The role of GIP in carbohydrate metabolism: Implications in the development of therapies for T2DM, a narrative review.

INTRODUCTION: For the last three decades, bariatric/metabolic surgeries have highlighted the relevance of certain gastrointestinal hormones in controlling and regulating glucose metabolism. The incretins have been a significant focus in developing therapies against Type 2 Diabetes Mellitus (T2DM). Glucagon-like peptide-1 (GLP-1) has been a primary focus in this field, leading to the development of analogues with high therapeutic potential and efficiency, such as semaglutide. However, recently another incretin, glucose-dependent insulinotropic polypeptide (GIP), has become a key target in T2DM drug development due to its complex pleiotropic effects, which include modulating insulin/glucagon secretion, acting on adipose tissue, and regulating appetite. The description of GIP properties as dual can be ambiguous, as this may refer either to its capacity to regulate both insulin and glucagon or to its distinct actions at the central versus peripheral level. Connecting this multifaceted activity was the rationale for developing combined GIP/GLP-1 analogues, like tirzepatide, and has culminated in triple-receptor agonists such as retratutide, which also engages the glucagon receptor (LY3437943). These multi-agonists potentially enhance the therapeutic potential of GLP-1 analogues.

COMMENTARIES: This review covers GIP physiology, its role within the context of T2DM, and the properties of GIP analogues, which represent a new line of drugs against T2DM. This field includes not only GIP analogues, since some are dual or triple agonists that also target GLP-1. We aim to elucidate the future perspectives offered by the use of these drugs.