Journal Article

GIP as a Therapeutic Target in Diabetes and Obesity: Insight From Incretin Co-agonists

Holst, Jens Juul, Rosenkilde, Mette Marie

2020

Overview

Abstract The 2 hormones responsible for the amplification of insulin secretion after oral as opposed to intravenous nutrient administration are the gut peptides, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). However, whereas GLP-1 also inhibits appetite and food intake and improves glucose regulation in patients with type 2 diabetes (T2DM), GIP seems to be devoid of these activities, although the 2 hormones as well as their receptors are highly related. In fact, numerous studies have suggested that GIP may promote obesity. However, chimeric peptides, combining elements of both peptides and capable of activating both receptors, have recently been demonstrated to have remarkable weight-losing and glucose-lowering efficacy in obese individuals with T2DM. At the same time, antagonists of the GIP receptor have been reported to reduce weight gain/cause weight loss in experimental animals including nonhuman primates. This suggests that both agonists and antagonist of the GIP receptor should be useful, at least for weight-losing therapy. How is this possible? We here review recent experimental evidence that agonist-induced internalization of the two receptors differs markedly and that modifications of the ligand structures, as in co-agonists, profoundly influence these cellular processes and may explain that an antagonist may activate while an agonist may block receptor signaling.

• Publisher: Oxford University Press
• Subject: Agonists / Anti-Obesity Agents - pharmacology / Anti-Obesity Agents - therapeutic use / Appetite / Appetite - drug effects / Blood Glucose - drug effects / Blood Glucose - metabolism / Body weight gain / Body weight loss / Dextrose / Diabetes / Diabetes mellitus (non-insulin dependent) / Diabetes Mellitus, Type 2 - blood / Diabetes Mellitus, Type 2 - drug therapy / Diabetes Mellitus, Type 2 - metabolism / Exenatide / Food intake / Gastric Inhibitory Polypeptide - metabolism / GIP protein / Glucagon / Glucagon-like peptide 1 / Glucagon-Like Peptide 1 - metabolism / Glucose / Health aspects / Humans / Hypoglycemic Agents - pharmacology / Hypoglycemic Agents - therapeutic use / Incretins - agonists / Incretins - metabolism / Insulin / Insulin secretion / Internalization / Intravenous administration / Liraglutide / Obesity / Obesity - blood / Obesity - drug therapy / Obesity - metabolism / Online Only / Peptides / Physiological aspects / Receptors, Gastrointestinal Hormone - agonists / Receptors, Gastrointestinal Hormone - antagonists & inhibitors / Receptors, Gastrointestinal Hormone - metabolism / Signal Transduction - drug effects / Therapeutic applications / Type 2 diabetes / Weight control / Weight Loss - drug effects