Overexpression of alpha2A-adrenergic receptors contributes to type 2 diabetes

• Several common genetic variations have been associated with type 2 diabetes, but the exact disease mechanisms are still poorly elucidated. Using congenic strains from the diabetic Goto-Kakizaki rat, we identified a 1.4-megabase genomic locus that was linked to impaired insulin granule docking at the plasma membrane and reduced beta cell exocytosis. In this locus, Adra2a, encoding the alpha2A-adrenergic receptor [alpha(2A)AR], was significantly overexpressed. Alpha(2A)AR mediates adrenergic suppression of insulin secretion. Pharmacological receptor antagonism, silencing of receptor expression, or blockade of downstream effectors rescued insulin secretion in congenic islets. Furthermore, we identified a single-nucleotide polymorphism in the human ADRA2A gene for which risk allele carriers exhibited overexpression of alpha(2A)AR, reduced insulin secretion, and increased type 2 diabetes risk. Human pancreatic islets from risk allele carriers exhibited reduced granule docking and secreted less insulin in response to glucose; both effects were counteracted by pharmacological alpha(2A)AR antagonists.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)

Nyckelord

Adolescent

Adrenergic alpha-2 Receptor Agonists

Adrenergic alpha-2 Receptor Antagonists

Adrenergic alpha-Agonists

Adrenergic alpha-Antagonists

Adult

Aged

Animals

Animals

Congenic

Blood Glucose

Cell Membrane

Cyclic AMP

Diabetes Mellitus

Type 2

Exocytosis

Genetic Association Studies

Genetic Predisposition to Disease

Humans

Insulin

Insulin-Secreting Cells

Middle Aged

Polymorphism

Single Nucleotide

RNA Interference

Rats

Rats

Inbred Strains

Receptors

Adrenergic

alpha-2

Risk Factors

Secretory Vesicles

Up-Regulation

Young Adult

Publikations- och innehållstyp

ref (ämneskategori)

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