Review

. 2025 May:95:102118.

doi: 10.1016/j.molmet.2025.102118. Epub 2025 Feb 28.

Glucose-dependent insulinotropic polypeptide (GIP)

Timo D Müller¹, Alice Adriaenssens², Bo Ahrén³, Matthias Blüher⁴, Andreas L Birkenfeld⁵, Jonathan E Campbell⁶, Matthew P Coghlan⁷, David D'Alessio⁸, Carolyn F Deacon⁹, Stefano DelPrato¹⁰, Jonathan D Douros¹¹, Daniel J Drucker¹², Natalie S Figueredo Burgos², Peter R Flatt¹³, Brian Finan⁷, Ruth E Gimeno⁷, Fiona M Gribble¹⁴, Matthew R Hayes¹⁵, Christian Hölscher¹⁶, Jens J Holst¹⁷, Patrick J Knerr¹¹, Filip K Knop¹⁸, Christine M Kusminski¹⁹, Arkadiusz Liskiewicz²⁰, Guillaume Mabilleau²¹, Stephanie A Mowery¹¹, Michael A Nauck²², Aaron Novikoff²³, Frank Reimann¹⁴, Anna G Roberts², Mette M Rosenkilde²⁴, Ricardo J Samms⁷, Philip E Scherer¹⁹, Randy J Seeley²⁵, Kyle W Sloop⁷, Christian Wolfrum²⁶, Denise Wootten²⁷, Richard D DiMarchi²⁸, Matthias H Tschöp²⁹

Affiliations

¹ Institute for Diabetes and Obesity, Helmholtz Munich, Germany; German Center for Diabetes Research, DZD, Germany; Walther-Straub Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University Munich (LMU), Germany. Electronic address: timo.mueller@helmholtz-muenchen.de.
² Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London, UK.
³ Department of Clinical Sciences, Lund, Lund University, Lund, Sweden.
⁴ Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany.
⁵ Department of Internal Medicine IV, University Hospital Tübingen, Tübingen 72076, Germany; Institute of Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich, Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany.
⁶ Duke Molecular Physiology Institute, Duke University, Durham, NC, USA; Department of Medicine, Division of Endocrinology, Duke University, Durham, NC, USA; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA.
⁷ Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
⁸ Department of Medicine, Division of Endocrinology, Duke University, Durham, NC, USA; Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.
⁹ School of Biomedical Sciences, Ulster University, Coleraine, UK; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁰ Interdisciplinary Research Center "Health Science", Sant'Anna School of Advanced Studies, Pisa, Italy.
¹¹ Indianapolis Biosciences Research Institute, Indianapolis, IN, USA.
¹² The Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, and the Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
¹³ Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland BT52 1SA, UK.
¹⁴ Institute of Metabolic Science-Metabolic Research Laboratories & MRC-Metabolic Diseases Unit, University of Cambridge, Cambridge, UK.
¹⁵ Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, USA; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁶ Neurodegeneration Research Group, Henan Academy of Innovations in Medical Science, Xinzheng, China.
¹⁷ Department of Biomedical Sciences and the Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
¹⁸ Center for Clinical Metabolic Research, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁹ Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
²⁰ Institute for Diabetes and Obesity, Helmholtz Munich, Germany; German Center for Diabetes Research, DZD, Germany; Department of Physiology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland.
²¹ Univ Angers, Nantes Université, ONIRIS, Inserm, RMeS UMR 1229, Angers, France; CHU Angers, Departement de Pathologie Cellulaire et Tissulaire, Angers, France.
²² Diabetes, Endocrinology and Metabolism Section, Department of Internal Medicine I, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.
²³ Institute for Diabetes and Obesity, Helmholtz Munich, Germany; German Center for Diabetes Research, DZD, Germany.
²⁴ Department of Biomedical Sciences, Faculty of Health and Medical Sciences University of Copenhagen, Copenhagen, Denmark.
²⁵ Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
²⁶ Institute of Food, Nutrition and Health, ETH Zurich, 8092, Schwerzenbach, Switzerland.
²⁷ Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia; ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
²⁸ Department of Chemistry, Indiana University, Bloomington, IN, USA.
²⁹ Helmholtz Munich, Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technical University of Munich, Munich, Germany.

PMID: 40024571
PMCID: PMC11931254
DOI: 10.1016/j.molmet.2025.102118

Review

Glucose-dependent insulinotropic polypeptide (GIP)

Timo D Müller et al. Mol Metab. 2025 May.

. 2025 May:95:102118.

doi: 10.1016/j.molmet.2025.102118. Epub 2025 Feb 28.

Authors

Affiliations

¹ Institute for Diabetes and Obesity, Helmholtz Munich, Germany; German Center for Diabetes Research, DZD, Germany; Walther-Straub Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University Munich (LMU), Germany. Electronic address: timo.mueller@helmholtz-muenchen.de.
² Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London, UK.
³ Department of Clinical Sciences, Lund, Lund University, Lund, Sweden.
⁴ Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany.
⁵ Department of Internal Medicine IV, University Hospital Tübingen, Tübingen 72076, Germany; Institute of Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich, Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany.
⁶ Duke Molecular Physiology Institute, Duke University, Durham, NC, USA; Department of Medicine, Division of Endocrinology, Duke University, Durham, NC, USA; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA.
⁷ Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
⁸ Department of Medicine, Division of Endocrinology, Duke University, Durham, NC, USA; Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.
⁹ School of Biomedical Sciences, Ulster University, Coleraine, UK; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁰ Interdisciplinary Research Center "Health Science", Sant'Anna School of Advanced Studies, Pisa, Italy.
¹¹ Indianapolis Biosciences Research Institute, Indianapolis, IN, USA.
¹² The Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, and the Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
¹³ Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland BT52 1SA, UK.
¹⁴ Institute of Metabolic Science-Metabolic Research Laboratories & MRC-Metabolic Diseases Unit, University of Cambridge, Cambridge, UK.
¹⁵ Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, USA; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁶ Neurodegeneration Research Group, Henan Academy of Innovations in Medical Science, Xinzheng, China.
¹⁷ Department of Biomedical Sciences and the Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
¹⁸ Center for Clinical Metabolic Research, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁹ Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
²⁰ Institute for Diabetes and Obesity, Helmholtz Munich, Germany; German Center for Diabetes Research, DZD, Germany; Department of Physiology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland.
²¹ Univ Angers, Nantes Université, ONIRIS, Inserm, RMeS UMR 1229, Angers, France; CHU Angers, Departement de Pathologie Cellulaire et Tissulaire, Angers, France.
²² Diabetes, Endocrinology and Metabolism Section, Department of Internal Medicine I, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.
²³ Institute for Diabetes and Obesity, Helmholtz Munich, Germany; German Center for Diabetes Research, DZD, Germany.
²⁴ Department of Biomedical Sciences, Faculty of Health and Medical Sciences University of Copenhagen, Copenhagen, Denmark.
²⁵ Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
²⁶ Institute of Food, Nutrition and Health, ETH Zurich, 8092, Schwerzenbach, Switzerland.
²⁷ Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia; ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
²⁸ Department of Chemistry, Indiana University, Bloomington, IN, USA.
²⁹ Helmholtz Munich, Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technical University of Munich, Munich, Germany.

PMID: 40024571
PMCID: PMC11931254
DOI: 10.1016/j.molmet.2025.102118

Abstract

Background: Glucose-dependent insulinotropic polypeptide (GIP) was the first incretin identified and plays an essential role in the maintenance of glucose tolerance in healthy humans. Until recently GIP had not been developed as a therapeutic and thus has been overshadowed by the other incretin, glucagon-like peptide 1 (GLP-1), which is the basis for several successful drugs to treat diabetes and obesity. However, there has been a rekindling of interest in GIP biology in recent years, in great part due to pharmacology demonstrating that both GIPR agonism and antagonism may be beneficial in treating obesity and diabetes. This apparent paradox has reinvigorated the field, led to new lines of investigation, and deeper understanding of GIP.

Scope of review: In this review, we provide a detailed overview on the multifaceted nature of GIP biology and discuss the therapeutic implications of GIPR signal modification on various diseases.

Major conclusions: Following its classification as an incretin hormone, GIP has emerged as a pleiotropic hormone with a variety of metabolic effects outside the endocrine pancreas. The numerous beneficial effects of GIPR signal modification render the peptide an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, drug-induced nausea and both bone and neurodegenerative disorders.

Keywords: Diabetes; GIP; GLP-1; Incretin; Insulin; Obesity.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interest DJD has served as a consultant or speaker within the past 12 months to Amgen, AstraZeneca, Boehringer Ingelheim, Kallyope and Novo Nordisk Inc. Neither DJD or his family members hold issued stock directly or indirectly in any of these companies. DJD holds non-exercised options in Kallyope. S.A.M, J.D.D., B.F., and P.J.K. are shareholders and former employees of Novo Nordisk. RJS has received research support from Novo Nordisk, Fractyl, Astra Zeneca, Congruence Therapeutics, Eli Lilly, Bullfrog AI, Glycsend Therapeutics and Amgen. RJS has served as a paid consultant for Novo Nordisk, Eli Lilly, CinRx, Fractyl, Structure Therapeutics, Crinetics, Amgen and Congruence Therapeutics. RJS has equity in Bullfrog AI and Rewind. MMR and JJH are co-founders and shareholders of Antag Therapeutics and Bainan Biotech. MB received honoraria as a consultant and speaker from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Daiichi-Sankyo, Lilly, Novo Nordisk, Novartis, Pfizer and Sanofi. DW is shareholder and on the scientific advisory board of Septerna Inc. and a co-founder and shareholder of Dacra therapeutics. MRH receives research SRA fundining from Boehringer Ingelheim, Eli Lilly & Co., Pfizer, Gila Therapeutics, and Novo Nordisk. MRH is a named inventor of patents pursuant to work that is owned by Syracuse University and the University of Pennsylvania. MRH is a founding scientists and shareholder of Coronation Bio. Inc. FMG and FR have received research support from Eli Lilly and AstraZeneca. FKK has served on scientific advisory panels, been part of speaker's bureaus for, served as a consultant to, owns stocks in and/or received research support from 89bio, Amgen, AstraZeneca, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, Gubra, MedImmune, MSD/Merck, Norgine, Novo Nordisk, Sanofi, ShouTi, SNIPR Biome, Zealand Pharma and Zucara. FKK is a co-founder of and minority shareholder in Antag Therapeutics. FKK is currently employed by Novo Nordisk; the present work was done independent of Novo Nordisk. CH is a named inventor on patents that cover GIP or dual GLP-1/GIP receptor agonists as treatments for AD/PD. He is the CSO of Kariya Pharmaceutics Ltd. JJH appears on advisory boards for Novo Nordisk. SDP has served as president of EASD/European Foundation for the Study of Diabetes (EFSD) (2020–2022) and is current president of Fondazione Menarini; has received research grants to the institution from AstraZeneca and Boehringer Ingelheim; has served as advisor for Abbott, Amarin Corporation, Amplitude, Applied Therapeutics, AstraZeneca, Biomea Fusion, Eli Lilly & Co., EvaPharma, Menarini International, Novo Nordisk, Sanofi, and Sun Pharmaceuticals; and has received fees for speaking from AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co., Laboratori Guidotti, Menarini International, Merck Sharpe & Dohme, and Novo Nordisk. PRF has served as consultant for Amgen, Ipsen, Novo Nordisk, Sanofi, Zealand and is co-founder and shareholder of Dia Beta Labs. MHT is a member of the scientific advisory board of ERX Pharmaceuticals, Cambridge, Mass. He was a member of the Research Cluster Advisory Panel (ReCAP) of the Novo Nordisk Foundation between 2017 and 2019. He attended a scientific advisory board meeting of the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, in 2016. He received funding for his research projects by Novo Nordisk (2016–2020) and Sanofi-Aventis (2012–2019). He was a consultant for Bionorica SE (2013–2017), Menarini Ricerche S.p.A. (2016), and Bayer Pharma AG Berlin (2016). As former Director of the Helmholtz Diabetes Center and the Institute for Diabetes and Obesity at Helmholtz Zentrum München (2011–2018), and since 2018, as CEO of Helmholtz Zentrum München, he has been responsible for collaborations with a multitude of companies and institutions, worldwide. In this capacity, he discussed potential projects with and has signed/signs contracts for his institute(s) and for the staff for research funding and/or collaborations with industry and academia, worldwide, including but not limited to pharmaceutical corporations like Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Medigene, Arbormed, BioSyngen, and others. In this role, he was/is further responsible for commercial technology transfer activities of his institute(s), including diabetes related patent portfolios of Helmholtz Zentrum München as, e.g., WO/2016/188932 A2 or WO/2017/194499 A1. MHT confirms that to the best of his knowledge none of the above funding sources were involved in the preparation of this paper. MAN has been member on advisory boards or has consulted with Boehringer Ingelheim, Eli Lilly & Co., Medtronic, Merck, Sharp & Dohme, NovoNordisk, Pfizer, Regor, Sun Pharma, and Structure Therapeutics (ShouTi, Gasherbrum). He has received grant support from Merck, Sharp & Dohme. He has also served on the speakers' bureau of Eli Lilly & Co., Merck, Sharp & Dohme, Medscape, Medical Learning Institute, and NovoNordisk. MAN has been member on advisory boards or has consulted with Boehringer Ingelheim, Eli Lilly & Co., Medtronic, Merck, Sharp & Dohme, NovoNordisk, Pfizer, Regor, Sun Pharma, and Structure Therapeutics (ShouTi, Gasherbrum). He has received grant support from Merck, Sharp & Dohme. He has also served on the speakers' bureau of Eli Lilly & Co., Merck, Sharp & Dohme, Medscape, Medical Learning Institute, and NovoNordisk. MAN has been member on advisory boards or has consulted with Boehringer Ingelheim, Eli Lilly & Co., Medtronic, Merck, Sharp & Dohme, NovoNordisk, Pfizer, Regor, Sun Pharma, and Structure Therapeutics (ShouTi, Gasherbrum). He has received grant support from Merck, Sharp & Dohme. He has also served on the speakers' bureau of Eli Lilly & Co., Merck, Sharp & Dohme, Medscape, Medical Learning Institute, and NovoNordisk. TDM receives funding from Novo Nordisk and has received speaking fees from Novo Nordisk, Eli Lilly, Boehringer Ingelheim, Merck, AstraZeneca, Mercodia and Berlin Chemie AG. TDM further holds stocks from Novo Nordisk and Eli Lilly. BA has served as a speaker within the past 12 months to Mankind and Novartis and is a shareholder of Astra Zeneca, Eli Lilly and Novo Nordisk AS. R.J.S., M.P.C., K.W.S., B.F. and R.E.G. are employees of Eli Lilly and Company and may own company stock.

Figures

**Figure 1**
Timeline highlighting major achievements in glucose and incretin hormone metabolism.

**Figure 2**
**Processing of incretin hormones by prohormone convertase.** In normal physiology proglucagon is processed into glucagon by prohormone convertase 2 (PC2) in the islet alpha cells, and into GLP-1 by prohormone convertase 1/3 (PC1/3) in intestinal L-cells. ProGIP is processed into GIP by PC1/3 in intestinal K-cells. Under certain conditions intra-islet production of GLP-1 and GIP potentially occurs through increased PC1/3 activity. Glucagon may be aberrantly produced in intestinal L-cells via PC2.

**Figure 3**
**The genetic encoding and peptide processing of GIP.** GIP in encoded by the *GIP* gene on chromosome 17, consisting of six exons. The majority of the sequence encoding GIP peptide is localised to exon 3 (highlighted in pink). A 153-amino acid long proGIP precursor is processed by prohormone convertase 1/3 to produce bioactive GIP1-42. GIP1-42 is rapidly degraded by dipeptidyl peptidase-4 (DPP4) into the inactive GIP3-42.

**Figure 4**
**Mechanisms underlying the release of GIP from intestinal enteroendocrine cells.** GIP is released from enteroendocrine K-cells that line the epithelium of the small intestine. K-cells span the crypt–villus axis and are equipped to sense nutrients and regulatory signals from both their luminal and basolateral surfaces. Dietary glucose is sensed through SGLT1 which couples glucose transport with sodium influx, thereby depolarising the cell membrane. Glucose is then metabolised to ATP, causing K_ATP channel closure, further membrane depolarisation, and the subsequent opening of voltage-gated calcium channels (VGCC). Rising intracellular Ca²⁺ concentrations stimulate GIP secretory vesicle release. Dietary oligopeptides and amino acids are transported into K-cells via sodium-coupled PEPT1 or proton-coupled BOAT1, resulting in membrane depolarisation. Amino acids and oligopeptides absorbed by neighbouring enterocytes may also act on the basolateral surface of K-cells through binding G_q-coupled GPCRs including CaSR and GPR142. CaSR and GPR142 binding stimulate the release of calcium from intracellular calcium stores, thereby increasing intracellular Ca²⁺ concentrations and promoting GIP vesicle release. Dietary fat is mainly sensed post-absorption at the basolateral surface of K-cells. Fatty acid transporters CD36 and FATP4 mediated free fatty acid (FFA) uptake by neighbouring enterocytes. FFAs are reesterified into triacylglycerols (TAGs) via the enzymes MGAT2 and DGAT1. TAGs are released from enterocytes, possibly as chylomicrons, to the basolateral side of the epithelium. Here, monoacylglycerols (MAGs) and long-chain fatty acids (LCFAs) bind GPCRs on K-cells to elicit GIP vesicle release. LCFA binding of GPR40 (FFAR1) or GPR120 (FFAR4) recruits Gαq, stimulating the release of calcium from intracellular calcium stores. Alternatively, MAG binding of GPR119 signals via the G_s-coupled pathway, stimulating cAMP levels and recruiting PKA and EPAC signalling pathways to enhance GIP vesicle release. B0AT1, neutral amino acid transporter 1; cAMP, cyclic adenosine monophosphate; CaSR, calcium-sensing receptor; CD36, cluster of differentiation 36; DGAT1, diacylglyceride acyltransferase 1; EPAC, exchange protein directly activated by cAMP; FATP4, fatty acid transporter protein 4; GPCR, G-protein-coupled receptor; LCFA, long-chain fatty acid; MAG, monoacylglycerol; MGAT2, monoacylglyceride acyltransferase 2; PKA, protein kinase A; PEPT1, peptide transporter 1; SGLT1, sodium-coupled glucose cotransporter 1; TAG, triacylglycerol; VGCC, voltage-gated calcium channel.

**Figure 5**
**Incretin-mediated regulation of pancreatic function.** (A) Postprandial insulin release is initiated by direct sensation of circulating glucose in pancreatic islet cells. Dietary glucose triggers GIP secretion from intestinal K-cells, which augments insulin release from pancreatic beta cells both directly and indirectly. (B) Glucose uptake into pancreatic beta cells is mediated by GLUT1 (human) of GLUT2 (rodent) transporters. Glucose is then metabolised via glycolysis and the tricarboxylic acid (TCA) cycle into ATP. The subsequent increase of intracellular ATP/ADP closes K_ATP channels, leading to membrane depolarisation and the opening of voltage-gated calcium channels (VGCC). Increased intracellular calcium triggers insulin granule exocytosis. GIP directly augments insulin release through binding GIPR expressed on the surface of beta cells. GIPR engagement increases cAMP levels through the recruitment of Gαs, leading to increased PKA/EPAC activity. Increased PKA/EPAC signalling enhances Ca²⁺ influx through VGCCs and primes insulin granules for Ca²⁺-dependent exocytosis. GIP indirectly increases insulin release through stimulating alpha cell activity and promoting alpha → beta cell paracrine regulation. Pancreatic alpha cells produce GLP-1 in addition to glucagon through alternative processing of the proglucagon precursor. The release of both glucagon and GLP-1 from alpha cells is thought to augment glucose stimulated insulin release through GLP-1R- and (to a lesser extent) GCGR-mediated increases in cAMP. cAMP, cyclic adenosine monophosphate; EPAC, exchange protein directly activated by cAMP; G-6-P, glucose-6-phosphatase; GPCR, G-protein-coupled receptor; GGCR, glucagon receptor; PKA, protein kinase A; TCA, tricarboxylic acid; VGCC, voltage-gated calcium channel.

**Figure 6**
**The effect of GIP on adipose tissue.** Incretin action on the endocrine pancreas stimulates postprandial insulin release. Insulin signalling in adipocytes stimulates glucose and free fatty acid (FFA) update. GIP signals directly in white adipose tissue, stimulating blood flow and the delivery of circulating nutrients, increasing lipoprotein lipase (LPL) activity, de novo lipogenesis, insulin sensitivity and lipolysis. GIP decreases macrophage-dependent inflammation.

**Figure 7**
**Schematic on the effects of GIP and GLP-1 on metabolism and energy balance.** In addition to their role in regulating postprandial insulin release, both GIP and GLP-1 target multiple organ systems to affect energy balance. These include actions targeting the brain, cardiovascular system, liver, gastrointestinal tract, adipose tissue, and bone.

**Figure 8**
**The central effects of GIP and GIP pharmacology.** The central GIPR signaling axis is engaged by stabilized GIP analogues and GIP released from the gastrointestinal epithelium. In the brainstem, GIPR agonism stimulates the release of GABA which binds GABA_A receptors on neighboring GLP-1R cells to inhibit nausea and malaise. Direct activation of GIPR neurons in the area postrema (AP) and the nucleus tractus solitarius (NTS) suppresses appetite. In the hypothalamus, activation of GIPR neurons decreases food intake. Alternatively, GIPR antagonism has been shown to alleviate hypothalamic leptin resistance. In the hippocampus and cortex, GIP promotes synaptic plasticity and progenitor cell proliferation to enhance memory and learning while reducing markers of inflammation.

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References

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Glucose-dependent insulinotropic polypeptide (GIP)

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Glucose-dependent insulinotropic polypeptide (GIP)

Authors

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Abstract

Conflict of interest statement

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