Glucose-dependent Insulinotropic Polypeptide (GIP)

In 1971 a 42 amino acid-polypeptide hormone was isolated from porcine intestine and shown to inhibit gastric secretion in dogs; the peptide hormone was, therefore, named “gastric inhibitory peptide”, GIP. Subsequently studies, however, demonstrated a glucose-dependent stimulation of insulin secretion by GIP in animals and humans, suggesting an incretin role for the peptide. GIP-induced inhibition of gastric acid secretion in man could not be demonstrated, and, therefore, the hormone was renamed glucose-dependent insulinotropic polypeptide, keeping the acronym, GIP, from its previous name.

Synthesis, secretion and degradation of GIP

GIP is synthesized and secreted from the enteroendocrine K cells, the majority of which are located in the duodenum and proximal jejunum, but with smaller numbers also occurring throughout the entire small intestine. After expression of the GIP gene in K cells the 153-amino acid precursor of GIP, preproGIP is formed. Subsequently this precursor is processed to GIP by prohormone convertase 1/3, which cleaves out the 42 amino acid-peptide GIP(1-42) (for storage in secretory granules), a signal peptide, an N-terminal peptide and a C-terminal peptide, which all - apart from GIP - seem biologically inactive. Some evidence suggests that pancreatic alpha cells may also be able to produce small amounts of preproGIP, which undergoes posttranslational processing by prohormone convertase 2 to form a C-terminally-truncated peptide, GIP(1-30). However, the physiological mechanisms of this peptide remain elusive.

In the fasting state plasma concentrations of GIP are low, but measureable, suggesting that there is a certain basal rate of secretion. It is believed that interaction between intraluminal nutritional components - particular carbohydrates and lipids[1], but also protein - and the luminal part of K cells results in release of GIP (from the basolateral membrane of K cells) into circulation. In line with this notion liquid meal ingestion elevates peripheral plasma concentrations several folds[2]. Interestingly, the rise in plasma GIP occurs almost immediately (generally within 5 minutes) following initiation of meal ingestion. Also, peak concentrations in plasma are reached as soon as 15-30 minutes after ingestion of e.g. glucose. This rapid secretion following ingestion of nutrients - before the substrates ingested may be present in the small intestine - has led to the notion of vagus-mediated stimulation of secretion[3]. However, whether such pathways play any significant role in human physiology remains to be established. Identification of glucokinase expression in the K cells indicates a glucose-sensing mechanism, similar to that operating in pancreatic beta cells, to be involved in the secretion of GIP. Thus, not only mere presence of nutrients in the lumen of the small intestine (and interaction with luminal parts of K cells), but also K cell absorption of nutrients seems to stimulate GIP secretion. In addition, paracrine effects from neighbouring enteroendocrine cells may affect K cell secretion of GIP. The exact mechanisms behind the rapid postprandial rises in plasma GIP concentrations remain to be established, but most likely they are attributable to the rapid introduction of nutrients to the duodenum (where GIP-secreting K cells are numerous) following liquid glucose loads or meals[4].

After the secretion of GIP the hormone is degraded by the enzyme dipeptidyl peptidase 4 (DPP-4). This enzyme, in addition to its localization at sites such as the intestinal and renal brush border membranes, is also found on capillary surfaces and in a soluble form in plasma[5]. It cleaves off the two N-terminal amino acids of peptides with a penultimate proline or alanine residue, and for GIP, this abolishes its insulinotropic activity[6]. The half-life for the intact, active hormone amounts to 7 minutes, whereas the truncated metabolite is eliminated more slowly through the kidneys, with a half-life of 17 minutes[7].

Pancreatic GIP effects

A specific receptor for GIP is found in the pancreatic beta cell plasma membrane. This receptor is a 7-transmembrane-spanning G protein-coupled receptor belonging to the glucagon subfamily of G protein-coupled receptors. Following binding and subsequent activation of adenylate cyclase, intracellular accumulation of cyclic adenosine mono-phosphate (cAMP), closure of adenosine tri-phosphate (ATP)-sensitive K+ channels and elevation of cytosolic Ca++ concentrations (via protein kinase A (PKA)), mobilization and exocytosis of insulin-containing granules occur[8]. The insulinotropic effect of GIP is strictly glucose-dependent and, thus, during low blood sugar concentrations GIP does not exert any effect on pancreatic insulin secretion whereas hyperglycaemic conditions permit GIP to exercise its strong insulinotropic capability[9][10]. In studies in humans, where GIP was infused together with iv glucose to concentrations approximately corresponding to those observed during oral glucose tolerance tests, this incretin hormone powerfully enhanced insulin secretion[11]. Furthermore, GIP up-regulates insulin gene expression and several steps in the biosynthesis of insulin including up-regulation of genes essential for beta cell function. GIP has also been shown to play a role in the maintenance of beta cell mass by stimulating cellular proliferation and decreasing apoptotic activity in beta cell lines[12]. In contrast to GLP-1, GIP has been shown to stimulate pancreatic glucagon secretion[13]. The GIP receptor is also present in rat pancreatic alpha cells; and activation of the receptor leads to increases in intracellular cAMP contents in amounts normally required for nutrient-induced glucagon secretion[14] and Ca2+-induced exocytosis by PKA-mediated mechanisms[15]. Recent human data suggest that the glucagonotropic effect of GIP is strictly glucose-dependent with no effect during hyperglycaemic conditions9. Thus, GIP seems to act as a blood glucose stabilizer with inverse glucose-dependent effects on pancreatic insulin and glucagon secretion, respectively9.

Extrapancreatic GIP effects

Besides being expressed in the pancreas the GIP receptor gene is expressed in the stomach, small intestine, adipose tissue, adrenal cortex, pituitary, heart, testis, endothelial cells, bone cells, trachea, spleen, thymus, lung, kidney, thyroid and several regions in the brain[16]. However, the physiological consequences of activation of these extrapancreatic receptors remain relatively elusive.

A number of studies provide evidence for a role of GIP in lipid metabolism: Lipids are strong stimulators of GIP secretion; 24-hour GIP profiles parallel plasma concentrations of triglycerides[17]; and functional GIP receptors are found on adipocytes[18]. Furthermore, administration of GIP has been reported to increase chylomicron clearance in dogs[19], lower postprandial triglyceride levels in rats[20] and increase glucose transport, fatty acid synthesis and lipoprotein lipase activity in rat adipocytes[21][22]. Also, GIP seems to increase insulin sensitivity of adipocytes thereby promoting glucose and fatty acid uptake and fatty acid storage in adipocytes. Interestingly, mice with a deletion of the GIP receptor gene become slightly glucose intolerant and, unlike wild type controls, they do not become obese when given a high fat diet[23]. In human studies GIP in combination with insulin and light hyperglycaemia was reported to increase adipose tissue blood flow and glucose uptake, and increase free fatty acid re-esterification; suggesting a role for GIP in adipose tissue triglyceride deposition. Thus, GIP may act as an anabolic regulator of fat metabolism, and increased GIP signalling may promote the development of obesity and insulin resistance.

GIP may also exert anabolic effects in bone tissue. Both osteoblasts and osteoclasts express the GIP receptor and GIP administration has been shown to inhibit bone resorption of osteoclasts and stimulate bone formation of osteoblasts. The original observation of GIP-induced inhibition of gastric secretion in dogs in the 1970’s, which resulted in the naming “gastric inhibitory peptide”, could, as mentioned, not be reproduced during physiological doses in human studies and so far human data on GIP do not provide evidence for any physiological effects on the gastrointestinal system or on food intake. Likewise the role of GIP and the GIP receptor in the central nervous system of humans remains elusive.

References

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  2. ^ Knop FK, Vilsbøll T, Larsen S, et al (2007) Increased postprandial responses of GLP-1 and GIP in patients with chronic pancreatitis and steatorrhea following pancreatic enzyme substitution. Am J Physiol Endocrinol Metab 292: E324-E330

  3. ^ Meier JJ, Nauck MA, Schmidt WE, Gallwitz B (2002) Gastric inhibitory the neglected incretin revisited. Regul Pept 107:1-13

  4. ^ Schirra J, Katschinski M, Weidmann C, et al (1996) Gastric emptying and release of incretin hormones after glucose ingestion in humans. J Clin Invest 97: 92-103

  5. ^ Mentlein R (1999) Dipeptidyl-peptidase IV (CD26)--role in the inactivation of regulatory peptides. Regul Pept 85:9-24

  6. ^ Deacon CF, Nauck MA, Meier J, Hucking K, Holst JJ (2000) 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 85:3575-3581

  7. ^ Vilsbøll T, Agersø H, Lauritsen T, et al (2006) The elimination rates of intact GIP as well as its primary metabolite, GIP 3-42, are similar in type 2 diabetic patients and healthy subjects. Regul Pept 137: 168-172

  8. ^ Ding WG, Renstrom E, Rorsman P, Buschard K, Gromada J (1997) GLP-1 and GIP stimulate Ca2+-induced secretion in rat alpha-cells by a protein kinase A-mediated mechanism. Diabetes 46:792-800

  9. ^ Christensen M, Vedtofte L, Holst JJ, Vilsbøll T, Knop FK (2011) Glucose-dependent insulinotropic a bifunctional glucose-dependent regulator of glucagon and insulin secretion in humans. Diabetes 60:3103-3109

  10. ^ Kreymann B, Williams G, Ghatei MA, Bloom SR (1987) Glucagon-like peptide-1 7-a physiological incretin in man. Lancet 2:1300-1304

  11. ^ Nauck M, Schmidt WE, Ebert R, et al (1989) Insulinotropic properties of synthetic human gastric inhibitory polypeptide in interactions with glucose, phenylalanine, and cholecystokinin-8. J Clin Endocrinol Metab 69:654-662

  12. ^ Trumper A, Trumper K, Horsch D (2002) Mechanisms of mitogenic and anti-apoptotic signaling by glucose-dependent insulinotropic polypeptide in beta(INS-1)-cells. J.Endocrinol. 174:233-246

  13. ^ Meier JJ, Gallwitz B, Siepmann N, et al (2003) Gastric inhibitory polypeptide (GIP) dose-dependently stimulates glucagon secretion in healthy human subjects at euglycaemia. Diabetologia 46:798-801

  14. ^ Moens K, Heimberg H, Flamez D, et al (1996) Expression and functional activity of glucagon, glucagon-like peptide I, and glucose-dependent insulinotropic peptide receptors in rat pancreatic islet cells. Diabetes 45:257-261

  15. ^ Ding WG, Gromada J (1997) Protein kinase A-dependent stimulation of exocytosis in mouse pancreatic beta-cells by glucose-dependent insulinotropic polypeptide. Diabetes 46:615-621

  16. ^ Asmar M (2011) New physiological effects of the incretin hormones GLP-1 and GIP. Dan Med Bull 58: B4248

  17. ^ Elliott RM, Morgan LM, Tredger JA, Deacon S, Wright J, Marks V (1993) Glucagon-like peptide-1 (7-36)amide and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in acute post-prandial and 24-h secretion patterns. J Endocrinol 138:159-166

  18. ^ Yip RG, Boylan MO, Kieffer TJ, Wolfe MM (1998) Functional GIP receptors are present on adipocytes. Endocrinology 139:4004-4007

  19. ^ Wasada T, McCorkle K, Harris V, Kawai K, Howard B, Unger RH (1981) Effect of gastric inhibitory polypeptide on plasma levels of chylomicron triglycerides in dogs. J.Clin.Invest 68:1106-1107

  20. ^ Ebert R, Nauck M, Creutzfeldt W (1991) Effect of exogenous or endogenous gastric inhibitory polypeptide (GIP) on plasma triglyceride responses in rats. Horm Metab Res 23:517-521

  21. ^ Knapper JM, Puddicombe SM, Morgan LM, Fletcher JM (1995) Investigations into the actions of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1(7-36)amide on lipoprotein lipase activity in explants of rat adipose tissue. J Nutr 125:183-188

  22. ^ Oben J, Morgan L, Fletcher J, Marks V (1991) Effect of the entero-pancreatic hormones, gastric inhibitory polypeptide and glucagon-like polypeptide-1(7-36) amide, on fatty acid synthesis in explants of rat adipose tissue. J Endocrinol 130:267-272

  23. ^ Miyawaki K, Yamada Y, Ban N, et al (2002) Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat Med 8:738-742

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