TY - JOUR

T1 - GIP as a Therapeutic Target in Diabetes and Obesity

T2 - Insight From Incretin Co-agonists

AU - Holst, Jens Juul

AU - Rosenkilde, Mette Marie

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - GLP-1

KW - type 2 diabetes

KW - weight-losing therapy

KW - glucose-dependent insulinotropic polypeptide

KW - receptor internalization

KW - co-agonists

KW - GLUCAGON-LIKE PEPTIDE-1

KW - GASTRIC-INHIBITORY POLYPEPTIDE

KW - DEPENDENT INSULINOTROPIC POLYPEPTIDE

KW - ENERGY-INTAKE

KW - POSTPRANDIAL GLUCOSE

KW - RECEPTOR AGONIST

KW - GLYCEMIC CONTROL

KW - DISPERSED ACINI

KW - ANTAGONIST

U2 - 10.1210/clinem/dgaa327

DO - 10.1210/clinem/dgaa327

M3 - Review

C2 - 32459834

VL - 105

SP - E2710-E2716

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 8

ER -