课件：糖尿病药物治疗新进展.ppt

* History of GLP-1 In 1930, Zunz and LaBarre described an intestinal extract that could produce hypoglycaemia. In a separate paper, LaBarre used the term ‘incretin’ to describe activity in the gut that might initiate pancreatic endocrine secretions. In 1963, McIntyre suggested that a humoral substance was released from the jejunum during glucose absorption, acting in concert with glucose to stimulate insulin release from pancreatic ?-cells. In 1969, Unger and Eisentraut referred to the gut—pancreas association as the enteroinsular axis. In 1979, this axis was subsequently described as involving nutrient, neural, and hormonal signals from the gut to the pancreatic islet cells that secrete insulin, glucagon, and somatostatin. Incretins acting on this pathway must be secreted in response to nutrient stimuli and must stimulate glucose-dependent insulin secretion (Creutzfeldt 1979). In the early 1980s, GLP-1, was discovered to be a product of the proglucagon gene. The GLP-1 receptor was initially cloned in 1992 by Bernard Thorens in the rat pancreatic islet cell (Thorens 1992). A year later, a human pancreatic GLP-1 receptor with 90% homology to the amino acid sequence of the rat receptor was cloned (Dillon et al. 1993, Graziano et al. 1993, Thorens et al. 1993). In 1993, Nauck et al. published the findings of a study investigating the blood glucose lowering potential of GLP-1 in ten type 2 diabetes patients with unsatisfactory metabolic control from diet or sulphonylurea treatment. Continuous intravenous (i.v.) infusion of GLP-1 during a fasting state significantly increased insulin and C-peptide secretion while reducing glucagon secretion. Plasma glucose returned to normal fasting glucose concentrations within 4 hours of GLP-1 administration: no such decrease was observed during placebo infusion. Once normal fasting plasma glucose levels were attained, insulin secretion and plasma glucose stabilised despite ongoing infusion of GLP-1, highlighting its glucose-depen