Pancreatic and extrapancreatic effects of GLP-1.
Glucagon-like peptide-1 (GLP-1), an incretin hormone which helps to regulate plasma glucose levels, is considered a potential agent for the treatment of type-2 diabetes mellitus, because of its insulinotropic capacity and insulinomimetic actions. In normal conditions, the beta-cell secretory response to GLP-1 is modulated by the extracellular concentration of D-glucose; however, the recognition of D-glucose by the beta-cell is often impaired in type-2 diabetes, and this could impede the full GLP-1 insulinotropic action. Non-glucidic substrates, such as the dimethyl ester of succinic acid, restore the effect of GLP-1 in the isolated perfused rat pancreas of normal or diabetic rats, in the absence of any other exogenous nutrient; likewise, the dimethyl ester of succinic or L-glutamic acid, and the monomethyl ester of pyruvic acid, potentiate the in vivo beta-cell secretory response to GLP-1 in normal and diabetic rats. Therefore, it was proposed that nutrients susceptible to bypass the site-specific defects of the diabetic beta-cell, could be used to potentiate and/or prolong the insulinotropic action of antidiabetic agents such as GLP-1. In vitro, GLP-1 insulin-like effects on glucose metabolism have been documented in normal and diabetic rat liver, and in rat and human skeletal muscle. In rat and human adipocytes, GLP-1 is lipolytic and/or lipogenic, and also stimulates parameters involved in the glucose metabolism. In liver, muscle and fat, GLP-1 seems to act through specific receptors, apparently different--at least in liver and muscle--in structure or signaling pathway from the pancreatic one. It is proposed that an inositolphosphoglycan might be a second messenger of GLP-1 action in extrapancreatic tissues.
Valverde
I
I
Dto. Metabolismo, Nutrición y Hormonas, Fundación Jiménez Díaz, Madrid, Spain. ivalverde@fjd.es
Villanueva-Peñacarrillo
M L
ML
Malaisse
W J
WJ
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D005934:Glucagon / Q000494:pharmacology* / Q000502:physiology* / Q000627:therapeutic use; D052216:Glucagon-Like Peptide 1; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D010179:Pancreas / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology* / Q000502:physiology* / Q000627:therapeutic use; D011498:Protein Precursors / Q000494:pharmacology* / Q000502:physiology* / Q000627:therapeutic use
D007328:Insulin; D010446:Peptide Fragments; D011498:Protein Precursors; D052216:Glucagon-Like Peptide 1; D005934:Glucagon