Dissecting the Physiology and Pathophysiology of Glucagon-Like Peptide-1

Abstract

An aging world population exposed to a sedentary life style is currently plagued by chronic metabolic diseases, such as type-2 diabetes, that are spreading worldwide at an unprecedented rate. One of the most promising pharmacological approaches for the management of type 2 diabetes takes advantage of the peptide hormone glucagon-like peptide-1 (GLP-1) under the form of protease resistant mimetics, and DPP-IV inhibitors. Despite the improved quality of life, long-term treatments with these new classes of drugs are riddled with serious and life-threatening side-effects, with no overall cure of the disease. New evidence is shedding more light over the complex physiology of GLP-1 in health and metabolic diseases. Herein, we discuss the most recent advancements in the biology of gut receptors known to induce the secretion of GLP-1, to bridge the multiple gaps into our understanding of its physiology and pathology.

Glucagon receptor antagonist upregulates circulating GLP-1 level by promoting intestinal L-cell proliferation and GLP-1 production in type 2 diabetes

“…Glucagon-like peptide-1 (GLP-1), primarily synthesized by and secreted from intestinal L-cells, forms the basis for dozens of novel drugs against T2D 12. GLP-1 exerts multiple important physiological effects, including stimulated glucose-dependent insulin secretion and inhibited glucagon release 12–14. In individuals with T2D, decreased levels of plasma GLP-1 and reduced numbers of GLP-1-producing L-cells are in association with obesity and insulin resistance 15.…”

Acute Effects of Lixisenatide on Energy Intake in Healthy Subjects and Patients with Type 2 Diabetes: Relationship to Gastric Emptying and Intragastric Distribution

“…Most GLP-1RAs are able to activate central GLP-1 receptors expressing neurons. Larger molecule GLP-1RAs that are unable to cross the blood–brain barrier appear to act via secondary signals from the vagus nerve [ 14 ], while smaller molecule GLP-1RAs, including lixisenatide, pass through the blood–brain barrier directly [ 15 ]. Possible mechanisms underlying weight loss by GLP-1RAs include satiation induced by the slowing of gastric emptying and a consequent prolongation of gastric distension, centrally-mediated anorexia, and the induction of nausea as an adverse effect [ 16 ].…”

New Insights into Beta-Cell GLP-1 Receptor and cAMP Signaling

“…In summary, although our understanding of incretin pathways has increased dramatically, there still Journal Pre-proof J o u r n a l P r e -p r o o f 26 remain many unknowns with the potential to explain, and possibly correct, the defects in secretion that occur in T2DM. [236] and regions of the brain [237] (reviewed in [238]). Under conditions of metabolic stress, GLP-1 may also be secreted by alpha cells within the islets of Langerhans where, along with GCG [46], it could act as a paracrine factor to regulate insulin secretion.…”