TY - JOUR

T1 - Recent advances of GIP and future horizons

AU - Holst, Jens Juul

AU - Rosenkilde, Mette Marie

PY - 2020

Y1 - 2020

N2 - Recently GIP-GLP-1 co-agonists with powerful effects on glycemic control and body weight in patients with type 2 diabetes have been described. While such effects are the expected ones from a glucagonlike peptide-1 receptor agonist, similar contributions from the GIP component of the co-agonist would be surprising and contrast to the existing literature. Conventionally, GIP is thought of as an important incretin hormone regulating postprandial insulin secretion in glucose tolerant individuals, but such effects are weak or absent in patients with type 2 diabetes, and GIP has been proposed to an obesity-promoting hormone, rather than the opposite. Recent studies with a GIP receptor antagonist suitable for human studies have confirmed these concepts regarding the actions of endogenous GIP and point to potential beneficial metabolic effects of GIP receptor antagonists rather than agonist in the treatment of obesity and type 2 diabetes. So how is it possible that apparently similar results can be obtained with GIP receptor agonists and antagonists? Maybe the explanation should be sought in GIP receptor dynamics, where the agonists clearly elicit beta-arrestin mediated receptor internalization, rendering the target tissues unresponsive, whereas antagonists block the internalization and increase receptor expression on the cell surfaces. This may explain that both antagonists and agonists show efficacy in obesity and type 2 diabetes.

AB - Recently GIP-GLP-1 co-agonists with powerful effects on glycemic control and body weight in patients with type 2 diabetes have been described. While such effects are the expected ones from a glucagonlike peptide-1 receptor agonist, similar contributions from the GIP component of the co-agonist would be surprising and contrast to the existing literature. Conventionally, GIP is thought of as an important incretin hormone regulating postprandial insulin secretion in glucose tolerant individuals, but such effects are weak or absent in patients with type 2 diabetes, and GIP has been proposed to an obesity-promoting hormone, rather than the opposite. Recent studies with a GIP receptor antagonist suitable for human studies have confirmed these concepts regarding the actions of endogenous GIP and point to potential beneficial metabolic effects of GIP receptor antagonists rather than agonist in the treatment of obesity and type 2 diabetes. So how is it possible that apparently similar results can be obtained with GIP receptor agonists and antagonists? Maybe the explanation should be sought in GIP receptor dynamics, where the agonists clearly elicit beta-arrestin mediated receptor internalization, rendering the target tissues unresponsive, whereas antagonists block the internalization and increase receptor expression on the cell surfaces. This may explain that both antagonists and agonists show efficacy in obesity and type 2 diabetes.

KW - Glucose-dependent insulinotropic polypeptide

KW - GIP-GLP-1 coagonists

KW - GIP 3-30NH2

KW - Arrestin

KW - Hormone internalization

KW - Hormone desensitization

KW - GASTRIC-INHIBITORY POLYPEPTIDE

KW - DEPENDENT INSULINOTROPIC POLYPEPTIDE

KW - GLUCAGON-LIKE PEPTIDE-1

KW - ENTEROINSULAR AXIS

KW - INCRETIN ACTIVITY

KW - RECEPTOR AGONIST

KW - 7-36 AMIDE

KW - GLUCOSE

KW - SECRETION

KW - HYPERGLYCEMIA

U2 - 10.1016/j.peptides.2019.170230

DO - 10.1016/j.peptides.2019.170230

M3 - Review

C2 - 31838219

VL - 125

JO - Peptides

JF - Peptides

SN - 0196-9781

M1 - 170230

ER -