Diabetes, Pharmaceutical Therapies for Managing Hyperglycemia, Incretins, GLP-1

Diabetes, Pharmaceutical Therapies for Managing Hyperglycemia, Incretins

GLP-1:

• One of several cleavage products of proglucagon produced in the intestines.
• Secretion is stimulated after a meal.
• Half-life in circulation is less than 2 minutes.
• Acts on the stomach to delay gastric emptying and slow the absorption of nutrients.
• Binds in a glucose-dependent manner to GLP-1 receptor on pancreatic beta cells where it has multiple activities.
• Stimulates insulin secretion but also regulates transcription and translation of insulin messenger RNA.
• Long lasting effects in pancreas.
• Improves glucose sensitivity of beta cells.
• Promotes generation and proliferation of new beta cells.
• Enhances beta cell survival.
• Inhibits glucagon secretion from pancreatic alpha cells.
• Indirectly decreases hepatic glucose output.
• Acts in the brain to send signals to the stomach to promote satiety, reduce food intake, and decrease body weight.

Incretin GLP-1 analogues:

• More stable in circulation than endogenous GLP-1.
• Able to slow glucose absorption.
• Increase satiety.
• Potentiate glucose stimulated insulin secretion.
• Produce modest weight loss.

DPP-4 inhibitors:

• Extend the half-life of endogenous GLP-1.
• Similar biological activity to incretins.
• Advantage of oral administration.
• Lack activity on gastric emptying and satiety.

GIP:

• Acts on a G-protein-coupled receptor that is expressed widely in tissues throughout the body.
• Stimulates insulin secretion from pancreatic beta cells and promotes beta cell survival.
• Has not been effective when tested as therapy in patients with type 2 diabetes.

Incretins:

• Secreted rapidly into the circulation following ingestion of a meal.
• GLP-1 is produced by endocrine L cells of the distal ileum and colon.
• GIP is produced by K cells of the proximal duodenum and jejunum.
• These peptides rapidly appear and disappear from circulation.
• Part of a complex system of peptide hormones secreted by the digestive tract to modulate energy uptake and utilization.
• Act on multiple tissues to facilitate glucose uptake and reduce endogenous glucose output.

• Gastrointestinal tract not only digests foods and absorbs nutrients, but also plays an important role in the regulation of energy homeostasis and glycemic control.
• Enteroendocrine cells of the stomach and intestines secret peptide hormones that act throughout the body to regulate energy intake and glucose homeostasis.

GLP-1 - Glucagon-Like Peptide-1

GIP - Glucose-Dependent Insulinotropic Polypeptide