Overexpression of Alpha2A-Adrenergic Receptors Contributes to Type 2 Diabetes

Anders H. Rosengren,¹ Ramunas Jokubka,^1,* Damon Tojjar,^1,* Charlotte Granhall,¹ Ola Hansson,¹ Dai-Qing Li,² Vini Nagaraj,¹ Thomas M. Reinbothe,¹ Jonatan Tuncel,³ Lena Eliasson,¹ Leif Groop,¹ Patrik Rorsman,⁴ Albert Salehi,¹ Valeriya Lyssenko,¹ Holger Luthman,¹ Erik Renström^1,

Abstract: 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 β 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.

¹ Lund University Diabetes Centre, Malmö, SE-20502 Malmö, Sweden.
² Key Laboratory of Hormones and Development, Ministry of Health, China, Tianjin Metabolic Diseases Hospital, Tianjin Medical University, China.
³ Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden.
⁴ Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK.

To whom correspondence should be addressed. E-mail: erik.renstrom{at}med.lu.se

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