title: Pancreatic alpha-cell dysfunction in diabetes.
abstract: A major, yet poorly understood, feature of type 2 diabetes is the excessive hepatic glucose production and the corresponding insulin resistance leading to fasting hyperglycaemia. The tremendous amount of work done to provide the physiological and molecular mechanisms explaining this impairment has led to the emergence of several consensual hypotheses. Among these, is the increased daily and unregulated plasma glucagon concentration in type 2 diabetic patients. Therefore, studies aiming to understand the physiological regulation of glucagon secretion and the corresponding impairment during diabetes are directly relevant to the treatment of type 2 diabetes. Glucagon secretion by alpha-cells is an immediate response to glucopenia. Abnormal secretion of glucagon and other counterregulatory hormones is a hallmark of type 1 and type 2 diabetes and a major limitation to the use of strong hypoglycaemia agents. A few molecular mechanisms of glucose detection triggering counterregulation and in particular inducing glucagon secretion or suppressing it during hyperglycaemic episodes, have been identified. Such mechanisms are related to those of the insulin secreted beta-cell. The glucose transporter GLUT2 and the K-ATP dependent channel, as well as regulatory mechanisms, involved the central nervous system and the gut-brain hormone GLP-1. Over the last years, glucoincretins have provided promising results for the normalization of plasma glucagon concentration of type 2 diabetic patients, which could partly explain the therapeutic benefits of incretin-related therapy. The underlined mechanisms of GLP-1 regulated glucagon secretion are most likely related to the action of the hormone on the activation of the portal and brain glucose sensors. Certainly, strategies aiming to restore glucose-regulated glucagon secretion are important milestones for the treatment of diabetic patient and the prevention of iatrogenic hypoglycaemia.
authors.affiliation: Institute of Molecular Medicine, team Functional genomic of metabolic diseases, Rangueil hospital, 1, av Prof Jean Poulhes, 31403 Toulouse Cedex, France. burcelin@toulouse.inserm.fr
authors.forename: R
authors.initials: R
authors.lastname: Burcelin
authors.forename: C
authors.initials: C
authors.lastname: Knauf
authors.forename: P D
authors.initials: PD
authors.lastname: Cani
mesh_terms: D003920:Diabetes Mellitus / Q000503:physiopathology*; D005934:Glucagon / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000503:physiopathology*
chemical_list: D005934:Glucagon