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Pharmacologic activation of the mitochondrial phosphoenolpyruvate cycle enhances islet function in vivo
- Publication Year :
- 2020
- Publisher :
- Cold Spring Harbor Laboratory, 2020.
-
Abstract
- SummaryThe mitochondrial GTP (mtGTP)-dependent phosphoenolpyruvate (PEP) cycle is an anaplerotic-cataplerotic mitochondrial shuttle utilizing mitochondrial PEPCK (PCK2) and pyruvate kinase (PK). PEP cycling stimulates insulin secretion via OxPhos-independent lowering of ADP by PK. We assess in vivo whether islet PCK2 is necessary for glucose sensing and if speeding the PEP cycle via pharmacological PK activators amplifies insulin secretion. Pck2-/- mice had severely impaired insulin secretion during islet perifusion, oral glucose tolerance tests and hyperglycemic clamps. Acute and chronic pharmacologic PK activator therapy improved islet insulin secretion from normal, high-fat diet (HFD) fed, or Zucker diabetic fatty (ZDF) rats, and glucolipotoxic or diabetic humans. A similar improvement in insulin secretion was observed in regular chow and HFD rats in vivo. Insulin secretion and cytosolic Ca2+ during PK activation were dependent on PCK2. These data provide a preclinical rationale for strategies, such as PK activation, that target the PEP cycle to improve glucose homeostasis.HighlightsLoss 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 BlurbAbudukadier et al. show that small molecule pyruvate kinase activation in vivo and in vitro increases insulin secretion in rodent and human models of diabetes. The phosphoenolpyruvate (PEP) cycling mechanism and its amplification are dependent on mitochondrial PEPCK (PCK2).
- Subjects :
- 0303 health sciences
geography
medicine.medical_specialty
Pyruvate dehydrogenase kinase
geography.geographical_feature_category
Chemistry
Activator (genetics)
030209 endocrinology & metabolism
Islet
03 medical and health sciences
0302 clinical medicine
Endocrinology
In vivo
PCK2
Internal medicine
medicine
Glucose homeostasis
Phosphoenolpyruvate carboxykinase
Pyruvate kinase
030304 developmental biology
Subjects
Details
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....f663f482e534797e533a3ccb6a183f9c