GIP

Summary

GIP (gastric inhibitory polypeptide, HGNC:4270) is a protein-coding gene on chromosome 17q21.32, encoding Gastric inhibitory polypeptide (P09681). Potent stimulator of insulin secretion and relatively poor inhibitor of gastric acid secretion.

This gene encodes an incretin hormone and belongs to the glucagon superfamily. The encoded protein is important in maintaining glucose homeostasis as it is a potent stimulator of insulin secretion from pancreatic beta-cells following food ingestion and nutrient absorption. This gene stimulates insulin secretion via its G protein-coupled receptor activation of adenylyl cyclase and other signal transduction pathways. It is a relatively poor inhibitor of gastric acid secretion.

Source: NCBI Gene 2695 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 24 total
• MANE Select transcript: NM_004123

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4270
Approved symbol	GIP
Name	gastric inhibitory polypeptide
Location	17q21.32
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000159224
Ensembl biotype	protein_coding
OMIM	137240
Entrez	2695

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000357424

RefSeq mRNA: 1 — MANE Select: NM_004123 NM_004123

CCDS: CCDS11542

Canonical transcript exons

ENST00000357424 — 6 exons

Exon	Start	End
ENSE00001044108	48964310	48964480
ENSE00001044115	48961727	48961819
ENSE00001192983	48958554	48958716
ENSE00001192994	48968517	48968596
ENSE00001192996	48960886	48960987
ENSE00001430288	48967147	48967253

Expression profiles

Bgee: expression breadth broad, 54 present calls, max score 98.84.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.5108 / max 274.4879, expressed in 10 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
166773	0.5108	10

Top tissues by expression

261 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	98.84	gold quality
duodenum	UBERON:0002114	96.25	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.46	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.44	gold quality
jejunum	UBERON:0002115	80.61	gold quality
buccal mucosa cell	CL:0002336	71.80	gold quality
oocyte	CL:0000023	65.22	gold quality
pancreatic ductal cell	CL:0002079	61.17	silver quality
frontal pole	UBERON:0002795	59.49	gold quality
middle frontal gyrus	UBERON:0002702	59.27	gold quality
paraflocculus	UBERON:0005351	59.09	gold quality
stromal cell of endometrium	CL:0002255	54.50	gold quality
male germ cell	CL:0000015	51.65	gold quality
sperm	CL:0000019	51.46	gold quality
cerebellar vermis	UBERON:0004720	50.86	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.18	gold quality
quadriceps femoris	UBERON:0001377	49.94	gold quality
thymus	UBERON:0002370	49.88	gold quality
metanephric glomerulus	UBERON:0004736	49.61	gold quality
vastus lateralis	UBERON:0001379	49.41	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
hair follicle	UBERON:0002073	49.18	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
myocardium	UBERON:0002349	48.87	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
left ventricle myocardium	UBERON:0006566	48.24	gold quality
oviduct epithelium	UBERON:0004804	48.21	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

8 targeting GIP, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-199A-3P	99.75	70.48	929
HSA-MIR-199B-3P	99.75	70.48	929
HSA-MIR-3129-5P	99.75	70.46	914
HSA-MIR-516B-5P	99.56	66.33	1495
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-5706	98.35	69.33	1463
HSA-MIR-558	97.50	67.16	977

Literature-anchored findings (GeneRIF, showing 40)

• Substitution of Glu(3) in GIP with proline produces a novel dipeptidylpeptidase IV-resistant GIP antagonist which inhibits GIP-induced cAMP generation and insulin secretion with high sensitivity and specificity in vitro. (PMID:11820780)
• activates the Raf-Mek1/2-ERK1/2 module via a cyclic AMP/cAMP-dependent protein kinase/Rap1-mediated pathway (PMID:12138104)
• Mutation in promoter region of gip receptor gene are unlikely to underlie GIP-dependent Cushing syndrome. (PMID:12530694)
• delayed elimination in renal insufficiency (PMID:14988249)
• Elevated plasma GIP levels are correlated with hyperinsulinemia in the impaired glucose-tolerant state, whereas type 2 diabetes is associated with a failure to secrete adequate amounts of GIP. (PMID:15220248)
• bombesin and nutrients additively stimulate GIP release from GIP/Ins cells. (PMID:15383372)
• Results describe the solution structure of GIP(1-30)amide, the major biologically active fragment of glucose-dependent insulinotropic polypeptide. (PMID:15522230)
• GIP augments glucose-stimulated insulin secretion and acts as an endogenous inhibitor of gastric acid secretion–REVIEW (PMID:15533777)
• Reduced secretion or action of GLP-1 or GIP does not explain a relative reduced beta-cell responsiveness to glucose or the slightly elevated plasma glucose concentrations observed in young low birth weight men (PMID:15899957)
• GIP stimulates insulin secretion by potentiating events underlying membrane depolarization and exerting direct effects on exocytosis. (PMID:15955806)
• The relationship between insulin resistance and the insulin secretion to GIP suggests that beta cell secretory function in response to different stimuli increases adaptively when insulin sensitivity is diminished, as in gestational diabetes. (PMID:16010522)
• GIP is rapidly degraded into inactive metabolites by the enzyme dipeptidyl-peptidase-IV. (review) (PMID:16142014)
• protein kinase B, LKB1, and AMP-activated protein kinase have roles in activation of lipoprotein lipase by glucose-dependent insulinotropic polypeptide in adipocytes (PMID:17244606)
• An inverse relationship between insulin concentrations and insulin clearance suggests that the secretion of insulin itself determines the rate of hepatic insulin clearance. (PMID:17609256)
• study identified a splice site mutation of the Glucose-dependent insulinotropic polypeptide (GIP) gene which results in a truncated protein and provides evidence for association of GIP receptor genotype with cardiovascular disease (PMID:17624916)
• physiologic role for GIP in lipid homeostasis and possibly in the pathogenesis of obesity. (PMID:18054552)
• concomitant expression of Pax6 and Pdx1 is important for glucose-dependent insulinotropic polypeptide expression (PMID:18593849)
• GIP secretion is blunted after the biliopancreatic diversion only in diabetic patients, suggesting a role in insulin resistance and diabetes. (PMID:19229515)
• GIP may mediate the attenuated glucose-stimulated insulin response after exercise/diet interventions (PMID:19351807)
• Inhibition of apoptosis by GIP is mediated via a key pathway involving Akt-dependent inhibition of apoptosis signal-regulating kinase 1, which subsequently prevents the pro-apoptotic actions of p38 MAPK and JNK. (PMID:19748889)
• GLP-1 but not GIP secretion is lower after meal ingestion and oral glucose, whereas GIP but not GLP-1 metabolism is increased after meal ingestion. (PMID:20008019)
• a binding mode of GIP to GIPR in which the N-terminal moiety of GIP was sited within transmembrane helices (TMH) 2, 3, 5, and 6 with biologically crucial Tyr1 interacting with Gln224 (TMH3), Arg300 (TMH5), and Phe357 (TMH6). (PMID:20061446)
• GIP is expressed in and secreted from pancreatic islets and promotes islet glucose competence and also could support islet development and/or survival. (PMID:20138041)
• We demonstrate for the first time that changes in insulin secretion after lifestyle intervention may be mediated via alterations in GIP secretion from intestinal K-cells (PMID:20200305)
• GLP-2, but not GIP, was found to stimulate the release of glucagon in patients with T1DM, suggesting a role for GLP-2 in the postprandial hyperglucagonaemia characterising individuals with T1DM (PMID:20580750)
• No statistically significant association was observed between any of the single nucleotide polymorphisms of GIP analysed and type 2 diabetes in our population. (PMID:20673334)
• These results suggest that Tyr/His(1) and Ile/Thr(7) of GIP/GLP-1 peptides confer differential ligand selectivity toward GIPR and GLP1R. (PMID:20799012)
• We report that the human GIP locus was differentially selected in East Asians about 8100 years ago based on the analysis of a nonsynonymous SNP (rs2291725). (PMID:20978139)
• Studies identified some potentially important additional C-terminal interactions of GIP with its N-terminal extracellular receptor domain. (PMID:21539943)
• may have a pro-obesogenic action [review] (PMID:21815989)
• GIP reduces free fatty acid release from adipose tissue by inhibition of lipolysis or by increased reesterification. (PMID:22179810)
• results indicate postprandial GIP secretion in early-phase after test meal in Japanese patients with type 2 diabetes was positively correlated with BMI, but not those with type 1 diabetes (PMID:22301939)
• Data suggest that reduced insulinotropic effect of GIP or GLP-1 (as in type 2 diabetes) can be induced in healthy subjects; this indicates that reduced incretin stimulation of insulin secretion results from insulin resistance/glucose intolerance. (PMID:22319034)
• The results suggest that circulating levels of GIP and GLP-1 as well as the beta cell response to these incretins are highly familial as compared with fasting and stimulated plasma glucose, serum insulin and serum C-peptide levels. (PMID:22349073)
• Hyperinsulinemia subjects with metabolic syndrome showed increased GIP secretion that could be responsible for the delayed glucagon suppression. (PMID:22391044)
• The changes in glucose metabolism and incretin (GLP-1/GIP) responses were different between pancreatoduodenectomy and distal pancreatectomy. (PMID:22422137)
• a lineage of mature enteroendocrine cells have the ability to coexpress members of a group of functionally related peptides: CCK, secretin, GIP, GLP-1, PYY, and neurotensin (PMID:23064014)
• GIP induces an inflammatory and prolipolytic response via the PKA -NF-kappaB-IL-1 pathway and impairs insulin sensitivity of glucose uptake in human adipocytes. (PMID:23092914)
• Data suggest that postprandial plasma levels of glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP1) are increased after consumption of buckwheat crackers versus rice crackers in healthy and type 2 diabetic subjects. (PMID:23485142)
• Patients with idiopathic gastroparesis exhibit abnormal GIP levels. (PMID:23663508)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gip	ENSDARG00000071306
mus_musculus	Gip	ENSMUSG00000014351
rattus_norvegicus	Gip	ENSRNOG00000006306

Protein

Protein identifiers

Gastric inhibitory polypeptide — P09681 (reviewed: P09681)

Alternative names: Glucose-dependent insulinotropic polypeptide, Incretin hormone

All UniProt accessions (1): P09681

UniProt curated annotations — full annotation on UniProt →

Function. Potent stimulator of insulin secretion and relatively poor inhibitor of gastric acid secretion.

Subcellular location. Secreted.

Similarity. Belongs to the glucagon family.

RefSeq proteins (1): NP_004114* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000532	Glucagon_GIP_secretin_VIP	Domain
IPR039078	GIP	Family

Pfam: PF00123

UniProt features (10 total): propeptide 2, sequence variant 2, signal peptide 1, peptide 1, region of interest 1, helix 1, turn 1, strand 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
2QKH	X-RAY DIFFRACTION	1.9
7DTY	ELECTRON MICROSCOPY	2.98
7RA3	ELECTRON MICROSCOPY	3.24
1T5Q	SOLUTION NMR
2B4N	SOLUTION NMR
2L70	SOLUTION NMR
2L71	SOLUTION NMR
2OBU	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P09681-F1	69.83	0.16

Antibody-complex structures (SAbDab): 2 — 7DTY, 7RA3

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-400511	Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP)
R-HSA-418555	G alpha (s) signalling events
R-HSA-420092	Glucagon-type ligand receptors

MSigDB gene sets: 144 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, GOBP_MEMORY, REACTOME_GLUCAGON_TYPE_LIGAND_RECEPTORS, GOBP_COGNITION, GOBP_BEHAVIOR, GOCC_SECRETORY_GRANULE, GOBP_ADULT_BEHAVIOR, GOBP_INSULIN_SECRETION, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_HORMONE_TRANSPORT, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ADULT_LOCOMOTORY_BEHAVIOR, GOBP_KETONE_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_CELL_CELL_SIGNALING

GO Biological Process (13): signal transduction (GO:0007165), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), memory (GO:0007613), adult locomotory behavior (GO:0008344), response to glucose (GO:0009749), sensory perception of pain (GO:0019233), endocrine pancreas development (GO:0031018), positive regulation of insulin secretion (GO:0032024), exploration behavior (GO:0035640), gastric inhibitory peptide signaling pathway (GO:0038192), regulation of fatty acid biosynthetic process (GO:0042304), response to starvation (GO:0042594), regulation of insulin secretion (GO:0050796)

GO Molecular Function (5): hormone activity (GO:0005179), gastric inhibitory polypeptide receptor binding (GO:0031767), glucagon receptor binding (GO:0031769), protein binding (GO:0005515), receptor ligand activity (GO:0048018)

GO Cellular Component (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endoplasmic reticulum lumen (GO:0005788), secretory granule lumen (GO:0034774)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Incretin synthesis, secretion, and inactivation	1
GPCR downstream signalling	1
Class B/2 (Secretin family receptors)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
insulin secretion	2
G protein-coupled receptor binding	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
learning or memory	1
locomotory behavior	1
adult behavior	1
response to hexose	1
sensory perception	1
pancreas development	1
endocrine system development	1
anatomical structure development	1
positive regulation of protein secretion	1
regulation of insulin secretion	1
positive regulation of peptide hormone secretion	1
behavior	1
G protein-coupled receptor signaling pathway	1
fatty acid biosynthetic process	1
regulation of fatty acid metabolic process	1
regulation of lipid biosynthetic process	1
response to stress	1
response to nutrient levels	1
regulation of protein secretion	1
regulation of peptide hormone secretion	1
receptor ligand activity	1
binding	1
signaling receptor binding	1
signal transduction	1
signaling receptor activator activity	1
cellular anatomical structure	1
endoplasmic reticulum	1
intracellular organelle lumen	1
secretory granule	1
cytoplasmic vesicle lumen	1

Protein interactions and networks

STRING

1178 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GIP	GIPR	P48546	999
GIP	GLP1R	P43220	996
GIP	GCG	P01275	970
GIP	INS	P01308	928
GIP	DPP4	P27487	926
GIP	SCT	P09683	914
GIP	CCK	P06307	866
GIP	VIP	P01282	861
GIP	PYY	P10082	850
GIP	GAST	P01350	796
GIP	GHRL	Q9UBU3	778
GIP	PPY	P01298	778
GIP	GPR119	Q8TDV5	740
GIP	IAPP	P10997	723
GIP	MLN	P12872	722

IntAct

29 interactions, top by confidence:

A	B	Type	Score
GIP	SGTA	psi-mi:“MI:0915”(physical association)	0.720
SGTA	GIP	psi-mi:“MI:0915”(physical association)	0.720
GIPR	GIP	psi-mi:“MI:0407”(direct interaction)	0.620
	GIP	psi-mi:“MI:0915”(physical association)	0.560
ADAMTSL4	GIP	psi-mi:“MI:0915”(physical association)	0.560
GIP	NOTCH2NLA	psi-mi:“MI:0915”(physical association)	0.560
GIP		psi-mi:“MI:0915”(physical association)	0.560
GIP	ADAMTSL4	psi-mi:“MI:0915”(physical association)	0.560
NOTCH2NLA	GIP	psi-mi:“MI:0915”(physical association)	0.560
GIP	SGTB	psi-mi:“MI:0915”(physical association)	0.560
GIP	CCNA2	psi-mi:“MI:0914”(association)	0.530
GIP	DPP4	psi-mi:“MI:0194”(cleavage reaction)	0.440
GIP	FAP	psi-mi:“MI:0194”(cleavage reaction)	0.440
DLX6	GIP	psi-mi:“MI:0915”(physical association)	0.400
GIP	GNPAT	psi-mi:“MI:0914”(association)	0.350
CALCA	PHF1	psi-mi:“MI:0914”(association)	0.350
GIP	ORC4	psi-mi:“MI:0914”(association)	0.350
GIP	SGTA	psi-mi:“MI:0915”(physical association)	0.000
GIP	SGTB	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (49): SGTA (Two-hybrid), ADAMTSL4 (Two-hybrid), KRTAP10-3 (Two-hybrid), NOTCH2NL (Two-hybrid), RNF41 (Affinity Capture-MS), CCNA2 (Affinity Capture-MS), COL14A1 (Affinity Capture-MS), POLR2J (Affinity Capture-MS), GIP (Two-hybrid), SGTB (Two-hybrid), BAI2 (Two-hybrid), BAI2 (FRET), BAI2 (Co-crystal Structure), ADD3 (Affinity Capture-MS), RNF41 (Affinity Capture-MS)

ESM2 similar proteins: A0A679PF76, A5LHG2, D2HJ50, D5J9S0, F5CPE8, P01172, P01286, P02822, P07480, P09681, P09916, P0DJK0, P0DJK1, P0DW25, P10683, P11242, P13207, P16043, P17640, P20800, P22389, P22466, P23943, P33745, P45644, P47212, P48143, P48756, P51694, P58844, P79799, P83228, Q06145, Q1RMJ9, Q5NRP8, Q5NRQ0, Q60549, Q62949, Q6DJ00, Q765Z5

Diamond homologs: O12956, O42143, O42144, P01272, P01273, P01274, P01275, P01281, P06883, P09566, P09680, P09681, P0C235, P15438, P18108, P29794, P33528, P48756, P55095, P68259, P68260, P68273, P68274, P68275, P68952, P68953, P68954, P68955, P81026, Q06145, Q8MJ25

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
GIP	“up-regulates activity”	GIPR	binding
α-D-glucose	“up-regulates quantity”	GIP

Disease & clinical

Clinical variants and AI predictions

ClinVar

24 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	24
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

998 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:48964348:A:C	F73L	0.995
17:48964348:A:T	F73L	0.995
17:48964350:A:G	F73L	0.995
17:48964349:A:G	F73S	0.994
17:48964349:A:C	F73C	0.993
17:48964337:A:G	L77P	0.992
17:48964390:A:C	S59R	0.991
17:48964390:A:T	S59R	0.991
17:48964392:T:G	S59R	0.991
17:48964339:C:A	W76C	0.989
17:48964339:C:G	W76C	0.989
17:48964381:A:C	S62R	0.987
17:48964381:A:T	S62R	0.987
17:48964383:T:G	S62R	0.987
17:48964388:T:A	D60V	0.985
17:48964341:A:G	W76R	0.982
17:48964341:A:T	W76R	0.982
17:48964388:T:C	D60G	0.979
17:48964391:C:A	S59I	0.978
17:48964389:C:G	D60H	0.977
17:48964388:T:G	D60A	0.975
17:48964404:C:G	G55R	0.975
17:48964404:C:T	G55R	0.975
17:48964334:A:G	L78P	0.974
17:48964370:T:A	D66V	0.973
17:48964404:C:A	G55W	0.973
17:48964387:G:C	D60E	0.972
17:48964387:G:T	D60E	0.972
17:48964397:A:G	F57S	0.971
17:48961816:C:A	W87C	0.968

dbSNP variants (sampled 300 via entrez): RS1000031676 (17:48962433 A>G), RS1000106420 (17:48962152 C>A,T), RS1001334309 (17:48966667 C>T), RS1001397478 (17:48958428 C>A,T), RS1001468858 (17:48967780 A>T), RS1001785420 (17:48966370 A>G), RS1001847326 (17:48960639 C>T), RS1002664499 (17:48959572 G>A), RS1003057737 (17:48966743 C>A), RS1003545096 (17:48966508 G>C), RS1003728965 (17:48964659 C>A), RS1004083010 (17:48964831 T>C), RS1004329659 (17:48962769 C>A), RS1004363411 (17:48969014 G>C), RS1004441727 (17:48968829 C>T)

Disease associations

OMIM: gene MIM:137240 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	2
bisphenol A	decreases methylation	1
benazol P	affects expression	1
entinostat	increases expression	1
jinfukang	increases expression	1
Orlistat	decreases expression	1
Cyclic AMP	affects binding, increases activity, increases chemical synthesis	1
Air Pollutants	decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cisplatin	decreases expression	1
Diethylhexyl Phthalate	increases expression	1
Endosulfan	decreases expression	1
Metoclopramide	increases secretion	1
Silicon Dioxide	decreases expression	1
Aflatoxin B1	increases methylation	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.