, like glycolysis, mitochondrial anaplerosis-cataplerosis can provide a source of PEP to PK that, in turn, is responsive to PK activation.…”
Section: The Gk-independent Actions Of Pk Are Powered By Mitochondrial Anaplerosissupporting
confidence: 90%
“…Thus, a key finding here is that PK underlies a separate mode of β-cell glucosesensing downstream of GK that may provide a mechanism dependent upon anaplerosis. While targeting OxPhos in β-cells has not been successful therapeutically, preclinical data suggest the anaplerotic mechanism may be of potential benefit (Abulizi et al, 2020).…”
Section: Discussionmentioning
confidence: 99%
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“…For example, small molecule activators of PK potently amplify GSIS by switching mitochondria from oxidative phosphorylation to anaplerotic phosphoenolpyruvate biosynthesis [11]. Moreover, PK activation ameliorates GSIS in islets obtained from animals and humans manifesting insulin resistance and type 2 diabetes [12].…”
Section: Discussionmentioning
confidence: 99%
“…Recent studies demonstrate that activation of PK promotes insulin section during glucose stimulation in INS-1 -cells and human islets [11]. Furthermore, PK activators can enhance insulin secretion from normal, high-fat diet fed, or Zucker diabetic fatty rats, and diabetic humans [12] indicating the significance of PK in regulating -cell secretory function.…”
Section: Introductionmentioning
confidence: 99%