Treatment of type 2 diabetes mellitus with agonists of the GLP-1 receptor or DPP-IV inhibitors.
Glucagon-like peptide-1 (GLP-1) is a peptide hormone from the gut that stimulates insulin secretion and protects beta-cells, inhibits glucagon secretion and gastric emptying, and reduces appetite and food intake. In agreement with these actions, it has been shown to be highly effective in the treatment of Type 2 diabetes, causing marked improvements in glycaemic profile, insulin sensitivity and beta-cell performance, as well as weight reduction. The hormone is metabolised rapidly by the enzyme dipeptidyl peptidase IV (DPP-IV) and, therefore, cannot be easily used clinically. Instead, resistant analogues of the hormone (or agonists of the GLP-1 receptor) are in development, along with DPP-IV inhibitors, which have been demonstrated to protect the endogenous hormone and enhance its activity. Agonists include both albumin-bound analogues of GLP-1 and exendin-4, a lizard peptide. Clinical studies with exendin have been carried out for > 6 months and have indicated efficacy in patients inadequately treated with oral antidiabetic agents. Orally active DPP-IV inhibitors, suitable for once-daily administration, have demonstrated similar efficacy. Diabetes therapy, based on GLP-1 receptor activation, therefore, appears very promising.
Holst
Jens Juul
JJ
The Panum Institute, University of Copenhagen, Denmark. holst@mfi.ku.dk
D000243:Adenosine Deaminase / Q000502:physiology; D058892:Adenosine Deaminase Inhibitors; D000344:Afferent Pathways / Q000502:physiology; D000818:Animals; D001066:Appetite / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D018819:Dipeptidyl Peptidase 4 / Q000502:physiology; D004359:Drug Therapy, Combination; D000077270:Exenatide; D005934:Glucagon / Q000819:agonists / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology* / Q000627:therapeutic use; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007031:Hypothalamus / Q000187:drug effects / Q000503:physiopathology; D007328:Insulin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D007413:Intestinal Mucosa / Q000294:innervation / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D000069450:Liraglutide; D008116:Lizards; D008301:Maleimides / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D010446:Peptide Fragments / Q000819:agonists / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use; D052336:Proglucagon; D011498:Protein Precursors / Q000819:agonists / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D051381:Rats; D011924:Rats, Zucker; D018027:Receptors, Glucagon / Q000819:agonists* / Q000172:deficiency / Q000502:physiology; D014688:Venoms / Q000494:pharmacology / Q000627:therapeutic use
D058892:Adenosine Deaminase Inhibitors; C473712:CJC 1131; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D006023:Glycoproteins; D007004:Hypoglycemic Agents; D007328:Insulin; D008301:Maleimides; D010446:Peptide Fragments; D010455:Peptides; D011498:Protein Precursors; D018027:Receptors, Glucagon; D014688:Venoms; D052336:Proglucagon; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000077270:Exenatide; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000243:Adenosine Deaminase