The AMP-activated protein kinase alpha2 catalytic subunit controls whole-body insulin sensitivity

J Clin Invest. 2003 Jan;111(1):91-8. doi: 10.1172/JCI16567.

Abstract

AMP-activated protein kinase (AMPK) is viewed as a fuel sensor for glucose and lipid metabolism. To better understand the physiological role of AMPK, we generated a knockout mouse model in which the AMPKalpha2 catalytic subunit gene was inactivated. AMPKalpha2(-/-) mice presented high glucose levels in the fed period and during an oral glucose challenge associated with low insulin plasma levels. However, in isolated AMPKalpha2(-/-) pancreatic islets, glucose- and L-arginine-stimulated insulin secretion were not affected. AMPKalpha2(-/-) mice have reduced insulin-stimulated whole-body glucose utilization and muscle glycogen synthesis rates assessed in vivo by the hyperinsulinemic euglycemic clamp technique. Surprisingly, both parameters were not altered in mice expressing a dominant-negative mutant of AMPK in skeletal muscle. Furthermore, glucose transport was normal in incubated isolated AMPKalpha2(-/-) muscles. These data indicate that AMPKalpha2 in tissues other than skeletal muscles regulates insulin action. Concordantly, we found an increased daily urinary catecholamine excretion in AMPKalpha2(-/-) mice, suggesting altered function of the autonomic nervous system that could explain both the impaired insulin secretion and insulin sensitivity observed in vivo. Therefore, extramuscular AMPKalpha2 catalytic subunit is important for whole-body insulin action in vivo, probably through modulation of sympathetic nervous activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases
  • Alleles
  • Animals
  • Biological Transport
  • Blotting, Southern
  • Body Weight
  • Catalytic Domain
  • Dose-Response Relationship, Drug
  • Genotype
  • Glucose / pharmacology
  • Glucose Tolerance Test
  • Glycogen / metabolism
  • Insulin / metabolism*
  • Insulin / pharmacology
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multienzyme Complexes / chemistry*
  • Multienzyme Complexes / metabolism*
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / metabolism
  • Muscles / metabolism
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / chemistry*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Time Factors

Substances

  • Insulin
  • Multienzyme Complexes
  • Glycogen
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Glucose