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AMP-activated protein kinase: a new beta-cell glucose sensor?: Regulation by amino acids and calcium ions

Isabelle Leclerc1, Guy A Rutter

  • 1Henry Wellcome Laboratories for Integrated Cell Signalling and Department of Biochemistry, School of Medical Sciences, University of Bristol, University Walk, BS8 1TD Bristol, UK.

Diabetes
|November 25, 2004
PubMed

Insights

AMP-activated protein kinase (AMPK) activity in pancreatic beta-cells is modulated by nutrients and ions, influencing insulin secretion. This study reveals how amino acids and calcium impact AMPK, offering insights into diabetes treatment.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Metabolic Regulation

Background:

  • AMP-activated protein kinase (AMPK) is a key metabolic regulator, primarily studied in skeletal muscle and liver for type 2 diabetes treatment.
  • Recent findings suggest AMPK activity changes in pancreatic islet beta-cells during elevated glucose, potentially linking it to insulin secretion.

Purpose of the Study:

  • To investigate the role of AMPK activity in pancreatic beta-cells in response to various secretagogues.
  • To explore the mechanisms by which nutrients and ions modulate AMPK activity and influence insulin secretion.

Main Methods:

  • Experiments using MIN6 beta-cells to assess AMPK activity.
  • Stimulation with glucose, amino acids (arginine, leucine, glutamine, glutamate), KCl, isobutylmethylxanthine, and forskolin.
  • Measurement of intracellular Ca2+ and cAMP levels, ATP/AMP ratio, and AMPK activity.

Main Results:

  • Metabolizable amino acids (arginine, leucine, glutamine, glutamate) decreased AMPK activity in a dose-dependent manner, correlating with insulin release.
  • Glucose also decreased AMPK activity, similar to amino acids.
  • Increased intracellular Ca2+ (via KCl depolarization) activated AMPK, independent of cAMP levels.
  • LKB1 and calmodulin kinase 1 kinase were implicated in AMPK regulation by amino acids and Ca2+, respectively.

Conclusions:

  • Metabolizable amino acids regulate beta-cell AMPK activity through changes in the ATP/AMP ratio and LKB1-mediated phosphorylation.
  • Intracellular Ca2+ may activate AMPK via calmodulin kinase 1 kinase, potentially serving as a feedback mechanism to limit excessive insulin secretion.

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