Antidiabetic Effects of GIP in T2DM and Obesity

gip peptide

In normal humans, glucose-dependent insulinotropic polypeptide (GIP) is secreted by enteroendocrine K cells, which are located in the proximal duodenum and jejunum. Its concentration rises rapidly following nutrient ingestion, promoting modest inhibitory effects on gastric acid secretion and motility.

Its 59 kDa G protein-coupled receptor is found in the beta cells of the pancreas and enables them to detect glucose and release insulin as a result. However, in patients with T2DM a reduction in the insulin response to GIP is observed, even at supraphysiological concentrations, implying that resistance to GIP has developed.

The inability of GIP to induce the glucose-induced insulin response in T2DM may be attributed to postreceptor defects, a fact that is supported by the evidence of a glycemic-induced reduction in GIP receptor expression and beta cell responsiveness (32, 35). In contrast, incubation with an exendin 9-39, which completely blocks GIPR signaling, has been shown to restore both receptor expression and beta cell responsiveness (27), as well as glucagon production.

A dual GIP and GLP-1 agonist, tirzepatide, has been demonstrated to reduce plasma glucose levels by up to 27%, improve insulin sensitivity, decrease weight, and significantly amend dyslipidemia favorably. Tirzepatide has been given as a once-weekly subcutaneous injection, and it appears that its beneficial effect on antidiabetic function is based on altered GIP and GLP-1 signaling pathways.

It is therefore conceivable that both the agonism of GIP and the antagonism of GIP could be responsible for its antidiabetic efficacy in T2DM and obesity. Careful molecular pharmacological experiments should soon shed light on this paradoxical, mind-boggling phenomenon.


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