Glucagon-like peptide-1 (GLP-1) and glucose-depended insulinotropic polypeptide (GIP) are the two peptides that have been confirmed to act as incretin hormones to date. GIP was the first incretin hormone identified. Glucagon like peptide-1 (GLP-1) is normally secreted by intestinal L-cells in response to food intake particularly carbohydrate, fat and proteins. It has multiple physiological actions including glucose-dependent insulin secretion and reduced glucagon secretion. In addition, GLP-1 also reduces gastric emptying and increases satiety. Endogenous GLP-1 is rapidly degraded by dipeptidyl peptidase-4 (DPP-4), and its insulin effect is short-lived. In vivo, GLP-1 is rapidly inactivated by the enzyme dipeptidyl peptidase-IV (DPP-IV) resulting in a plasma half-life of 1-2 minutes. To overcome this, DPP-IV resistant analogues of human GLP-1 have been developed for clinical use.
|Sequence||HAEGTFTSDVSSYLEGQAAK [N-(1-oxohexadecyl)-L-γ-glutamyl] EFI AWLVRGRG|
Liraglutide and type 2 diabetes
Liraglutide, an analog with 97% homology to human glucagon-like peptide (GLP-1) and acts as a GLP-1 receptor agonist, has been approved for the treatment of type 2 diabetes. This 97% homology was achieved by substituting arginine for lysine at position 34 of endogenous GLP-1. GLP-1 mimetics improve glycemic control through multiple mechanisms similar to the endogenous incretin hormone GLP-1. Liraglutide is the second in class of glucagon like peptide-1 (GLP-1) mimetics now available for the treatment of type 2 diabetes. The first product licensed was exenatide which is a twice-daily delivered functional partly dipeptidyl peptidase-IV (DPP-IV) resistant analogue of human GLP-1 which is now in established use.
Liraglutide contains a fatty acid molecule that binds to albumin and prolongs the half-life of the structure. Receptors for GLP-1 are found in pancreatic alpha and beta cells; the central and peripheral nervous systems; and the heart, lungs, and gastrointestinal (GI) tract. Several studies have demonstrated that GLP-1 receptor agonists may improve pancreatic beta cell function, which may delay disease progression if maintained over the long term. Through the messenger intracellular cyclic adenosine monophosphate (cAMP), liraglutide causes insulin to be secreted in the presence of elevated glucose levels. Because of the receptor locations, liraglutide also inhibits glucagon secretion and delays gastric emptying.
Liraglutide and weight loss
Liraglutide has also been associated with weight loss and improved patient satisfaction and health-related quality of life. It has been shown to be effective at inducing and sustaining weight loss in a population of obese patients including those with hypertension, dyslipidemia, type 2 diabetes and obstructive sleep apnea. Studies suggest that weight loss with liraglutide is greater than that seen with orlistat or lorcaserin, but slightly less than weight loss seen with phentermine/topiramate combination treatment. In addition, discontinuation due to adverse effects (primarily gastrointestinal) is highest for liraglutide and naltrexone/bupropion and lowest for lorcaserin. Of course, additional studies are needed to determine liraglutide’s long term outcomes, including its effects on cardiovascular morbidity and mortality, in a large and diverse population with varying races/ethnicities, for a weight loss indication. For now, liraglutide remains another important option in the physician's toolkit to combat the growing obesity epidemic in the United States and abroad.
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