Adrenoceptor Expression and Function in the Endocrine Pancreas

The sympathetic nervous system plays an important role in the regulation of endocrine pancreatic function, most importantly insulin release. Among the nine adrenoceptor (AR) subtypes, the α_2A-AR appears to be the subtype most abundantly expressed in the human pancreas. While α₂- and β-AR have opposing effects, the net response to sympathetic stimulation is inhibition of insulin secretion mediated by α₂-AR located in the plasma membrane of pancreatic β cells. This inhibition may be present physiologically as evidenced by increased insulin secretion in healthy and diabetic humans and animals in response to α₂-AR antagonists, a finding that was confirmed in all studies. Based on such data and on an association of an α_2A-AR polymorphism, that increases receptor expression levels, with an elevated risk for diabetes, increased α_2A-AR signaling in the pancreatic β cells has been proposed as a risk factor for the development of type 2 diabetes. Thus, the α_2A-AR was proposed as a drug target for the treatment of some forms of type 2 diabetes. Drug research and development programs leveraging this mechanism have reached the clinical stage, but none have resulted in an approved medicine due to a limited efficacy. While β-AR agonists can increase circulating insulin levels in vivo, it remains controversial whether this includes a direct effect on β cells or occurs secondary to general metabolic effects. Therefore, the regulation of endocrine pancreatic function is physiologically interesting but may be of limited therapeutic relevance.