Disease relevance of GIPR

• We conclude that the GIPR overexpression and its coupling to steroidogenesis underlie GIP-dependent Cushing's syndrome [1].
• We conclude that GIP-dependent nodular hyperplasia can progress in an asynchronous manner and that GIPR overexpression is an early event in this syndrome [2].
• We previously demonstrated that sequences between -1 and -100 of the GIPR gene were sufficient to direct transcription in a rat insulinoma cell line (RIN38) [3].
• The exact understanding of GIP receptor regulation and signal transduction will aid in the understanding of the incretin hormone's failure to exert its biological action at the pancreatic B-cell in type II diabetes mellitus [4].
• In the present study, we describe a novel case of a GIP receptor-expressive adrenocortical adenomatous nodule, detected incidentally by computed tomography scanning in a 41-yr-old lady with hirsutism but no clinical signs of Cushing's syndrome, on physical examination [5].

Psychiatry related information on GIPR

• These data suggest that the GIP receptor plays a role in the regulation of locomotor activity and exploration [6].

High impact information on GIPR

• However, a recent study using GIP receptor knockout mice suggests that inhibition of GIP signalling might be a new target for anti-obesity drugs [7].
• GIP is a gastrointestinal peptide hormone of 42 amino acids that is released from duodenal endocrine K-cells after absorption of glucose or fat and exerts its effects by binding to its specific receptor, the GIP receptor [8].
• By generating and characterizing mice with a targeted mutation of the GIP receptor gene, we have shown that GIP has not only an insulinotropic role, but also physiological roles on fat accumulation into adipose tissues and calcium accumulation into bone [8].
• Similar protective effects were found with dispersed islet cells from C57BL/6 mice, but not with those from GIP receptor knock-out (GIPR(-/-)) mice [9].
• GIP treatment reduced glucolipotoxicity-induced cell death in C57 BL/6 and Bax(-/-) islets, but not GIPR(-/-) mouse islets [9].

Chemical compound and disease context of GIPR

• OBJECTIVE: The molecular mechanisms responsible for glucose-dependent insulinotrophic peptide receptor or gastric inhibitory polypeptide receptor (GIPR) ectopic expression and function in GIP-dependent Cushing's syndrome (CS) are still unknown [10].
• Food-dependent androgen and cortisol secretion by a gastric inhibitory polypeptide-receptor expressive adrenocortical adenoma leading to hirsutism and subclinical Cushing's syndrome: in vivo and in vitro studies [5].
• The best characterized example to date is the aberrant expression of the gastric inhibitory polypeptide receptor that causes 'food-dependent hypercortisolism'. Aberrant expression of the luteinizing hormone, 2-adrenergic, interleukin receptors have also been reported [11].

Biological context of GIPR

• Furthermore, GRK-mediated receptor phosphorylation is not required for endocytosis of the GIPR [12].
• Lastly, chromatin immunoprecipitation analyses revealed that both Sp1 and Sp3 bind to the GIPR promoter region in RIN38 cells [3].
• The human GIPR gene is about 13.8 kb long, consists of 14 exons, and carries 17 Alu repeats [13].
• We evaluated whether mutations or polymorphisms in the regulatory region of the GIPR gene could lead to this aberrant expression [14].
• The analysis of the promoter region of human (h) GIP-R gene revealed six consensus sequences important in regulating the reporter gene activity and capable of binding to Sp1 and Sp3 transcription factors [15].

Anatomical context of GIPR

• We have previously characterized the receptor for glucose-dependent insulinotropic polypeptide (GIPR) in vascular endothelial cells (EC) [16].
• We studied 9.0kb upstream and 1.3kb downstream of the GIPR gene putative promoter (pProm) by sequencing leukocyte DNA from controls and from adrenal tissues of GIP- and non-GIP-dependent CS patients [14].
• Using a human multiple-expression tissue array, GIP-R was found to be expressed in a large number of human adult and fetal tissues, but not in the adrenal gland [15].
• Gastric inhibitory polypeptide (GIP)-dependent Cushing's syndrome (CS) results from the ectopic expression of non-mutated GIP receptor (hGIPR) in the adrenal cortex [14].
• Cyclic adenosine 3'5' monophosphate (cAMP) production was assessed in Chinese hamster lung fibroblast cells transfected with the human GIP receptor [17].

Associations of GIPR with chemical compounds

• However, there was no trend toward low fasting or high postprandial cortisol in the other cases, suggesting that the presence of detectable GIPR alone, albeit with definite function in vitro, is not sufficient to cause clinically food-dependent CS [18].
• Elimination of incretin receptor action in GIPR-/- or GLP-1R-/- mice produces only modest impairment in glucose homeostasis [19].
• GIPR presumably acts, like the ACTH receptor (ACTHR), through the Gs protein/cyclic AMP/protein kinase A (PKA) pathway to stimulate steroidogenesis [10].
• Mutation of the threonine at position 340 in the sixth transmembrane spanning domain to proline (T340P) led to agonist-independent constitutive activity and exhibited a four-fold increase in basal cAMP level as compared to the wild-type GIP-R [20].
• Gastric inhibitory polypeptide receptor in hamster pancreatic beta cells. Direct cross-linking, solubilization and characterization as a glycoprotein [21].

Other interactions of GIPR

• We have isolated the human gene (GIPR) and cDNA encoding the GIP receptor by a combination of the conventional screening and polymerase chain reaction procedures [13].
• The glucose-dependent insulinotropic polypeptide receptor (GIPR) is a member of class II G protein-coupled receptors [12].
• Role of G protein-coupled receptor kinases in glucose-dependent insulinotropic polypeptide receptor signaling [12].
• GIP-R and RGS1, -2, -3, and -4 complementary DNAs were cotransfected into human embryonic kidney cells (L293) [22].
• GIP receptor messenger ribonucleic acid (RNA), assessed by RT-PCR, was highly expressed in the tumor, whereas it was undetectable in the adjacent hypotrophic adrenal tissue, in two adrenal tumors responsible for food-independent Cushing's syndrome, and in two hyperplastic adrenals associated with ACTH hypersecretion [23].

Analytical, diagnostic and therapeutic context of GIPR

• RESULTS: RT-PCR revealed GIPR expression in all hyperplastic adrenals studied [18].
• Assignment of the gastric inhibitory polypeptide receptor gene (GIPR) to chromosome bands 19q13.2-q13.3 by fluorescence in situ hybridization [24].
• A right adrenalectomy was performed; GIP receptor messenger ribonucleic acid was overexpressed in both adrenal nodules and in the adjacent cortex [2].
• This study demonstrates the molecular cloning of a cDNA for the GIP-receptor from a human insulinoma lambda gt11 cDNA library [4].
• Collectively these data demonstrate that (Pro(3))GIP is a novel and potent enzyme-resistant GIP receptor antagonist capable of blocking the ability of native GIP to increase cAMP, stimulate insulin secretion, and improve glucose homeostasis in a commonly employed animal model of type 2 diabetes [25].

GIPR in GH-secreting pituitary adenomas

• By qPCR in GH-secreting pituitary adenomas and in normal pituitaries we show that nearly 25% of cases showed GIPR overexpression [26].
• None of the GIPR-overexpressing somatotropinoma showed somatic mutation in the GNAS1 gene [26].
• Immunostaining data showed both membrane and cytoplasmic reactivity. Different staining pattern could be observed among GIPR overexpressing somatotropinomas [26].
• GIPR overexpression in associated with paradoxical increase of GH after OGTT [26] [27].

References