1932

Abstract

Glucose-dependent insulinotropic polypeptide (GIP) is released from the upper small intestine in response to food intake and contributes to the postprandial control of nutrient disposition, including of sugars and fats. Long neglected as a potential therapeutic target, the GIPR axis has received increasing interest recently, with the emerging data demonstrating the metabolically favorable outcomes of adding GIPR agonism to GLP-1 receptor agonists in people with type 2 diabetes and obesity. This review examines the physiology of the GIP axis, from the mechanisms underlying GIP secretion from the intestine to its action on target tissues and therapeutic development.

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2022-08-22
2024-03-28
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Literature Cited

  1. 1.
    Abdullah N, Beg M, Soares D, Dittman JS, McGraw TE. 2016. Downregulation of a GPCR by β-arrestin2-mediated switch from an endosomal to a TGN recycling pathway. Cell Rep 17:2966–78
    [Google Scholar]
  2. 2.
    Adriaenssens AE, Biggs EK, Darwish T, Tadross J, Sukthankar T et al. 2019. Glucose-dependent insulinotropic polypeptide receptor-expressing cells in the hypothalamus regulate food intake. Cell Metab 30:987–96.e6
    [Google Scholar]
  3. 3.
    Adriaenssens AE, Svendsen B, Lam BY, Yeo GS, Holst JJ et al. 2016. Transcriptomic profiling of pancreatic alpha, beta and delta cell populations identifies delta cells as a principal target for ghrelin in mouse islets. Diabetologia 59:2156–65
    [Google Scholar]
  4. 4.
    Alberti KG, Christensen NJ, Christensen SE, Hansen AP, Iversen J et al. 1973. Inhibition of insulin secretion by somatostatin. Lancet 2:1299–301
    [Google Scholar]
  5. 5.
    Antonson P, Matic M, Portwood N, Kuiper RV, Bryzgalova G et al. 2014. aP2-Cre-mediated inactivation of estrogen receptor alpha causes hydrometra. PLOS ONE 9:e85581
    [Google Scholar]
  6. 6.
    Asmar M, Simonsen L, Asmar A, Holst JJ, Dela F, Bulow J 2016. Insulin plays a permissive role for the vasoactive effect of GIP regulating adipose tissue metabolism in humans. J. Clin. Endocrinol. Metab. 101:3155–62
    [Google Scholar]
  7. 7.
    Asmar M, Simonsen L, Madsbad S, Stallknecht B, Holst JJ, Bulow J. 2010. Glucose-dependent insulinotropic polypeptide may enhance fatty acid re-esterification in subcutaneous abdominal adipose tissue in lean humans. Diabetes 59:2160–63
    [Google Scholar]
  8. 8.
    Ast J, Arvaniti A, Fine NHF, Nasteska D, Ashford FB et al. 2020. Super-resolution microscopy compatible fluorescent probes reveal endogenous glucagon-like peptide-1 receptor distribution and dynamics. Nat. Commun. 11:467
    [Google Scholar]
  9. 9.
    Beaudry JL, Kaur KD, Varin EM, Baggio LL, Cao X et al. 2019. Physiological roles of the GIP receptor in murine brown adipose tissue. Mol. Metab. 28:14–25
    [Google Scholar]
  10. 10.
    Beumer J, Artegiani B, Post Y, Reimann F, Gribble F et al. 2018. Enteroendocrine cells switch hormone expression along the crypt-to-villus BMP signalling gradient. Nat. Cell Biol. 20:909–16
    [Google Scholar]
  11. 11.
    Boer GA, Keenan SN, Miotto PM, Holst JJ, Watt MJ. 2021. GIP receptor deletion in mice confers resistance to high-fat diet-induced obesity via alterations in energy expenditure and adipose tissue lipid metabolism. Am. J. Physiol. Endocrinol. Metab. 320:E835–45
    [Google Scholar]
  12. 12.
    Bollag RJ, Zhong Q, Phillips P, Min L, Zhong L et al. 2000. Osteoblast-derived cells express functional glucose-dependent insulinotropic peptide receptors. Endocrinology 141:1228–35
    [Google Scholar]
  13. 13.
    Borner T, Geisler CE, Fortin SM, Cosgrove R, Alsina-Fernandez J et al. 2021. GIP receptor agonism attenuates GLP-1 receptor agonist-induced nausea and emesis in preclinical models. Diabetes 70:2545–53
    [Google Scholar]
  14. 14.
    Bossart M, Wagner M, Elvert R, Evers A, Hübschle T et al. 2022. Effects on weight loss and glycemic control with SAR441255, a potent unimolecular peptide GLP-1/GIP/GCG receptor triagonist. Cell Metab. 34:159–74.e10
    [Google Scholar]
  15. 15.
    Bowker N, Hansford R, Burgess S, Foley CN, Auyeung VPW et al. 2021. Genetically predicted glucose-dependent insulinotropic polypeptide (GIP) levels and cardiovascular disease risk are driven by distinct causal variants in the GIPR region. Diabetes 70:2706–19
    [Google Scholar]
  16. 16.
    Buchan AM, Polak JM, Capella C, Solcia E, Pearse AG. 1978. Electronimmunocytochemical evidence for the K cell localization of gastric inhibitory polypeptide (GIP) in man. Histochemistry 56:37–44
    [Google Scholar]
  17. 17.
    Campbell JE, Beaudry JL, Svendsen B, Baggio LL, Gordon AN et al. 2022. GIPR is predominantly localized to nonadipocyte cell types within white adipose tissue. Diabetes 71:51115–27
    [Google Scholar]
  18. 18.
    Capozzi ME, Svendsen B, Encisco SE, Lewandowski SL, Martin MD et al. 2019. β Cell tone is defined by proglucagon peptides through cAMP signaling. JCI Insight 4:5e126742
    [Google Scholar]
  19. 19.
    Carobbio S, Pellegrinelli V, Vidal-Puig A. 2017. Adipose tissue function and expandability as determinants of lipotoxicity and the metabolic syndrome. Adv. Exp. Med. Biol. 960:161–96
    [Google Scholar]
  20. 20.
    Cataland S, Crockett SE, Brown JC, Mazzaferri EL. 1974. Gastric inhibitory polypeptide (GIP) stimulation by oral glucose in man. J. Clin. Endocrinol. Metab. 39:223–28
    [Google Scholar]
  21. 21.
    Chia CW, Carlson OD, Kim W, Shin YK, Charles CP et al. 2009. Exogenous glucose-dependent insulinotropic polypeptide worsens post prandial hyperglycemia in type 2 diabetes. Diabetes 58:1342–49
    [Google Scholar]
  22. 22.
    Christensen LW, Kuhre RE, Janus C, Svendsen B, Holst JJ. 2015. Vascular, but not luminal, activation of FFAR1 (GPR40) stimulates GLP-1 secretion from isolated perfused rat small intestine. Physiol. Rep. 3:9e12551
    [Google Scholar]
  23. 23.
    Christensen M, Vedtofte L, Holst JJ, Vilsboll T, Knop FK. 2011. Glucose-dependent insulinotropic polypeptide: a bifunctional glucose-dependent regulator of glucagon and insulin secretion in humans. Diabetes 60:3103–9
    [Google Scholar]
  24. 24.
    Christensen MB, Lund A, Calanna S, Jorgensen NR, Holst JJ et al. 2018. Glucose-dependent insulinotropic polypeptide (GIP) inhibits bone resorption independently of insulin and glycemia. J. Clin. Endocrinol. Metab. 103:288–94
    [Google Scholar]
  25. 25.
    Christensen MB, Lund AB, Jorgensen NR, Holst JJ, Vilsboll T, Knop FK. 2020. Glucose-dependent insulinotropic polypeptide (GIP) reduces bone resorption in patients with type 2 diabetes. J. Endocr. Soc. 4:bvaa097
    [Google Scholar]
  26. 26.
    Chu ZL, Carroll C, Alfonso J, Gutierrez V, He H et al. 2008. A role for intestinal endocrine cell-expressed G protein-coupled receptor 119 in glycemic control by enhancing glucagon-like peptide-1 and glucose-dependent insulinotropic peptide release. Endocrinology 149:2038–47
    [Google Scholar]
  27. 27.
    Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S et al. 2018. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: from discovery to clinical proof of concept. Mol. Metab. 18:3–14
    [Google Scholar]
  28. 28.
    De Marinis YZ, Salehi A, Ward CE, Zhang Q, Abdulkader F et al. 2010. GLP-1 inhibits and adrenaline stimulates glucagon release by differential modulation of N- and L-type Ca2+ channel-dependent exocytosis. Cell Metab 11:543–53
    [Google Scholar]
  29. 29.
    Ding WG, Gromada J. 1997. Protein kinase A-dependent stimulation of exocytosis in mouse pancreatic β-cells by glucose-dependent insulinotropic polypeptide. Diabetes 46:615–21
    [Google Scholar]
  30. 30.
    Ding WG, Renstrom E, Rorsman P, Buschard K, Gromada J. 1997. Glucagon-like peptide I and glucose-dependent insulinotropic polypeptide stimulate Ca2+-induced secretion in rat α-cells by a protein kinase A–mediated mechanism. Diabetes 46:792–800
    [Google Scholar]
  31. 31.
    Dupre J, Ross SA, Watson D, Brown JC. 1973. Stimulation of insulin secretion by gastric inhibitory polypeptide in man. J. Clin. Endocrinol. Metab. 37:826–28
    [Google Scholar]
  32. 32.
    Edfalk S, Steneberg P, Edlund H. 2008. Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion. Diabetes 57:2280–87
    [Google Scholar]
  33. 33.
    Edholm T, Cejvan K, Abdel-Halim SM, Efendic S, Schmidt PT, Hellström PM. 2009. The incretin hormones GIP and GLP-1 in diabetic rats: effects on insulin secretion and small bowel motility. Neurogastroenterol. Motil. 21:313–21
    [Google Scholar]
  34. 34.
    Egerod KL, Engelstoft MS, Grunddal KV, Nohr MK, Secher A et al. 2012. A major lineage of enteroendocrine cells coexpress CCK, secretin, GIP, GLP-1, PYY, and neurotensin but not somatostatin. Endocrinology 153:5782–95
    [Google Scholar]
  35. 35.
    Ehses JA, Pelech SL, Pederson RA, McIntosh CH. 2002. Glucose-dependent insulinotropic polypeptide activates the Raf-Mek1/2-ERK1/2 module via a cyclic AMP/cAMP-dependent protein kinase/Rap1-mediated pathway. J. Biol. Chem. 277:37088–97
    [Google Scholar]
  36. 36.
    Ekberg JH, Hauge M, Kristensen LV, Madsen AN, Engelstoft MS et al. 2016. GPR119, a major enteroendocrine sensor of dietary triglyceride metabolites coacting in synergy with FFA1 (GPR40). Endocrinology 157:4561–9
    [Google Scholar]
  37. 37.
    El K, Gray SM, Capozzi ME, Knuth ER, Jin E et al. 2021. GIP mediates the incretin effect and glucose tolerance by dual actions on α cells and β cells. Sci. Adv. 7:11eabf1948
    [Google Scholar]
  38. 38.
    Elahi D, McAloon-Dyke M, Fukagawa NK, Meneilly GS, Sclater AL et al. 1994. The insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (7–37) in normal and diabetic subjects. Regul. Pept. 51:63–74
    [Google Scholar]
  39. 39.
    Elliott RM, Morgan LM, Tredger JA, Deacon S, Wright J, Marks V 1993. Glucagon-like peptide-1(7–36)amide and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: acute post-prandial and 24-h secretion patterns. J. Endocrinol. 138:159–66
    [Google Scholar]
  40. 40.
    Eur. Assoc. Study Diabetes 2021. 57th EASD Annual Meeting of the European Association for the Study of Diabetes. Diabetologia 64:1–380
    [Google Scholar]
  41. 41.
    Feng J, Kang C, Wang C, Ding L, Zhu W, Hang S 2019. L-phenylalanine increased gut hormone secretion through calcium-sensing receptor in the porcine duodenum. Animals 9:8476
    [Google Scholar]
  42. 42.
    Finan B, Ma T, Ottaway N, Muller TD, Habegger KM et al. 2013. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci. Transl. Med. 5:209ra151
    [Google Scholar]
  43. 43.
    Finan B, Yang B, Ottaway N, Smiley DL, Ma T et al. 2015. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat. Med. 21:27–36
    [Google Scholar]
  44. 44.
    Flatt PR, Bailey CJ, Kwasowski P, Swanston-Flatt SK, Marks V 1983. Abnormalities of GIP in spontaneous syndromes of obesity and diabetes in mice. Diabetes 32:433–35
    [Google Scholar]
  45. 45.
    Flatt PR, Kwasowski P, Howland RJ, Bailey CJ. 1991. Gastric inhibitory polypeptide and insulin responses to orally administered amino acids in genetically obese hyperglycemic (ob/ob) mice. J. Nutr. 121:1123–28
    [Google Scholar]
  46. 46.
    Fortin JP, Schroeder JC, Zhu Y, Beinborn M, Kopin AS. 2010. Pharmacological characterization of human incretin receptor missense variants. J. Pharmacol. Exp. Ther. 332:274–80
    [Google Scholar]
  47. 47.
    Frias JP, Bastyr EJ 3rd, Vignati L, Tschop MH, Schmitt C et al. 2017. The sustained effects of a dual GIP/GLP-1 receptor agonist, NNC0090–2746, in patients with type 2 diabetes. Cell Metab 26:343–52.e2
    [Google Scholar]
  48. 48.
    Frias JP, Nauck MA, Van J, Kutner ME, Cui X et al. 2018. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial. Lancet 392:2180–93
    [Google Scholar]
  49. 49.
    Friedrichsen BN, Neubauer N, Lee YC, Gram VK, Blume N et al. 2006. Stimulation of pancreatic β-cell replication by incretins involves transcriptional induction of cyclin D1 via multiple signalling pathways. J. Endocrinol. 188:481–92
    [Google Scholar]
  50. 50.
    Fu Y, Kaneko K, Lin HY, Mo Q, Xu Y et al. 2020. Gut hormone GIP induces inflammation and insulin resistance in the hypothalamus. Endocrinology 161:9bqaa102
    [Google Scholar]
  51. 51.
    Gabe MBN, van der Velden WJC, Gadgaard S, Smit FX, Hartmann B et al. 2020. Enhanced agonist residence time, internalization rate and signalling of the GIP receptor variant [E354Q] facilitate receptor desensitization and long-term impairment of the GIP system. Basic Clin. Pharmacol. Toxicol. 126:Suppl. 6122–32
    [Google Scholar]
  52. 52.
    Gabery S, Salinas CG, Paulsen SJ, Ahnfelt-Rønne J, Alanentalo T et al. 2020. Semaglutide lowers body weight in rodents via distributed neural pathways. JCI Insight 5:6e133429
    [Google Scholar]
  53. 53.
    Gasbjerg LS, Bergmann NC, Stensen S, Christensen MB, Rosenkilde MM et al. 2020. Evaluation of the incretin effect in humans using GIP and GLP-1 receptor antagonists. Peptides 125:170183
    [Google Scholar]
  54. 54.
    Gault VA, Flatt PR, Bailey CJ, Harriott P, Greer B et al. 2002. Enhanced cAMP generation and insulin-releasing potency of two novel Tyr1-modified enzyme-resistant forms of glucose-dependent insulinotropic polypeptide is associated with significant antihyperglycaemic activity in spontaneous obesity-diabetes. Biochem. J. 367:913–20
    [Google Scholar]
  55. 55.
    Gault VA, Flatt PR, Harriott P, Mooney MH, Bailey CJ, O'Harte FP. 2003. Improved biological activity of Gly2- and Ser2-substituted analogues of glucose-dependent insulinotrophic polypeptide. J. Endocrinol. 176:133–41
    [Google Scholar]
  56. 56.
    Gehart H, van Es JH, Hamer K, Beumer J, Kretzschmar K et al. 2019. Identification of enteroendocrine regulators by real-time single-cell differentiation mapping. Cell 176:1158–73.e16
    [Google Scholar]
  57. 57.
    Gerich JE, Lorenzi M, Hane S, Gustafson G, Guillemin R, Forsham PH. 1975. Evidence for a physiologic role of pancreatic glucagon in human glucose homeostasis: studies with somatostatin. Metabolism 24:175–82
    [Google Scholar]
  58. 58.
    Goldspink DA, Lu VB, Miedzybrodzka EL, Smith CA, Foreman RE et al. 2020. Labeling and characterization of human GLP-1-secreting L-cells in primary ileal organoid culture. Cell Rep 31:107833
    [Google Scholar]
  59. 59.
    Gorboulev V, Schurmann A, Vallon V, Kipp H, Jaschke A et al. 2012. Na+-d-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion. Diabetes 61:187–96
    [Google Scholar]
  60. 60.
    Greenfield JR, Farooqi IS, Keogh JM, Henning E, Habib AM et al. 2009. Oral glutamine increases circulating glucagon-like peptide 1, glucagon, and insulin concentrations in lean, obese, and type 2 diabetic subjects. Am. J. Clin. Nutr. 89:106–13
    [Google Scholar]
  61. 61.
    Gremlich S, Porret A, Hani EH, Cherif D, Vionnet N et al. 1995. Cloning, functional expression, and chromosomal localization of the human pancreatic islet glucose-dependent insulinotropic polypeptide receptor. Diabetes 44:1202–8
    [Google Scholar]
  62. 62.
    Habib AM, Richards P, Cairns LS, Rogers GJ, Bannon CA et al. 2012. Overlap of endocrine hormone expression in the mouse intestine revealed by transcriptional profiling and flow cytometry. Endocrinology 153:3054–65
    [Google Scholar]
  63. 63.
    Hansen KB, Rosenkilde MM, Knop FK, Wellner N, Diep TA et al. 2011. 2-Oleoyl glycerol is a GPR119 agonist and signals GLP-1 release in humans. J. Clin. Endocrinol. Metab. 96:E1409–17
    [Google Scholar]
  64. 64.
    He YL, Haynes W, Meyers CD, Amer A, Zhang Y et al. 2019. The effects of licogliflozin, a dual SGLT1/2 inhibitor, on body weight in obese patients with or without diabetes. Diabetes Obes. Metab. 21:1311–21
    [Google Scholar]
  65. 65.
    Helsted MM, Gasbjerg LS, Lanng AR, Bergmann NC, Stensen S et al. 2020. The role of endogenous GIP and GLP-1 in postprandial bone homeostasis. Bone 140:115553
    [Google Scholar]
  66. 66.
    Hinke SA, Gelling RW, Pederson RA, Manhart S, Nian C et al. 2002. Dipeptidyl peptidase IV-resistant [d-Ala2]glucose-dependent insulinotropic polypeptide (GIP) improves glucose tolerance in normal and obese diabetic rats. Diabetes 51:652–61
    [Google Scholar]
  67. 67.
    Holst JJ, Jensen SL, Knuhtsen S, Nielsen OV, Rehfeld JF. 1983. Effect of vagus, gastric inhibitory polypeptide, and HCl on gastrin and somatostatin release from perfused pig antrum. Am. J. Physiol. 244:G515–22
    [Google Scholar]
  68. 68.
    Holst JJ, Rosenkilde MM. 2020. Recent advances of GIP and future horizons. Peptides 125:170230
    [Google Scholar]
  69. 69.
    Holt MK, Richards JE, Cook DR, Brierley DI, Williams DL et al. 2019. Preproglucagon neurons in the nucleus of the solitary tract are the main source of brain GLP-1, mediate stress-induced hypophagia, and limit unusually large intakes of food. Diabetes 68:21–33
    [Google Scholar]
  70. 70.
    Højberg PV, Vilsbøll T, Rabøl R, Knop FK, Bache M et al. 2009. Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. Diabetologia 52:199–207
    [Google Scholar]
  71. 71.
    Ismail S, Dubois-Vedrenne I, Laval M, Tikhonova IG, D'Angelo R et al. 2015. Internalization and desensitization of the human glucose-dependent-insulinotropic receptor is affected by N-terminal acetylation of the agonist. Mol. Cell. Endocrinol. 414:202–15
    [Google Scholar]
  72. 72.
    Iwasaki K, Harada N, Sasaki K, Yamane S, Iida K et al. 2015. Free fatty acid receptor GPR120 is highly expressed in enteroendocrine K cells of the upper small intestine and has a critical role in GIP secretion after fat ingestion. Endocrinology 156:837–46
    [Google Scholar]
  73. 73.
    Jepsen SL, Grunddal KV, Wewer Albrechtsen NJ, Engelstoft MS, Gabe MBN et al. 2019. Paracrine crosstalk between intestinal L- and D-cells controls secretion of glucagon-like peptide-1 in mice. Am. J. Physiol. Endocrinol. Metab. 317:E1081–93
    [Google Scholar]
  74. 74.
    Jiang Y, Rose AJ, Sijmonsma TP, Broer A, Pfenninger A et al. 2015. Mice lacking neutral amino acid transporter B0AT1 (Slc6a19) have elevated levels of FGF21 and GLP-1 and improved glycaemic control. Mol. Metab. 4:406–17
    [Google Scholar]
  75. 75.
    Johnson DG, Ensinck JW, Koerker D, Palmer J, Goodner CJ. 1975. Inhibition of glucagon and insulin secretion by somatostatin in the rat pancreas perfused in situ. Endocrinology 96:370–74
    [Google Scholar]
  76. 76.
    Joo E, Harada N, Yamane S, Fukushima T, Taura D et al. 2017. Inhibition of gastric inhibitory polypeptide receptor signaling in adipose tissue reduces insulin resistance and hepatic steatosis in high-fat diet–fed mice. Diabetes 66:868–79
    [Google Scholar]
  77. 77.
    Jujić A, Atabaki-Pasdar N, Nilsson PM, Almgren P, Hakaste L et al. 2020. Glucose-dependent insulinotropic peptide and risk of cardiovascular events and mortality: a prospective study. Diabetologia 63:1043–54
    [Google Scholar]
  78. 78.
    Kaneko K, Fu Y, Lin HY, Cordonier EL, Mo Q et al. 2019. Gut-derived GIP activates central Rap1 to impair neural leptin sensitivity during overnutrition. J. Clin. Investig. 129:3786–91
    [Google Scholar]
  79. 79.
    Kay RG, Foreman RE, Roberts GP, Hardwick R, Reimann F, Gribble FM. 2020. Mass spectrometric characterisation of the circulating peptidome following oral glucose ingestion in control and gastrectomised patients. Rapid Commun. Mass Spectrom. 34:e8849
    [Google Scholar]
  80. 80.
    Kieffer TJ, Buchan AM, Barker H, Brown JC, Pederson RA. 1994. Release of gastric inhibitory polypeptide from cultured canine endocrine cells. Am. J. Physiol. 267:E489–96
    [Google Scholar]
  81. 81.
    Kieffer TJ, McIntosh CH, Pederson RA. 1995. Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology 136:3585–96
    [Google Scholar]
  82. 82.
    Killion EA, Chen M, Falsey JR, Sivits G, Hager T et al. 2020. Chronic glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism desensitizes adipocyte GIPR activity mimicking functional GIPR antagonism. Nat. Commun. 11:4981
    [Google Scholar]
  83. 83.
    Killion EA, Wang J, Yie J, Shi SD, Bates D et al. 2018. Anti-obesity effects of GIPR antagonists alone and in combination with GLP-1R agonists in preclinical models. Sci. Transl. Med. 10:472eaat3392
    [Google Scholar]
  84. 84.
    Kim SJ, Nian C, Widenmaier S, McIntosh CH. 2008. Glucose-dependent insulinotropic polypeptide-mediated up-regulation of β-cell antiapoptotic Bcl-2 gene expression is coordinated by cyclic AMP (cAMP) response element binding protein (CREB) and cAMP-responsive CREB coactivator 2. Mol. Cell. Biol. 28:1644–56
    [Google Scholar]
  85. 85.
    Kim SJ, Winter K, Nian C, Tsuneoka M, Koda Y, McIntosh CH. 2005. Glucose-dependent insulinotropic polypeptide (GIP) stimulation of pancreatic β-cell survival is dependent upon phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signaling, inactivation of the forkhead transcription factor Foxo1, and down-regulation of bax expression. J. Biol. Chem. 280:22297–307
    [Google Scholar]
  86. 86.
    Kizilkaya HS, Sørensen KV, Kibsgaard CJ, Gasbjerg LS, Hauser AS et al. 2021. Loss of function glucose-dependent insulinotropic polypeptide receptor variants are associated with alterations in BMI, bone strength and cardiovascular outcomes. Front. Cell Dev. Biol. 9:749607
    [Google Scholar]
  87. 87.
    Kuhre RE, Gribble FM, Hartmann B, Reimann F, Windelov JA et al. 2014. Fructose stimulates GLP-1 but not GIP secretion in mice, rats, and humans. Am. J. Physiol. Gastrointest. Liver Physiol. 306:G622–30
    [Google Scholar]
  88. 88.
    Kuhre RE, Wewer Albrechtsen NJ, Larsen O, Jepsen SL, Balk-Moller E et al. 2018. Bile acids are important direct and indirect regulators of the secretion of appetite- and metabolism-regulating hormones from the gut and pancreas. Mol. Metab. 11:84–95
    [Google Scholar]
  89. 89.
    Lee EY, Zhang X, Miyamoto J, Kimura I, Taknaka T et al. 2018. Gut carbohydrate inhibits GIP secretion via a microbiota/SCFA/FFAR3 pathway. J. Endocrinol. 239:267–76
    [Google Scholar]
  90. 90.
    Light PE, Manning Fox JE, Riedel MJ, Wheeler MB 2002. Glucagon-like peptide-1 inhibits pancreatic ATP-sensitive potassium channels via a protein kinase A- and ADP-dependent mechanism. Mol. Endocrinol. 16:2135–44
    [Google Scholar]
  91. 91.
    Lu WJ, Yang Q, Yang L, Lee D, D'Alessio D, Tso P 2012. Chylomicron formation and secretion is required for lipid-stimulated release of incretins GLP-1 and GIP. Lipids 47:571–80
    [Google Scholar]
  92. 92.
    Ludwig MQ, Todorov PV, Egerod KL, Olson DP, Pers TH. 2021. Single-cell mapping of GLP-1 and GIP receptor expression in the dorsal vagal complex. Diabetes 70:1945–55
    [Google Scholar]
  93. 93.
    Lund A, Vilsbøll T, Bagger JI, Holst JJ, Knop FK. 2011. The separate and combined impact of the intestinal hormones, GIP, GLP-1, and GLP-2, on glucagon secretion in type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 300:E1038–46
    [Google Scholar]
  94. 94.
    Lyssenko V, Eliasson L, Kotova O, Pilgaard K, Wierup N et al. 2011. Pleiotropic effects of GIP on islet function involve osteopontin. Diabetes 60:2424–33
    [Google Scholar]
  95. 95.
    MacDonald PE, Wang X, Xia F, El-kholy W, Targonsky ED et al. 2003. Antagonism of rat β-cell voltage-dependent K+ currents by exendin 4 requires dual activation of the cAMP/protein kinase A and phosphatidylinositol 3-kinase signaling pathways. J. Biol. Chem. 278:52446–53
    [Google Scholar]
  96. 96.
    Margolskee RF, Dyer J, Kokrashvili Z, Salmon KS, Ilegems E et al. 2007. T1R3 and gustducin in gut sense sugars to regulate expression of Na+-glucose cotransporter 1. PNAS 104:15075–80
    [Google Scholar]
  97. 97.
    Marks V. 2020. The early history of GIP 1969–2000: from enterogastrone to major metabolic hormone. Peptides 125:170276
    [Google Scholar]
  98. 98.
    McGlone ER, Malallah K, Cuenco J, Wewer Albrechtsen NJ, Holst JJ et al. 2021. Differential effects of bile acids on the postprandial secretion of gut hormones: a randomized crossover study. Am. J. Physiol. Endocrinol. Metab. 320:E671–79
    [Google Scholar]
  99. 99.
    Mentis N, Vardarli I, Kothe LD, Holst JJ, Deacon CF et al. 2011. GIP does not potentiate the antidiabetic effects of GLP-1 in hyperglycemic patients with type 2 diabetes. Diabetes 60:1270–76
    [Google Scholar]
  100. 100.
    Miki T, Minami K, Shinozaki H, Matsumura K, Saraya A et al. 2005. Distinct effects of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 on insulin secretion and gut motility. Diabetes 54:1056–63
    [Google Scholar]
  101. 101.
    Min T, Bain SC. 2021. The role of tirzepatide, dual GIP and GLP-1 receptor agonist, in the management of type 2 diabetes: the SURPASS clinical trials. Diabetes Ther 12:143–57
    [Google Scholar]
  102. 102.
    Miyawaki K, Yamada Y, Ban N, Ihara Y, Tsukiyama K et al. 2002. Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat. Med. 8:738–42
    [Google Scholar]
  103. 103.
    Modvig IM, Kuhre RE, Holst JJ. 2019. Peptone-mediated glucagon-like peptide-1 secretion depends on intestinal absorption and activation of basolaterally located calcium-sensing receptors. Physiol. Rep. 7:e14056
    [Google Scholar]
  104. 104.
    Moens K, Heimberg H, Flamez D, Huypens P, Quartier E et al. 1996. Expression and functional activity of glucagon, glucagon-like peptide I, and glucose-dependent insulinotropic peptide receptors in rat pancreatic islet cells. Diabetes 45:257–61
    [Google Scholar]
  105. 105.
    Mohammad S, Patel RT, Bruno J, Panhwar MS, Wen J, McGraw TE. 2014. A naturally occurring GIP receptor variant undergoes enhanced agonist-induced desensitization, which impairs GIP control of adipose insulin sensitivity. Mol. Cell. Biol. 34:3618–29
    [Google Scholar]
  106. 106.
    Moller CL, Vistisen D, Faerch K, Johansen NB, Witte DR et al. 2016. Glucose-dependent insulinotropic polypeptide is associated with lower low-density lipoprotein but unhealthy fat distribution, independent of insulin: the ADDITION-PRO study. J. Clin. Endocrinol. Metab. 101:485–93
    [Google Scholar]
  107. 107.
    Morgan LM, Morris BA, Marks V. 1978. Radioimmunoassay of gastric inhibitory polypeptide. Ann. Clin. Biochem. 15:172–77
    [Google Scholar]
  108. 108.
    Morgan LM, Wright JW, Marks V. 1979. The effect of oral galactose on GIP and insulin secretion in man. Diabetologia 16:235–39
    [Google Scholar]
  109. 109.
    Moss CE, Marsh WJ, Parker HE, Ogunnowo-Bada E, Riches CH et al. 2012. Somatostatin receptor 5 and cannabinoid receptor 1 activation inhibit secretion of glucose-dependent insulinotropic polypeptide from intestinal K cells in rodents. Diabetologia 55:3094–103
    [Google Scholar]
  110. 110.
    Mroz PA, Finan B, Gelfanov V, Yang B, Tschöp MH et al. 2019. Optimized GIP analogs promote body weight lowering in mice through GIPR agonism not antagonism. Mol. Metab. 20:51–62
    [Google Scholar]
  111. 111.
    Murata Y, Harada N, Kishino S, Iwasaki K, Ikeguchi-Ogura E et al. 2021. Medium-chain triglycerides inhibit long-chain triglyceride-induced GIP secretion through GPR120-dependent inhibition of CCK. iScience 24:102963
    [Google Scholar]
  112. 112.
    NamKoong C, Kim MS, Jang BT, Lee YH, Cho YM, Choi HJ. 2017. Central administration of GLP-1 and GIP decreases feeding in mice. Biochem. Biophys. Res. Commun. 490:247–52
    [Google Scholar]
  113. 113.
    Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W. 1993. Preserved incretin activity of glucagon-like peptide 1 [7–36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J. Clin. Investig. 91:301–7
    [Google Scholar]
  114. 114.
    Nissen A, Christensen M, Knop FK, Vilsboll T, Holst JJ, Hartmann B. 2014. Glucose-dependent insulinotropic polypeptide inhibits bone resorption in humans. J. Clin. Endocrinol. Metab. 99:E2325–29
    [Google Scholar]
  115. 115.
    Nyberg J, Anderson MF, Meister B, Alborn AM, Ström AK et al. 2005. Glucose-dependent insulinotropic polypeptide is expressed in adult hippocampus and induces progenitor cell proliferation. J. Neurosci. 25:1816–25
    [Google Scholar]
  116. 116.
    Nyberg J, Jacobsson C, Anderson MF, Eriksson PS 2007. Immunohistochemical distribution of glucose-dependent insulinotropic polypeptide in the adult rat brain. J. Neurosci. Res. 85:2099–119
    [Google Scholar]
  117. 117.
    O'Harte FP, Gault VA, Parker JC, Harriott P, Mooney MH et al. 2002. Improved stability, insulin-releasing activity and antidiabetic potential of two novel N-terminal analogues of gastric inhibitory polypeptide: N-acetyl-GIP and pGlu-GIP. Diabetologia 45:1281–91
    [Google Scholar]
  118. 118.
    Ogata H, Seino Y, Harada N, Iida A, Suzuki K et al. 2014. KATP channel as well as SGLT1 participates in GIP secretion in the diabetic state. J. Endocrinol. 222:191–200
    [Google Scholar]
  119. 119.
    Okawa M, Fujii K, Ohbuchi K, Okumoto M, Aragane K et al. 2009. Role of MGAT2 and DGAT1 in the release of gut peptides after triglyceride ingestion. Biochem. Biophys. Res. Commun. 390:377–81
    [Google Scholar]
  120. 120.
    Overton HA, Babbs AJ, Doel SM, Fyfe MC, Gardner LS et al. 2006. Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents. Cell Metab 3:167–75
    [Google Scholar]
  121. 121.
    Parker HE, Habib AM, Rogers GJ, Gribble FM, Reimann F. 2009. Nutrient-dependent secretion of glucose-dependent insulinotropic polypeptide from primary murine K cells. Diabetologia 52:289–98
    [Google Scholar]
  122. 122.
    Piteau S, Olver A, Kim SJ, Winter K, Pospisilik JA et al. 2007. Reversal of islet GIP receptor down-regulation and resistance to GIP by reducing hyperglycemia in the Zucker rat. Biochem. Biophys. Res. Commun. 362:1007–12
    [Google Scholar]
  123. 123.
    Powell DR, Smith M, Greer J, Harris A, Zhao S et al. 2013. LX4211 increases serum glucagon-like peptide 1 and peptide YY levels by reducing sodium/glucose cotransporter 1 (SGLT1)-mediated absorption of intestinal glucose. J. Pharmacol. Exp. Ther. 345:250–59
    [Google Scholar]
  124. 124.
    Psichas A, Glass LL, Sharp SJ, Reimann F, Gribble FM. 2016. Galanin inhibits GLP-1 and GIP secretion via the GAL1 receptor in enteroendocrine L and K cells. Br. J. Pharmacol. 173:888–98
    [Google Scholar]
  125. 125.
    Roberts GP, Larraufie P, Richards P, Kay RG, Galvin SG et al. 2019. Comparison of human and murine enteroendocrine cells by transcriptomic and peptidomic profiling. Diabetes 68:1062–72
    [Google Scholar]
  126. 126.
    Rogers GJ, Tolhurst G, Ramzan A, Habib AM, Parker HE et al. 2011. Electrical activity-triggered glucagon-like peptide-1 secretion from primary murine L-cells. J. Physiol. 589:1081–93
    [Google Scholar]
  127. 127.
    Rorsman P, Huising MO. 2018. The somatostatin-secreting pancreatic δ-cell in health and disease. Nat. Rev. Endocrinol. 14:404–14
    [Google Scholar]
  128. 128.
    Rudenko O, Shang J, Munk A, Ekberg JP, Petersen N et al. 2019. The aromatic amino acid sensor GPR142 controls metabolism through balanced regulation of pancreatic and gut hormones. Mol. Metab. 19:49–64
    [Google Scholar]
  129. 129.
    Saltiel MY, Kuhre RE, Christiansen CB, Eliasen R, Conde-Frieboes KW et al. 2017. Sweet taste receptor activation in the gut is of limited importance for glucose-stimulated GLP-1 and GIP secretion. Nutrients 9:4418
    [Google Scholar]
  130. 130.
    Samms RJ, Christe ME, Collins KA, Pirro V, Droz BA et al. 2021. GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice. J. Clin. Investig. 131:12e146353
    [Google Scholar]
  131. 131.
    Sankoda A, Harada N, Iwasaki K, Yamane S, Murata Y et al. 2017. Long-chain free fatty acid receptor GPR120 mediates oil-induced GIP secretion through CCK in male mice. Endocrinology 158:1172–80
    [Google Scholar]
  132. 132.
    Sankoda A, Harada N, Kato T, Ikeguchi E, Iwasaki K et al. 2019. Free fatty acid receptors, G protein-coupled receptor 120 and G protein-coupled receptor 40, are essential for oil-induced gastric inhibitory polypeptide secretion. J. Diabetes Investig. 10:1430–37
    [Google Scholar]
  133. 133.
    Saxena R, Hivert MF, Langenberg C, Tanaka T, Pankow JS et al. 2010. Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nat. Genet. 42:142–48
    [Google Scholar]
  134. 134.
    Segerstolpe A, Palasantza A, Eliasson P, Andersson EM, Andreasson AC et al. 2016. Single-cell transcriptome profiling of human pancreatic islets in health and type 2 diabetes. Cell Metab 24:593–607
    [Google Scholar]
  135. 135.
    Shibasaki T, Takahashi H, Miki T, Sunaga Y, Matsumura K et al. 2007. Essential role of Epac2/Rap1 signaling in regulation of insulin granule dynamics by cAMP. PNAS 104:19333–38
    [Google Scholar]
  136. 136.
    Shibue K, Yamane S, Harada N, Hamasaki A, Suzuki K et al. 2015. Fatty acid-binding protein 5 regulates diet-induced obesity via GIP secretion from enteroendocrine K cells in response to fat ingestion. Am. J. Physiol. Endocrinol. Metab. 308:E583–91
    [Google Scholar]
  137. 137.
    Siegel EG, Schulze A, Schmidt WE, Creutzfeldt W. 1992. Comparison of the effect of GIP and GLP-1 (7–36amide) on insulin release from rat pancreatic islets. Eur. J. Clin. Investig. 22:154–57
    [Google Scholar]
  138. 138.
    Sjolund K, Sanden G, Hakanson R, Sundler F. 1983. Endocrine cells in human intestine: an immunocytochemical study. Gastroenterology 85:1120–30
    [Google Scholar]
  139. 139.
    Skelin M, Rupnik M. 2011. cAMP increases the sensitivity of exocytosis to Ca2+ primarily through protein kinase A in mouse pancreatic beta cells. Cell Calcium 49:89–99
    [Google Scholar]
  140. 140.
    Sommer CA, Mostoslavsky G. 2014. RNA-Seq analysis of enteroendocrine cells reveals a role for FABP5 in the control of GIP secretion. Mol. Endocrinol. 28:1855–65
    [Google Scholar]
  141. 141.
    Sparre-Ulrich AH, Gabe MN, Gasbjerg LS, Christiansen CB, Svendsen B et al. 2017. GIP(3–30)NH2 is a potent competitive antagonist of the GIP receptor and effectively inhibits GIP-mediated insulin, glucagon, and somatostatin release. Biochem. Pharmacol. 131:78–88
    [Google Scholar]
  142. 142.
    Stensen S, Gasbjerg LS, Helsted MM, Hartmann B, Christensen MB, Knop FK. 2020. GIP and the gut-bone axis—physiological, pathophysiological and potential therapeutic implications. Peptides 125:170197
    [Google Scholar]
  143. 143.
    Stensen S, Gasbjerg LS, Krogh LL, Skov-Jeppesen K, Sparre-Ulrich AH et al. 2021. Effects of endogenous GIP in patients with type 2 diabetes. Eur. J. Endocrinol. 185:33–45
    [Google Scholar]
  144. 144.
    Stephens JW, Bodvarsdottir TB, Wareham K, Prior SL, Bracken RM et al. 2011. Effects of short-term therapy with glibenclamide and repaglinide on incretin hormones and oxidative damage associated with postprandial hyperglycaemia in people with type 2 diabetes mellitus. Diabetes Res. Clin. Pract. 94:199–206
    [Google Scholar]
  145. 145.
    Svendsen B, Capozzi ME, Nui J, Hannou SA, Finan B et al. 2020. Pharmacological antagonism of the incretin system protects against diet-induced obesity. Mol. Metab. 32:44–55
    [Google Scholar]
  146. 146.
    Svendsen B, Larsen O, Gabe MBN, Christiansen CB, Rosenkilde MM et al. 2018. Insulin secretion depends on intra-islet glucagon signaling. Cell Rep 25:1127–34.e2
    [Google Scholar]
  147. 147.
    Sykes S, Morgan LM, English J, Marks V. 1980. Evidence for preferential stimulation of gastric inhibitory polypeptide secretion in the rat by actively transported carbohydrates and their analogues. J. Endocrinol. 85:201–7
    [Google Scholar]
  148. 148.
    Thomas FB, Mazzaferri EL, Crockett SE, Mekhjian HS, Gruemer HD, Cataland S. 1976. Stimulation of secretion of gastric inhibitory polypeptide and insulin by intraduodenal amino acid perfusion. Gastroenterology 70:523–27
    [Google Scholar]
  149. 149.
    Tolhurst G, Heffron H, Lam YS, Parker HE, Habib AM et al. 2012. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes 61:364–71
    [Google Scholar]
  150. 150.
    Torekov SS, Harsløf T, Rejnmark L, Eiken P, Jensen JB et al. 2014. A functional amino acid substitution in the glucose-dependent insulinotropic polypeptide receptor (GIPR) gene is associated with lower bone mineral density and increased fracture risk. J. Clin. Endocrinol. Metab. 99:E729–33
    [Google Scholar]
  151. 151.
    Tseng CC, Jarboe LA, Landau SB, Williams EK, Wolfe MM. 1993. Glucose-dependent insulinotropic peptide: structure of the precursor and tissue-specific expression in rat. PNAS 90:1992–96
    [Google Scholar]
  152. 152.
    Tsukiyama K, Yamada Y, Yamada C, Harada N, Kawasaki Y et al. 2006. Gastric inhibitory polypeptide as an endogenous factor promoting new bone formation after food ingestion. Mol. Endocrinol. 20:1644–51
    [Google Scholar]
  153. 153.
    Ugleholdt R, Pedersen J, Bassi MR, Füchtbauer EM, Jørgensen SM et al. 2011. Transgenic rescue of adipocyte glucose-dependent insulinotropic polypeptide receptor expression restores high fat diet-induced body weight gain. J. Biol. Chem. 286:44632–45
    [Google Scholar]
  154. 154.
    Usdin TB, Mezey E, Button DC, Brownstein MJ, Bonner TI. 1993. Gastric inhibitory polypeptide receptor, a member of the secretin-vasoactive intestinal peptide receptor family, is widely distributed in peripheral organs and the brain. Endocrinology 133:2861–70
    [Google Scholar]
  155. 155.
    Vilsbøll T, Krarup T, Madsbad S, Holst JJ. 2002. Defective amplification of the late phase insulin response to glucose by GIP in obese Type II diabetic patients. Diabetologia 45:1111–19
    [Google Scholar]
  156. 156.
    Vilsbøll T, Krarup T, Madsbad S, Holst JJ. 2003. Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects. Regul. Pept. 114:115–21
    [Google Scholar]
  157. 157.
    Vyavahare SS, Mieczkowska A, Flatt PR, Chappard D, Irwin N, Mabilleau G. 2020. GIP analogues augment bone strength by modulating bone composition in diet-induced obesity in mice. Peptides 125:170207
    [Google Scholar]
  158. 158.
    Wang C, Kang C, Xian Y, Zhang M, Chen X et al. 2018. Sensing of L-arginine by gut-expressed calcium sensing receptor stimulates gut satiety hormones cholecystokinin and glucose-dependent insulinotropic peptide secretion in pig model. J. Food Sci. 83:2394–401
    [Google Scholar]
  159. 159.
    Wang T, Ma X, Tang T, Higuchi K, Peng D et al. 2017. The effect of glucose-dependent insulinotropic polypeptide (GIP) variants on visceral fat accumulation in Han Chinese populations. Nutr. Diabetes 7:e278
    [Google Scholar]
  160. 160.
    West JA, Tsakmaki A, Ghosh SS, Parkes DG, Grønlund RV et al. 2021. Chronic peptide-based GIP receptor inhibition exhibits modest glucose metabolic changes in mice when administered either alone or combined with GLP-1 agonism. PLOS ONE 16:e0249239
    [Google Scholar]
  161. 161.
    Wu T, Zhao BR, Bound MJ, Checklin HL, Bellon M et al. 2012. Effects of different sweet preloads on incretin hormone secretion, gastric emptying, and postprandial glycemia in healthy humans. Am. J. Clin. Nutr. 95:78–83
    [Google Scholar]
  162. 162.
    Zhang C, Kaye JA, Cai Z, Wang Y, Prescott SL, Liberles SD. 2021. Area postrema cell types that mediate nausea-associated behaviors. Neuron 109:461–72.e5
    [Google Scholar]
  163. 163.
    Zhang CL, Katoh M, Shibasaki T, Minami K, Sunaga Y et al. 2009. The cAMP sensor Epac2 is a direct target of antidiabetic sulfonylurea drugs. Science 325:607–10
    [Google Scholar]
  164. 164.
    Zhang Q, Delessa CT, Augustin R, Bakhti M, Collden G et al. 2021. The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling. Cell Metab 33:833–44.e5
    [Google Scholar]
  165. 165.
    Zhang ZQ, Holscher C. 2020. GIP has neuroprotective effects in Alzheimer and Parkinson's disease models. Peptides 125:170184
    [Google Scholar]
  166. 166.
    Zhao X, Xian Y, Wang C, Ding L, Meng X et al. 2018. Calcium-sensing receptor-mediated L-tryptophan-induced secretion of cholecystokinin and glucose-dependent insulinotropic peptide in swine duodenum. J. Vet. Sci. 19:179–87
    [Google Scholar]
  167. 167.
    Zhong Q, Itokawa T, Sridhar S, Ding KH, Xie D et al. 2007. Effects of glucose-dependent insulinotropic peptide on osteoclast function. Am. J. Physiol. Endocrinol. Metab. 292:E543–48
    [Google Scholar]
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