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Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP

Russell A Miller1, Qingwei Chu, Jianxin Xie

  • 1Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Nature
|January 8, 2013
PubMed

Insights

Metformin, a key type-2 diabetes drug, reduces liver glucose production by blocking the action of glucagon. This occurs through AMP accumulation, which inhibits cyclic AMP and protein kinase A, ultimately lowering blood sugar.

Area of Science:

  • Biochemistry
  • Endocrinology
  • Pharmacology

Background:

  • Hepatic glucose production is vital for brain function during fasting.
  • Insulin resistance impairs the suppression of liver glucose output, leading to hyperglycemia in type-2 diabetes.
  • Biguanides, like metformin, are established therapeutics for reducing glucose production, but their mechanism is unclear.

Purpose of the Study:

  • To elucidate the mechanism of action of metformin in reducing hepatic glucose production.
  • To investigate the role of glucagon signaling in metformin's glucose-lowering effects.
  • To challenge the prevailing AMP-activated protein kinase (AMPK) activation hypothesis.

Main Methods:

  • Experiments were conducted using mouse hepatocytes.
  • Metformin's effects on cellular metabolites, including AMP and cyclic AMP (cAMP), were measured.
  • Protein kinase A (PKA) activity and its downstream phosphorylation targets were assessed.
  • Glucagon-stimulated glucose output was measured in the presence of metformin.

Main Results:

  • Metformin induced the accumulation of AMP and related nucleotides in hepatocytes.
  • This accumulation inhibited adenylate cyclase, leading to reduced cAMP levels and PKA activity.
  • Metformin abrogated the phosphorylation of PKA targets and blocked glucagon-dependent glucose production.
  • These effects were observed independently of AMPK activation.

Conclusions:

  • Metformin acts by antagonizing glucagon signaling, not primarily through AMPK activation.
  • The accumulation of AMP and subsequent inhibition of the cAMP/PKA pathway mediate metformin's glucose-lowering effect.
  • This provides a novel mechanism for metformin and suggests new therapeutic targets for diabetes.

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