Table of Contents
Glucagon like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) are secreted from the L cells of intestines, on meal ingestion and work in concert to promote postprandial insulin secretion and regulate glucagon secretion [1, 2]. GLP-1 also suppresses appetite, and slows gastric emptying, whereas GIP has a role in modulating lipid metabolism. Interestingly, incretins have become more important due to their role as GLP-1 receptor agonists for the treatment of type 2 diabetes (T2DM), obesity and cardiovascular diseases (CVDs). Combining the glucose and body weight-lowering effects of GLP-1 causing greater improvement in β cell function through additional GIP action may offer a more effective treatment of obesity and T2DM. This combination may have improved efficacy as well as lower adverse effects compared to selective GLP-1R agonists. Therefore, new drugs, the twin incretins, designed to co-activate both the GIP receptor and the GLP-1 receptors simultaneously, are under development [1-3]. The present review aims to address advances in the field of receptor signaling related to GIP and GLP-1 co-agonism, which may have beneficial effects on obesity, T2DM, metabolic syndrome and CVDs.
 Skow MA, Bergmann NC, Knop FK. Diabetes and obesity treatment based on dual incretin receptor activation: ‘twincretins’. Diabetes Obes Metab 2016; 18 (9):8 47-854. doi: 10.1111 /dom.12685.
 Frias JP, Davies MJ, Rosenstock J, SURPASS-2 Investigators. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med 2021; 385: 503-515.
 Zhao F, Zhou Q, Cong Z, Hang K, Zou X, Zhang C, Chen Y, Dai A, Liang A, Ming Q, Wang M, Chen LN, Xu P, Chang R, Feng W, Xia T, Zhang Y, Wu B, Yang D, Zhao L, Xu HE, Wang MW. Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors. Nat Commun 2022; 13 (1): 1057.
 Mathiesen DS, Bagger JI, Bergmann NC, Lund A, Christensen MB, Vilsbøll T, Knop FK. The effects of dual GLP-1/GIP receptor agonism on glucagon secretion-a review. Int J Mol Sci 2019; 20 (17): 4092.
 Christensen M, Vedtofte L, Holst JJ, Vilsbøll T, Knop FK. Glucose-dependent insulinotropic polypeptide: a bifunctional glucose-dependent regulator of glucagon and insulin secretion in humans. Diabetes 2011; 60: 3103-3109.
 Yip RG, Boylan MO, Kieffer TJ, Wolfe MM. Functional GIP receptors are present on adipocytes. Endocrinology 1998; 139: 4004-4007.
 Samms RJ, Coghlan MP, Sloop KW. How may GIP enhance the therapeutic efficacy of GLP-1? Trends Endocrinol Metab 2020; 31: 410-421.