GIP receptor

The GIP receptor (GIPR) was initially cloned from a rat cerebral cortex cDNA library and was followed by the cloning of the hamster and human GIPRs.  The human GIPR gene is comprised of 14 exons that span approximately 14 kb and is localized to chromosome 19, band q13.3.  The GIPR gene is expressed in the pancreas, stomach, small intestine, adipose tissue, adrenal cortex, pituitary, heart, testis, endothelial cells, bone, trachea, spleen, thymus, lung, kidney, thyroid, and several regions in the CNS.  Like the GLP-1R, the GIPR is a member of the seven-transmembrane spanning, heterotrimeric G-protein-coupled receptor superfamily.

Little is known about the factors responsible for regulating GIPR expression. The GIPR gene 5’-flanking region contains a cAMP response element, and binding sites for Oct-1, Sp1 and Sp3 transcription factors.  In addition, cis-acting negative regulatory sequences that control cell-specific GIPR gene expression have been identified in more distal 5'-flanking regions.  GIPR mRNA and protein levels are reduced in islets of diabetic rats, consistent with the observation of defective GIP action in diabetic animals and humans.

Genetic variation in the GIP receptor gene may account for differences in insulin secretion and postprandial control of glucose in non-diabetic subjects. Genome Wide Association Studies identified that the rs10423928 SNP (located within an intron) was associated with reduced insulin secretion following oral but not intravenous glucose challenge. This SNP is also in linkage disequlibrium with a missense mutation E354Q that may be associated with modest reduction of GIPR action. A preliminary analysis of Gipr expression did not reveal reduced levels of RNA transcripts in islets from individuals carrying the rs10423928 allele. See Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge Nat Genet. 2010 Jan 17. [Epub ahead of print]. Similarly, analysis of incretin receptor expression in human islets isolated from subjects with T2DM revealed decreased levels of both Gipr and Glp1r mRNA transcripts, and reduced protein levels of TCF7L2, and knock down of TCF7L2 in human islets was also associated with reduced levels of incretin receptors and diminished responsivity to exogenous GIP and GLP-1 Decreased TCF7L2 protein levels in type 2 diabetes mellitus correlate with downregulation of GIP- and GLP-1 receptors and impaired beta-cell function Hum Mol Genet. 2009 Jul 1;18(13):2388-99.

Genetics variation in the Gipr was also one of several dozen locia associated with body mass index in a large genetic analysis of 123,865 subjects, subsequently verified in another 125,931 subjects. Among the 32 SNPs (loci) associated with BMI, the rs2287019 Gipr SNP was associated with BMI. Whether this SNP modifies the biology of the Gipr in the b-cell, adipose tissue, or CNS is unknown. See Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index Nature Genetics Published online: 10 October 2010 | doi:10.1038/ng.686

Remarkably, Ahlqvist and colleagues used RT-PCR to isolate and sequence Gipr splice variants from human adipose tissue. Over 60 different splice variants were detected, however only 2 Gipr mRNA transcripts actually contained a full length GIPR open reading frame. A link between GIP and osteopontin in adipose tissue and insulin resistance Diabetes. 2013 Jan 24

Activation of GIPR signaling is coupled to increases in cAMP and intracellular Ca²⁺ levels, as well as activation of PI-3K, PKA, PKB, MAPK and phospholipase A2.  In vitro structure/function studies indicate that the N-terminal domain and the first extracellular loop of the GIPR are essential for high-affinity GIP binding, whereas portions of the N-terminal domain and the first transmembrane domain are important for receptor activation and cAMP coupling.  Although the majority of the C-terminal tail of the GIPR appears to be dispensable for intracellular signaling, a minimum receptor length of approximately 405 amino acids is required for efficient transport and plasma membrane insertion.

The GIPR undergoes very rapid and reversible homologous desensitization and site-directed mutagenesis and C-terminal deletion analyses demonstrate the importance of particular serine residues in the C-terminal tail of the GIPR.  Specifically, serines 406 and 411 are important for receptor desensitization, whereas serines 426 and 427 regulate the rate of GIPR internalization.  In addition, regulator of G-protein signaling-2 (RGS-2), G-protein receptor kinase 2 (GRK 2), and ß-arrestin 1 have all been implicated in GIPR desensitization.

An important issue surrounding the biology of GIP action is the mechanism underlying the diminished GIP responsivity in experimental and clinical models of type 2 diabetes. Several studies have examined the expression of the GIP receptor in experimental models of diabetes, and the available evidence suggests that hyperglycemia may be associated with reduced GIP receptor expression, possibly contributing to reduced GIP action in the setting of diabetes. See Defective glucose-dependent insulinotropic polypeptide receptor expression in diabetic fatty Zucker rats. Diabetes. 2001 May;50(5):1004-11and Downregulation of GLP-1 and GIP receptor expression by hyperglycemia: possible contribution to impaired incretin effects in diabetes. Diabetes. 2007 Jun;56(6):1551-8  Ubiquitination may also be important for the hyperglycemia-associated downregulation of islet GIP receptor expression as outlined in Ubiquitination is involved in glucose-mediated down-regulation of GIP receptors in islets. Am J Physiol Endocrinol Metab. 2007 May 15;

Gupta and colleagues assessed GIPR expression through mechanisms converging on PPAR-g-DNA analysis revealed a PPAR-g response element was in the Gipr gene promoter.  Reduction of PAR-g expression in INS-1 cells lowered basal levels of Gipr RNA transcripts, whereas troglitazone treatment increased Gipr gene expression. Mutations in the Gipr PPARE lowered basal expression in transfection studies, and eliminated the transcriptional response to troglitazone. Analysis of mice with a pancreas-specific deletion of PPAR-ggenerated using a Pdx1-CRE excission system revealed lower islet GIPR expression and histochemical staining in these mildly hyperglycemic mice. Troglitazone increased GIPR expression and the insulin response to GIP in isolated mouse islets. Levels of PPAR-g and GIPR expression were correlated in experimental models of dysglycemia, and the authors suggest that reduced PPAR-g expression may contribute to the defective expression of GIPR expression in type 2 diabetes Physiologic and Pharmacologic Modulation of GIP Receptor Expression in ss-cells by PPAR{gamma} Signaling: Possible Mechanism for the GIP Resistance in Type 2 Diabetes. Diabetes 2010 Mar 23. [Epub ahead of print]

GIP receptor mRNA transcripts have also been detected in human tumors, predominantly neuroendocrine tumors (NETs). A combination of in situ autoradiography with [125I]-GIP(1-30). GIP binding sites were detected in functional and non-functional NETS from ileum, pancreas, and lung, including tumors that were negative for somatostatin or GLP-1 receptors. GIPR expression was also detected in 5/19 pancreatic adenocarcinomas. Glucose-Dependent Insulinotropic Polypeptide Receptors in Most Gastroenteropancreatic and Bronchial Neuroendocrine Tumors J Clin Endocrinol Metab. 2011 Nov 23.

             The GIP receptor knockout mouse

Experimental data derived from studies of the GIP receptor knockout mouse strongly implicates a role for the GIP receptor in the regulation of body weight. The Seino lab has  shown that GIPR-/- mice are resistant to the development of diet-induced obesity. Furthermore, GIPR-deficient ob/ob double mutant mice exhibited a 41% reduction in body weight compared to normal ob/ob mice and plasma lipids such as triglycerides, free fatty acids, and cholesterols were lower in GIPR-deficient ob/ob mice than in normal ob/ob mice. Moreover, energy expenditure was increased following high fat feeding in mice with absent GIPR signaling, indicating that inhibition of the GIP signal ameliorates obesity and obesity-related hyperglycemia, and dyslipidemia. These findings are described in Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat Med. 2002 Jul;8(7):738-42. 

GIP may also be important for regulation of adipokine secretion. Gipr-/- mice exhibit reduced adipocyte mass and defective upregulation of PAI-1 and resistin following high fat feeding. Furthermore, GIP, but not exendin-4, upregulates levels of plasma resistin  in acute or chronic experiments, as outlined in Extrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure. J Clin Invest. 2007 Jan 2;117(1):143-152. The stimulation of resistin secretion appears to be direct, as GIP, in the presence of insulin,  increased resistin secretion through a pathway involving p38 mitogen activated protein kinase (p38 MAPK) and the stress-activated protein kinase/Jun-amino-terminal kinase (SAPK/JNK) in differentiated 3T3L1 adipocytes. Intriguingly, resistin mimics many of the molecular aspects of GIP action on adipocytes in vitro, as shown in Resistin is a key mediator of glucose-dependent insulinotropic polypeptide (GIP) stimulation of lipoprotein lipase (LPL) activity in adipocytes. J Biol Chem. 2007 Sep 20; [Epub ahead of print]. Adiponectin levels and WAT adiponectin mRNA transcrpts were elevated in high fat fed Gipr-/- mice and may contribute to the phenotype of increased fat oxidation and improved insulin action after high fat feeding Inhibition of GIP signaling modulates adiponectin levels under high-fat diet in mice Inhibition of GIP signaling modulates adiponectin levels under high-fat diet in mice Biochem Biophys Res Commun. 2008 Nov 7;376(1):21-5

Gipr-/- mice are also resistant to the deleterious effects of ovariectomy on weight gain and impairment of insulin action, despite no change in locomoter and energy expenditure. Intriguingly, food intake was reduced in in OVX Gipr-/- mice and associated with significantly lower hypothalamic mRNA expression of the orexigenic neuropeptide Y (NPY). See Deficiency of glucose-dependent insulinotropic polypeptide receptor prevents ovariectomy-induced obesity in mice Am J Physiol Endocrinol Metab. 2008 Aug;295(2):E350-5

Although the GIP receptor-/- mouse exhibits only mild glucose intolerance, upregulation of the β-cell responsivity to GLP-1 may contribute to maintenance of insulin secretion in this murine model. See Glucose-dependent Insulinotropic Polypeptide Receptor Null Mice (GIPR-/-) Exhibit Compensatory Changes in the Enteroinsular Axis. Am J Physiol Endocrinol Metab. 2003 284; E931-9.

GIP and the Gipr have also been identified in multiple cell types in the rodent CNS, including neurons, Schwann cells and oligodendrocytes. A functional role for the Gipr in the response to neuronal injury was revealed through studies demonstrating that traumatic injury of Gipr mouse sciatic nerve was associated with impaired axonal regeneration compared with wild-type mice. Glucose-dependent insulinotropic polypeptide (GIP) and its receptor (GIPR): cellular localization, lesion-affected expression, and impaired regenerative axonal growth J Neurosci Res. 2009 Jun;87(8):1858-70.

The GIP receptor has also been identified in murine and human colon cancer cell lines. Prabakaran and colleagues pursued the hypothesis that elevated GIP levels sometimes observed in obese subjects may be associated with the increased rates of colon cancer described in obese populations. Gipr expression was detected in colon cancer cell lines and GIP stimulated cell proliferation, cAMP accumulation and PI3K/AKT activity in MC-26 cells. Glucose-dependent insulinotropic polypeptide stimulates the proliferation of colorectal cancer cells Regul Pept. 2010 Apr 28. [Epub ahead of print]

Ussher and colleagues examined the cardiovascular phenotype of the GIP receptor-/- mouse, as well as WT mice treated with a GIPR agonist. Although sustained GIPR agonism did not modify the major phenotypes associated with coronary artery occlusion and myocardial infarction, whole body GIP receptor-/- mice exhibited reduced infarct size and improved survival following induction of sustained ischemic cardiac injury. These cardioprotective phenotypes were associated with reduced cardiac HSL phosphorylation and increased cardiac accumulation of triacylglycerol. Chemical or genetic enhancement of cardiac HSL activity partially revsersed the cardioprotective phenotypes associated with GIPR deficiency. The GIP receptor-/- mouse did not exhibit more favorable outcomes in exerimental models of heart failure secondary to doxorubicin or pressure overlaod. A full length Gipr mRNA transcript was expressed in all 4 chambers of the mouse and human heart as assessed by RT-PCR and ISH. Remarkably, selective genetic elimination of the cardiomyocyte Gipr phenocopied the cardioprotective phenotype of whole body GIP receptor-/- mice in the context of coronary artery ligation. Hence, GIP regulates cardiac fuel metabolism and conditional loss of the cardiomyocyte GIPR in adult mice leads to profound resistance to ischemic cardiac injury Inactivation of the Glucose-Dependent Insulinotropic Polypeptide Receptor Improves Outcomes Following Experimental Myocardial Infarction Cell Metabolism 2017 27: https://doi.org/10.1016/j.cmet.2017.11.003

Jacqueline Beaudry and colleagues examined the importance of GIP receptor expression in mouse brown adipose tissue cells and tissues. Whole body Gipr KO mice exhibited enhanced resistance to cold associated with increased energy expenditure. GIP gain and loss of function directly modulated genes related to inflammation and thermogenesis in BAT cells. Low but detectable levels of Gipr were detected in mouse BAT. Elimination of Gipr from BAT using Myf5-Cre produced modest abnormalities in thermogenesis in mice housed at room temperature and 30C but no resistance to diet-induced weight gain. In contrast, loss of the Gipr in BAT was associated with resistance to diet-induced obesity in mice housed at 4C. Hence, the BAT GIPR is functional, but does not appear to meaningfully contribute to whole body energy homeostasis in normal or high fat diet-fed mice.  Beaudry, J., et al   Physiological roles of the GIP receptor in murine brown adipose tissue Molecular Metabolism 28 (2019) 14-25

Watch the Animated Video describing GIPR in BAT

The GIPR/Gipr is also expressed in white adipose tissue (WAT) and studies of differentiated adipocytes ex vivo have identified a functional GIPR in cell lines and differentiated cells ex vivo. Nevertheless, it has been much more difficult, and more controversial, to identify canonical GIPR expression within white adipocytes in vivo in mouse or human tissues. Campbell and colleagues used multiple genetic approaches, including adiponectin-Cre lines, to attempt to reduce Gipr expression within white adipocytes, however Gipr was not reduced in Gipr floxed mice targeted by adiponectin-Cre. Single nucleus RNA-Seq analyses of WAT GIPR expression was carried out by Emont and colleagues A single-cell atlas of human and mouse white adipose tissue Nature. 2022 Mar;603(7903):926-933. doi: 10.1038/s41586-022-04518-2 As analyzed by Campbell et al, mouse adipose tissue Gipr expression was predominantly localized to pericytes whereas the human GIPR was localized to pericytes and mesothelial cells, but not adipocytes GIPR Is Predominantly Localized to Nonadipocyte Cell Types Within White Adipose Tissue Diabetes. 2022 May 1;71(5):1115-1127. 

To review the data on GIP and human diabetes, see GIP and human diabetes