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

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

Research output: Contribution to journalArticleResearchpeer-review

7 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)751-766
Number of pages16
JournalCell Metabolism
Volume32
Issue number5
DOIs
Publication statusPublished - 3 Nov 2020

Keywords

  • anaplerosis
  • cataplerosis
  • fatty liver
  • human islets
  • insulin resistance
  • insulin secretion
  • mitochondrial GTP
  • mitochondrial PEPCK
  • phosphoenolpyruvate cycle
  • pyruvate kinase

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