Extrapancreatic glucagon: present status.

Pancreatic alpha cells are generally considered the only source of glucagon secretion in humans. In the 1970s several groups investigating totally pancreatectomised animals reported that glucagon-like immunoreactive material could be detected in the gastrointestinal tract and reopened the question of an extrapancreatic source of glucagon proposed in 1948 when a hyperglycaemic substance was found in the gastrointestinal tract of dogs and rabbits. Nevertheless, over the years, controversy about the existence of extrapancreatic glucagon has flourished as it proved difficult to accurately measure fully processed 29-amino acid glucagon. Recent advances in analytical methods have increased sensitivity and specificity of glucagon assays and, furthermore, technical advances in mass spectrometry-based proteomics have made the detection of low-abundant peptides, such as glucagon, in human plasma more accurate. Here we review new data on extrapancreatic glucagon secretion in the context of historical data and recent analytical breakthroughs. Furthermore, the source, regulation and potential physiological role of extrapancreatic glucagon are discussed and ongoing challenges and knowledge-gaps are outlined.