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Pharmacological interventions that directly stimulate or modulate insulin secretion from pancreatic β ‐cell: implications for the treatment of type 2 diabetes
Author(s) -
Farret Anne,
LugoGarcia Laura,
Galtier Florence,
Gross René,
Petit Pierre
Publication year - 2005
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/j.1472-8206.2005.00375.x
Subject(s) - medicine , endocrinology , insulin , insulin oscillation , hypoglycemia , type 2 diabetes , diabetes mellitus , insulin resistance , beta cell , pancreatic hormone , hormone , biology , islet
Abstract Blood glucose concentration is controlled by a number of hormone and neurotransmitter signals, either increasing or reducing glucose levels in the case of hypoglycemia or hyperglycemia, respectively. The pancreatic β ‐cell responds to an increase in circulating glucose levels by a cascade of metabolic and electrophysiological events leading to the secretion of insulin. Type 2 diabetes is a metabolic disorder characterized by chronic hyperglycemia; the progressive pancreatic β ‐cell dysfunction, with altered insulin production and secretion, is a major pathophysiological determinant of the disease together with the resistance of insulin‐sensitive tissues to the action of the hormone. Hence, drugs which stimulate or enhance insulin secretion will reduce plasma glucose concentrations; this lowering of hyperglycemia will, in turn, reduce the occurrence of long‐term complications. K ATP channels play a critical role in insulin secretion and can be considered as transducers of glucose‐induced metabolic changes into biophysical events leading to the exocytosis of insulin granules. All currently marketed insulin secretagogues, sulfonylureas and glinides, target the β ‐cell K ATP channels and reduce their opening probability. They induce insulin release regardless of the plasma glucose concentration, thus favoring the occurrence of hypoglycemia in the fasting state. Despite the intensive use of current drugs, many patients suffering from type 2 diabetes still exhibit poor glycemic control, others fail to respond to the treatment, and some develop serious complications. Therefore, there is a real need for innovative compounds, either enhancing insulin secretion from the pancreas or improving insulin action on the hormone‐sensitive tissues. Here, we overview the existing and novel approaches targeting the β ‐cell to enhance the release of insulin, with special emphasis on new ways of amplifying insulin secretion in a glucose‐dependent manner.