GIP, also known as gastric inhibitory polypeptide, or glucose-dependent insulinotropic polypeptide, is a 42 amino acid peptide hormone synthesized in and secreted from K cells in the intestinal epithelium. The majority of intestinal K cells are located in the proximal duodenum. GIP secretion is primarily regulated by nutrients, especially fats Intriguingly, bioactive truncated GIP has also been detected in pancreatic a-cells, raising the possibility of an intra-islet a-cell to b-cell connection Glucose-dependent insulinotropic polypeptide (GIP) is expressed in pancreatic islet alpha-cells and promotes insulin secretion Gastroenterology. 2010 Feb 2. [Epub ahead of print]. GIP exhibits potent incretin activity in rodents and human subjects. Unlike GLP-1, which exerts multiple non-incretin activities in the regulation of blood glucose, the primary action of GIP is the stimulation of glucose-dependent insulin secretion. GIP may also play a role in adipocyte biology, however the physiological significance of GIP action in the adipocyte is less well defined. The interaction of GIP with its receptor has been studied at high resolution, demonstrating the importance of hydrophobic interactions for interaction of the GIP alpha helix with the extracellular domain of the GIP receptor as outlined in Crystal structure of the incretin-bound extracellular domain of a G protein-coupled receptor. Proc Natl Acad Sci U S A. 2007 Aug 21; [Epub ahead of print]
To review in more detail the receptor-dependent mechanisms mediating GIP action, see GIP Receptor
The site of GIP expression, the gut endocrine K cell, clearly possesses the molecular machinery required for sensing nutrient intake and secreting GIP following nutrient ingestion. Targeting a modified human insulin transgene to the murine K cell results in appropriate glucose-and meal-related insulin secretion in vivo. See Glucose-dependent insulin release from genetically engineered K cells Science. 2000 Dec 8;290(5498):1959-62. As gut K cells are sparse and difficult to study, there is little known about the molecular biology of the GIP-secreting K cell. Parker and colleagues isolated purified populations of non-immortalized murine K cells from transgenic mice expressing a yellow fluorscent protein under the control of the GIP promoter. Murine K cells were found to express Kir6.2, Sur1, Sglt1, GPR40, GPR119, and GPR120 and GIP secretion was stimulated by glucose, cyclic AMP and linoleic acid as well as tolbutamide but not by modulation of tast receptor activity. GIP+ cells also expressed the proglucagon gene, and at a much higher level, the Pyy gene. See Nutrient-dependent secretion of glucose-dependent insulinotropic polypeptide from primary murine K cells. Diabetologia. 2009 Feb;52(2):289-98.
Th importance of the K cell for glucose homeostasis and energy conservation has been studied in mice with targeted transgenic ablation of GIP-producing K cells using a Diphtheria toxin transgene under the control of the rat GIP promoter. Substantial ablation of K cells was achieved and associated with almost complete extinction of GIP expression in the murine small bowel. Unexpectedly, the incretin response was completeky lost in these mice, despite normal levels of GLP-1. Moreover, the mice exhibited a partial restoration of the incretin response after high fat feeding yet were resistant to diet-induced obesity, and exhibited a phenotype partially resembling Gipr-/- mice, with increased energy expenditure and enhanced insulin sensitivity Targeted ablation of GIP-producing cells in transgenic mice reduces obesity and insulin resistance induced by a high fat diet J Biol Chem. 2008 Apr 17; [Epub ahead of print]
The physiological actions of GIP have been studied by administration of GIP to cells, and infusion in rodents and human subjects. Although classically viewed as an incretin, GIP may also modulate plasma insulin via effects on insulin extraction or clearance in specific experimental conditions. Although GIP infusion in normal human subjects did not affect glucose, insulin, or C-peptide at normoglycemia (5 mM glucose), GIP co-administered with the SU glibenclamide increased plasma insulin but not C-peptide. The mechanisms underlying this intriguing observation remain unclear. See Glucose-dependent insulinotropic hormone potentiates the hypoglycemic effect of glibenclamide in healthy volunteers: evidence for an effect on insulin extraction. J Clin Endocrinol Metab. 2001 May;86(5):2015-9
An important determinant of GIP action is the N-terminal cleavage of the peptide to the inactive GIP (3-42). The enzyme DPP-4, which also cleaves GLP-1 and GLP-2, rapidly inactivates GIP both in vitro and in vivo. See Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7-36)amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur J Biochem. 1993 Jun 15;214(3):829-35 and Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV.Endocrinology. 1995 Aug;136(8):3585-96 and Investigation of glucose-dependent insulinotropic polypeptide-(1-42) and glucagon-like peptide-1-(7-36) degradation in vitro by dipeptidyl peptidase IV using matrix-assisted laser desorption/ionization-time of flight mass spectrometry. A novel kinetic approach J Biol Chem. 1996 Sep 20; 271 (38) :23222-9;
Modification of the GIP N-terminus, such as substitution of D-Ala at position 2, may confer resistance to DPP-4-mediated degradation and result in GIP derivatives with enhanced biological potency. Indeed, [D-Ala2]-GIP1-42 acts a more potent "super agonist" at the GIP receptor in normal rats in vivo when compared to native GIP alone. Furthermore, even greater potency, as assessed by glucose lowering GIP1-42 were not completely correlated with the effects of this molecule on plasma insulin. See Dipeptidyl Peptidase IV-Resistant [D-Ala2]Glucose- Dependent Insulinotropic Polypeptide (GIP) Improves Glucose Tolerance in Normal and Obese Diabetic Rats Diabetes 2002 51: 652-661
Whether enhancement of GIP receptor signaling is a viable strategy for the treatment of Type 2 diabetes remains unclear, as human data demonstrating efficacy of GIP agonists in the setting of Type 2 diabetes is quite limited, as discussed below.
Consistent with the role of DPP-4 in the degradation of GIP, levels of intact GIP (1-42) are significantly increased in CD26 (DPP-4)-/- knockout mice, as illustrated in Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26. Proc Natl Acad Sci U S A 2000 97(12):6874-6879.
Accordingly, analysis of GIP in tissues or in the circulation with a C-terminal assay alone may lead to an overestimation of the concentration of full length bioactive GIP (1-42). The majority of circulating GIP immunoreactivity in both the fasting and postprandial states corresponds to the biologically inactive GIP (3-42). GIP Infused into human subjects is rapidly degraded, with a t1/2 of ~7.2 minutes as estimated using N-terminal-specific assays Degradation of endogenous and exogenous gastric inhibitory polypeptide in healthy and in type 2 diabetic subjects as revealed using a new assay for the intact peptide. J Clin Endocrinol Metab. 2000 Oct;85(10):3575-81.
GIP physiology has also been examined using peptide antagonists, antisera against the GIP receptor, and GIP Receptor-/- mice for "removal" or attenuation of GIP biological activity as outlined in GIP antagonists.
To review the data on GIP and human diabetes, see GIP and human diabetes
GIP and the islet β-cell
GIP has been shown to stimulate b-cell proliferation and exert anti-apoptotic actions in vitro. Studies using INS-1 b-cellshave shown stimulation of b-cell proliferation and enhancedb-cell survival; See Glucose-Dependent Insulinotropic Polypeptide Is a Growth Factor for beta (INS-1) Cells by Pleiotropic Signaling. Mol Endocrinol. 2001 Sep;15(9):1559-70. and Mechanisms of mitogenic and anti-apoptotic signaling by glucose-dependent insulinotropic polypeptide in beta(INS-1)-cells. J Endocrinol. 2002 Aug;174(2):233-46. and Glucose-dependent insulinotropic polypeptide promotes beta-(INS-1) cell survival via cyclic adenosine monophosphate-mediated caspase-3 inhibition and regulation of p38 mitogen-activated protein kinase. Endocrinology. 2003 Oct;144(10):4433-45
In contrast, there is much less data examining whether GIP can also exert robust stimulation of b-cell proliferation or promotion of b-cell survival in vivo. Maida and colleagues compared the actions of a degradation-resistant GIP analogue, with those of exendin-4 or the DPP-4 inhibitor sitagliptin, in murine models of b-cell apoptosis or regeneration in the context of streptozotocin administration. Exendin-4 promoted robust expansion of b-cell mass after STZ, and also reduced the extent of b-cell apoptosis. Sitagliptin had very little effect on b-cell apoptosis but did increase b-cell mass after chronic administration. In contrast, d[Ala2]-GIP had only a modest anti-apoptotic effect and was unable to increase b-cell mass in chronic studies. Furthermore, Gipr-/- mice did not exhibit enhanced susceptibility to STZ-induced b-cell apoptosis in vivo. Hence, the GLP-1 receptor appears to be consistently linked to b-cell proliferation and survival pathways in vivo, whereas the GIP receptor promotes b-cell survival in vitro, but whether GIP exerts significant prosurvival effects in vivo remain uncertain. See Differential importance of GIP vs. GLP-1 receptor signaling for beta-cell survival in mice. Gastroenterology. 2009 Sep 17. [Epub ahead of print]
The potent anti-apoptotic actions of GIP on the islet β-cell in vitro were examined in INS-1(832/13) β cells, subjected to glucoliptocicity. GIP increased Akt, and restored cytoplasmic localization of Foxo1, in association with increased Foxo1 phsophorylation, leading to reduction of Bax expression. Similar findings were observed in primary islet cultures prepared from C57BL/6 mice. Furthermore, a 2 week treatment of Vancouver ZDF rats with intravenous GIP decreased Bax, and upregulated Bcl-2 in β-cells, as described in GIP stimulation of pancreatic beta-cell survival is dependent upon phosphatidylinositol 3-kinase (PI3-K)/ protein kinase B (PKB) signaling, inactivation of the forkhead transcription factor Foxo1 and downregulation of bax expression. J Biol Chem. 2005 Apr 6; [Epub ahead of print]
The actions of GIP to activate Akt appear to be mediated through unique pathways independent of PI3K. Both GIP and GLP-1 stimulated Akt activation in kinase assays and promoted b-cell survival (INS-1 cells and mouse islets) through pathways that likely involved cAMP but not phosphorylation of T308 or S473. See Non-canonical activation of Akt/PKB in beta -cells by the incretin hormone glucose-dependent insulinotropic polypeptide (GIP). J Biol Chem. 2009 Feb 20.
Consistent with the differences seen comparing GIP vs. GLP-1 on the β-cell secretion response in experimental and clinical diabetes, pre-clinical studies have illustrated differences in the b-cell signaling molecules triggered by these two related peptides. Intriguingly, although SUR-/- mice exhibit a defect in the response to GLP-1 despite an increase in the levels of cyclic AMP in SUR-/- islets Sulfonylurea receptor type 1 knock-out mice have intact feeding-stimulated insulin secretion despite marked impairment in their response to glucose. J Biol Chem. 2002 Oct 4;277(40):37176-83, In contrast, mice with a targeted inactivation of the Kir6.2 gene retain an insulinotropic response to GLP-1, but not GIP, as illustrated in Distinct effects of glucose-dependent insulinotropic polypeptide and glucagon-like Peptide-1 on insulin secretion and gut motility. Diabetes. 2005 Apr;54(4):1056-63
GIP, adipocytes and obesity
GIP receptors are expressed on adipocytes and may transduce a large number of actions on adipocyte biology, as reviewed in GIP biology and fat metabolism. Life Sci. 2000;66(2):91-103. 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]
GIP promotes induction of LPL activity and triglyceride (TG) accumulation in differentiated insulin-treated 3T3-L1 adipocytes, in association with phosphorylation of protein kinase B (PKB) and reductions in phosphorylated LKB1 and AMP-activated protein kinase (AMPK). Similar findings were observed in experiments with human adipocytes. Moreover, treatment of Vancouver Diabetic Fatty (VDF) Zucker rats with GIP led to increased LPL activity and triglyceride accumulation in adipose tissue-See Activation of lipoprotein lipase (LPL) by glucose-dependent insulinotropic polypeptide (GIP) in adipocytes: A role for a protein kinase B (PKB), LKB1 and AMP-activated protein kinase (AMPK) cascade. J Biol Chem. 2007 Jan 23; [Epub ahead of print]
GIP and the central nervous system
Although very little is known about the role of GIP in the brain, GIP was found to be expressed in the rodent hippocampus and the extent of GIP expression correlated with the rate of cell proliferation in the experimental model system. Furthermore, the GIP receptor was also expressed in the dentate gyrus, and activation of GIP receptor signaling stimulated cell proliferation, whereas adult GIP receptor knock-out mice exhibit a significantly lower number of newborn cells in the hippocampal DG compared with wild-type mice Glucose-dependent insulinotropic polypeptide is expressed in adult hippocampus and induces progenitor cell proliferation. J Neurosci. 2005 Feb 16;25(7):1816-25
GIP may also exert actions in the peripheral nervous system. Both GIP and GIPR RNA were detectable in peripheral nerves and sciatic root ganglia and in sections from spinal cord, and GIP and GIPR RNA transcripts were transiently upregulated in the spinal cord following peripheral nerve crush injury. Immunocytochemical studies demonstrated localization of GIP and GIPR immunopositivity to distinct populations of cells within the rat spinal cord, including neurons, Schwann cells and oligodendrocytes but not astrocytes. Functionally, spontaneous nerve generation was impaired in Gipr-/- mice following crush injury as outlined in Glucose-dependent insulinotropic polypeptide (GIP) and its receptor (GIPR): Cellular localization, lesion-affected expression, and impaired regenerative axonal growth J Neurosci Res. 2009 Jan 23. [Epub ahead of print]
GIP and bone
GIPis anabolic for bone and appears to exert direct actions on osteoblasts as GIPR mRNA and protein are expressed in normal bone and osteoblast-like cell lines. GIP stimulates increases in cAMP and intracellular Ca2+ levels in cultured osteoblasts and these effects are coupled to markers of new bone formation, including elevations in alkaline phosphatase activity and collagen type 1 mRNA as outlined in Osteoblast-derived cells express functional glucose-dependent insulinotropic peptide receptors. Endocrinology 2000;141:1228-35. GIP also increases bone mineral density in ovariectomized rats, a rodent model of postmenopausal osteoporosis Glucose-dependent insulinotropic peptide is an integrative hormone with osteotropic effects. Mol Cell Endocrinol 2001;177:35-41. Relative to age-matched wild type mice, younger Gipr-/- mice exhibit reduced bone size and mass, abnormal bone microarchitecture, impaired biomechanical properties and altered bone turnover Glucose-dependent insulinotropic polypeptide receptor knockout mice have altered bone turnover. Bone 2005;37:759-69 . However, as the mice age, these differences become less apparent. The presence of GIPR mRNA and protein has also recently been detected in rodent osteoclast cells and GIP administration was found to have inhibitory effects on bone resorption Effects of glucose-dependent insulinotropic peptide on osteoclast function. Am J Physiol Endocrinol Metab. 2007 Feb;292(2):E543-8. Moreover, adult Gipr-/- mice exhibit reductions in parameters of bone formation, including altered bone size and bone mass as well as increases in plasma Ca2+ levels following meal ingestion, and increased numbers of osteoclasts associated with enhanced bone turnover, suggesting that GIP may provide a direct link between Ca2+ from a meal and calcium deposition in bone Glucose-dependent insulinotropic polypeptide receptor knockout mice have altered bone turnover. Bone. 2005 Dec;37(6):759-69 and Gastric inhibitory polypeptide as an endogenous factor promoting new bone formation after food ingestion. Mol Endocrinol. 2006 Jul;20(7):1644-51. These studies implicate an important and novel role for GIP in the regulation of bone remodeling. However, acute administration of GIP does not alter markers of bone turnover in human studies Role of gastrointestinal hormones in postprandial reduction of bone resorption. J Bone Miner Res. 2003 Dec;18(12):2180-9, and whether more long-term application of GIP will modulate bone turnover in humans is not known.