Fig. 1: cAMP production and binding properties of the 47 non-synonymous GIPR variants.
a, Localization of GIP-secreting cells in the gastrointestinal tract. b, GIP secretion in response to ingestion of low (25 g), moderate (50–75 g) or high (100–125 g) amounts of glucose according to previous human studies (N = 8)12,13. The blue box highlights the range from low (10 pM) to high (100 pM) levels of GIP. c, The corresponding area of the physiological range of GIP on a WT GIPR dose-response curve for cAMP production. d, cAMP production at 100 pM GIP, shown as percentage of activity compared with WT GIPR. Grey, WT-like activity and dark red, below 50% activity of WT. The data represent the mean ± s.e.m. WT GIPR: N = 18; R12Q, S64P, Y73H, R164Q, P195R–A207V, S382T–S382Y, S415I–G449A: N = 6; L13F–R38L, V99I–R101H, R164W, T168A, L261H, E461*–E463Q: N = 4; R43G, M67R, C84P–W90L, I221M, R336P: N = 5; T116R–A150T, H166Y, R183Q–A185V, W233*–Y258S, E291K–R300W, E354Q–I378M, K397N–V399M: N = 3; R190Q: N = 9; E288G: N = 8; L304R: N = 7. Independent experiments were performed in duplicate. e,f, Homologous competition binding of GIP, showing maximum binding capacity (Bmax) and affinity (Kd) compared with WT GIPR. The variants are arranged in the same order as in b. NB, no binding. The data represent the mean ± s.e.m. WT GIPR: N = 18; R12Q: N = 5; L13F–R101H, G144S–A207V, W233*, E288G, E354Q, S382T–G449A, E463Q: N = 3; T116R, I221M, Y258S–L261H, E291K–R336P, I378M, E461*: N = 4. Independent experiments were performed in duplicate. g, Illustration of the GIPR with variants located at functional sites (orange) and non-functional sites (blue). Green area: ligand binding site; yellow area: (micro) switches; red area: G protein interface (left). Mean difference in cAMP efficacy between variants at functional (N = 13) and non-functional (N = 34) sites (right). No significant difference was observed between the efficacy of 100 pM, P = 0.30. Statistical significance was assessed using the Wilcoxon rank-sum test (two sided).
