Uric Acid-Dependent Inhibition of AMP Kinase Induces Hepatic Glucose Production in Diabetes and Starvation: Evolutionary Implications of the Uricase Loss in Hominids

FASEB J. 2014 Aug;28(8):3339-50. doi: 10.1096/fj.13-243634. Epub 2014 Apr 22.

Abstract

Reduced AMP kinase (AMPK) activity has been shown to play a key deleterious role in increased hepatic gluconeogenesis in diabetes, but the mechanism whereby this occurs remains unclear. In this article, we document that another AMP-dependent enzyme, AMP deaminase (AMPD) is activated in the liver of diabetic mice, which parallels with a significant reduction in AMPK activity and a significant increase in intracellular glucose accumulation in human HepG2 cells. AMPD activation is induced by a reduction in intracellular phosphate levels, which is characteristic of insulin resistance and diabetic states. Increased gluconeogenesis is mediated by reduced TORC2 phosphorylation at Ser171 by AMPK in these cells, as well as by the up-regulation of the rate-limiting enzymes PEPCK and G6Pc. The mechanism whereby AMPD controls AMPK activation depends on the production of a specific AMP downstream metabolite through AMPD, uric acid. In this regard, humans have higher uric acid levels than most mammals due to a mutation in uricase, the enzyme involved in uric acid degradation in most mammals, that developed during a period of famine in Europe 1.5 × 10(7) yr ago. Here, working with resurrected ancestral uricases obtained from early hominids, we show that their expression on HepG2 cells is enough to blunt gluconeogenesis in parallel with an up-regulation of AMPK activity. These studies identify a key role AMPD and uric acid in mediating hepatic gluconeogenesis in the diabetic state, via a mechanism involving AMPK down-regulation and overexpression of PEPCK and G6Pc. The uricase mutation in the Miocene likely provided a survival advantage to help maintain glucose levels under conditions of near starvation, but today likely has a role in the pathogenesis of diabetes.

Keywords: gluconeogenesis; insulin; phosphate; urate.

Publication types

  • Historical Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP Deaminase / antagonists & inhibitors
  • AMP Deaminase / genetics
  • AMP Deaminase / physiology*
  • AMP-Activated Protein Kinases / physiology
  • Animals
  • Diabetes Mellitus, Experimental / metabolism
  • Europe
  • Gene Expression Regulation, Enzymologic
  • Gluconeogenesis / drug effects
  • Gluconeogenesis / physiology*
  • Glucose-6-Phosphatase / biosynthesis
  • Hep G2 Cells
  • History, Ancient
  • Hominidae / physiology
  • Humans
  • Insulin / metabolism
  • Insulin Resistance
  • Insulin Secretion
  • Liver / enzymology
  • Liver / metabolism*
  • Male
  • Mechanistic Target of Rapamycin Complex 2
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • Multiprotein Complexes / physiology
  • Phosphates / metabolism
  • Phosphates / pharmacology
  • Phosphoenolpyruvate Carboxykinase (ATP) / biosynthesis
  • Recombinant Fusion Proteins / metabolism
  • Selection, Genetic
  • Specific Pathogen-Free Organisms
  • Starvation / history
  • Starvation / physiopathology*
  • TOR Serine-Threonine Kinases / physiology
  • Transduction, Genetic
  • Urate Oxidase / genetics
  • Urate Oxidase / history
  • Urate Oxidase / metabolism
  • Uric Acid / metabolism*
  • Uric Acid / pharmacology

Substances

  • Insulin
  • Multiprotein Complexes
  • Phosphates
  • Recombinant Fusion Proteins
  • Uric Acid
  • Urate Oxidase
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 2
  • AMP-Activated Protein Kinases
  • Glucose-6-Phosphatase
  • AMP Deaminase
  • AMPD2 protein, human
  • AMPD2 protein, mouse
  • Phosphoenolpyruvate Carboxykinase (ATP)