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 α 2 - and β-AR have opposing effects, the net response to sympathetic stimulation is inhibition of insulin secretion mediated by α 2 -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 α 2 -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.