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alpha2A-adrenergic receptors in the genetics, pathogenesis, and treatment of type 2 diabetes

Stephen B Liggett1

  • 1University of Maryland School of Medicine, Baltimore, MD 21201, USA. sligg001@umaryland.edu.

Science Translational Medicine
|April 8, 2010
PubMed

Insights

Increased alpha(2A)-adrenergic receptors (alpha(2A)ARs) in pancreatic beta cells impair insulin secretion, a key factor in type 2 diabetes. Genetic links to ADRA2A gene expression and type 2 diabetes suggest a new therapeutic target.

Area of Science:

  • Endocrinology
  • Genetics
  • Metabolic Diseases

Background:

  • Insulin secretion from pancreatic islets is regulated by alpha(2A)-adrenergic receptors (alpha(2A)ARs).
  • Activation of alpha(2A)ARs inhibits insulin release, potentially contributing to type 2 diabetes pathogenesis.
  • Elevated expression of alpha(2A)ARs may lead to reduced insulin secretion.

Purpose of the Study:

  • To investigate the association between the alpha(2A)AR gene (Adra2a) and insulin secretion in a type 2 diabetes model.
  • To explore the role of a single-nucleotide polymorphism in the human ADRA2A gene in insulin secretion and type 2 diabetes risk.

Main Methods:

  • Utilized congenic rats from a type 2 diabetes model to examine the chromosomal region containing the Adra2a gene.
  • Analyzed messenger RNA and protein expression levels of alpha(2A)AR.
  • Assessed insulin release in response to glucose challenge in humans with a specific ADRA2A gene polymorphism.

Main Results:

  • A specific chromosomal region including Adra2a was linked to increased alpha(2A)AR expression and reduced insulin release in diabetic rats.
  • A single-nucleotide polymorphism in the human ADRA2A gene correlated with decreased insulin secretion during glucose challenge.
  • This genetic variant was also associated with an increased risk of type 2 diabetes.

Conclusions:

  • The Adra2a gene is a potential genetic locus associated with type 2 diabetes.
  • Concordant expression and biochemical phenotypes support the role of alpha(2A)AR in diabetes pathogenesis.
  • Targeting alpha(2A)AR represents a potential therapeutic strategy for type 2 diabetes.

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