Merck
  • Home
  • Search Results
  • Multi-Tissue Acceleration of the Mitochondrial Phosphoenolpyruvate Cycle Improves Whole-Body Metabolic Health.

Multi-Tissue Acceleration of the Mitochondrial Phosphoenolpyruvate Cycle Improves Whole-Body Metabolic Health.

Cell metabolism (2020-11-05)
Abudukadier Abulizi, Rebecca L Cardone, Romana Stark, Sophie L Lewandowski, Xiaojian Zhao, Joelle Hillion, Lingjun Ma, Raghav Sehgal, Tiago C Alves, Craig Thomas, Charles Kung, Bei Wang, Stephan Siebel, Zane B Andrews, Graeme F Mason, Jesse Rinehart, Matthew J Merrins, Richard G Kibbey
ABSTRACT

The mitochondrial GTP (mtGTP)-dependent phosphoenolpyruvate (PEP) cycle couples mitochondrial PEPCK (PCK2) to pyruvate kinase (PK) in the liver and pancreatic islets to regulate glucose homeostasis. Here, small molecule PK activators accelerated the PEP cycle to improve islet function, as well as metabolic homeostasis, in preclinical rodent models of diabetes. In contrast, treatment with a PK activator did not improve insulin secretion in pck2-/- mice. Unlike other clinical secretagogues, PK activation enhanced insulin secretion but also had higher insulin content and markers of differentiation. In addition to improving insulin secretion, acute PK activation short-circuited gluconeogenesis to reduce endogenous glucose production while accelerating red blood cell glucose turnover. Four-week delivery of a PK activator in vivo remodeled PK phosphorylation, reduced liver fat, and improved hepatic and peripheral insulin sensitivity in HFD-fed rats. These data provide a preclinical rationale for PK activation to accelerate the PEP cycle to improve metabolic homeostasis and insulin sensitivity.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
α-Glucosidase from Saccharomyces cerevisiae, Type I, lyophilized powder, ≥10 units/mg protein (using p-nitrophenyl α-D-glucoside as substrate.)
Sigma-Aldrich
Dulbecco′s Modified Eagle′s Medium, Without glucose, L-glutamine, phenol red, sodium pyruvate and sodium bicarbonate, powder, suitable for cell culture
Sigma-Aldrich
Dulbecco′s Modified Eagle′s Medium - high glucose, With 4500 mg/L glucose and L-glutamine, without sodium bicarbonate, powder, suitable for cell culture
Sigma-Aldrich
Dulbecco′s Modified Eagle′s Medium - low glucose, With 1000 mg/L glucose, and sodium bicarbonate, without L-glutamine and phenol red, liquid, sterile-filtered, suitable for cell culture
Roche
cOmplete, Mini, EDTA-free Protease Inhibitor Cocktail, Protease Inhibitor Cocktail Tablets provided in a glass vial, Tablets provided in a glass vial