This 42-amino acid peptide first isolated in 1969, Can J Physiol Pharmacol. 1969 Jan;47(1):113-4. was initially thought to act as an endogenous gastric acid inhibitor based on animal studies and accordingly named -Gastric Inhibitory Peptide. Studies in humans later brought to light its major role as an incretin hormone with the new name while preserving the acronym!
Even as early as 1906, gut extracts were recognised to have insulin like or insulinotropic action as evidenced by their use in diabetes mellitus. On the treatment of diabetes mellitus by acid extract of duodenal mucous membrane. Biochemistry Journal 1906; I: 28-38 It has been known since 1964, that oral glucose elicits higher insulin levels in blood than intravenous glucose. J Clin Endocrinol Metab. 1964 Oct;24:1076-82 Factors in the gut were thought to be responsible for this glucose-mediated higher insulin response. GLP-1 and GIP were later found to be the major players in this entero-insular axis, accounting for up to 60% of the post-prandial insulin secretion by the pancreas. J Clin Endocrinol Metab. 1993 Apr;76(4):912-7 |
GIP is secreted from the K cells in the upper small intestine (predominantly duodenum) in response to fat and carbohydrate absorption. Am J Surg. 1975 Aug;130(2):128-35; Am J Physiol. 1985 Aug;249(2 Pt 1):E195-200 Fasting GIP levels of 10 pmol/L reach post prandial levels of 70-150 pmol/L, in 30-60 minutes depending on meal size and composition. GIP cells in the intestines are co-localized with GLP-1 cells, Regul Pept. 2003 Jul 15;114(2-3):189-96. and a strong correlation exists between GIP and GLP-1 secretion after oral glucose. Absorption of food, rather than its mere presence in the gut, is needed to elicit secretion, Diabetologia. 1979 Feb;16(2):75-85 as evidenced by lower GIP levels in malabsorptive states Lancet. 1978 Apr 15;1(8068):785-8 and chronic pancreatitis, Diabetologia. 1976 Dec;12(6):609-12 with restoration of GIP levels with pancreatic enzyme supplementation in the latter condition. Diabetologia. 1980 Sep;19(3):198-204
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Most of the GIP secreted is immediately degraded in the capillaries of the gut mucosa by the enzyme Dipeptidyl peptidase IV (DPP-IV) Endocrinology. 1999 Nov;140(11):5356-63. which also degrades GLP-1, Neuropeptide Y, Oxyntomodulin and GLP-2. The GIP is converted into the truncated form GIP(3-42) Endocrinology. 1995 Aug;136(8):3585-96 which seems to act as a GIP receptor antagonist in vivo. J Endocrinol. 2002 Nov;175(2):525-33. The half life of GIP is thus a mere 3-5 minutes. A DPP-IV independent mechanism of GIP degradation is also likely as DPP-IV inhibition does not totally prevent GIP degradation. Diabetes. 2001 Jul;50(7):1588-97 The final elimination of GIP is contributed to by the renal capillary peptidases in the kidneys. Am J Surg. 1984 Dec;148(6):732-5. GIP receptor mRNA has been shown to be present in various tissues including the pancreas gut, heart, pituitary, and inner layers of the adrenal cortex. Endocrinology. 1993 Dec;133(6):2861-70. It is also expressed in the cerebral cortex, hippocampus, and olfactory bulb. GIP receptors have been demonstrated in the adipose tissue, Endocrinology. 1993 Dec;133(6):2861-70. and it is possible that GIP may have a role in adipose tissue regulation. The fact that fatty meals stimulate GIP J Clin Endocrinol Metab. 1975 Aug;41(2):260-5. and that GIP induces lipoprotein lipaseDiabetes. 1979 Dec;28(12):1141-2. while reducing glucagon stimulated lipolysis, Metabolism. 1976 Nov;25(11):1197-9 further emphasize its potential role in lipid regulation.
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GIP Actions
Mice with a targeted deletion of GIP receptor gene become glucose intolerant. Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):14843-7 But this glucose intolerance is not marked probably due to compensatory rise in GLP1 secretion. GLP-1 receptor ablated mice show compensatory rise in GIP secretion and pancreatic sensitivity to GIP. Diabetes. 1998 Jul;47(7):1046-52. The insulinotropic contribution of GIP is equivalent to GLP-1 in the physiologic plasma glucose rangesRegul Pept. 2003 Jul 15;114(2-3):115-21 and is predominantly evident in hyperglycaemic conditions, while insulin secretion during euglycemic fasting conditions is minimally affected. No change in glucose levels during GIP administration has been observed in normoglycaemic subjects. Metabolism. 2003 Dec;52(12):1579-85 Combined infusion of GLP1 and GIP produces an additive response. J Clin Endocrinol Metab. 1993 Apr;76(4):912-7. The summative response is indirectly borne out by the effect in mice with double knock out of GIP and GLP-1 receptors. J Clin Invest. 2004 Feb;113(4):635-45. Insulin secretion is augmented more by GIP administration in the form of a bolus rather than as an infusion. Apart from an insulinotropic effect, GIP stimulates the growth, differentiation and proliferation of pancreatic beta cells, Diabetes. 2003 Mar;52(3):741-50 with anti-apoptotic properties. J Endocrinol. 2002 Aug;174(2):233-46 GIP exerts peripheral effects on glucose metabolism including inhibition of hepatic glucose production and increasing the uptake of glucose in isolated mouse muscle. J Endocrinol. 1998 Feb;156(2):237-43. |
GIP does not seem to delay gastric emptying in contrast to GLP-1. Am J Physiol Endocrinol Metab. 2004 Apr;286(4):E621-5. In contrast to GLP-1 (which decreases glucagon) Diabetologia. 1993 Aug;36(8):741-4 , GIP seems to produce an increase in glucagon in euglycaemic healthy subjects. Diabetologia. 2003 Jun;46(6):798-801. although no glucagon stimulation was noted during hyperglycaemic clamp conditions Diabetes. 2001 Nov;50(11):2497-504. or in diabetics. J Clin Invest. 1993 Jan;91(1):301-7. GIP has no significant effect on gastric acid secretion Digestion. 1992;52(3-4):214-21. Glucose as well as fat stimulate GIP secretion. J Clin Endocrinol Metab. 1975 Aug;41(2):260-5. Despite demonstration of induction of lipoprotein lipase in isolated rat-adipocytes by GIP, Diabetes. 1979 Dec;28(12):1141-2, and promotion of increased fatty acid synthesis, J Endocrinol. 1991 Aug;130(2):267-72. its overall effect on triglycerides and free fatty acid concentrations in man after a mixed meal seems unimpressive. Best Pract Res Clin Endocrinol Metab. 2004 Dec;18(4):587-606 |
GIP and Diabetes
Defective GIP signalling in rodents results in raised post prandial glucose levels but normal fasting glucose. J Clin Invest.1996 Dec 1;98(11):2440-5. Type2 diabetic patients tend to have normal or high GIP secretion. Diabetologia. 1989 Sep;32(9):668-77 Both type 1 and type 2 diabetic patients have normal GIP responses to meals compared to healthy subjects. J Clin Endocrinol Metab. 2003 Jun;88(6):2706-13. Thus, in contrast to the impaired GLP-1 secretion in type 2 diabetics, Diabetes. 2001 Mar;50(3):609-13. there is no identified secretory defect for GIP in type 2 diabetes. The elimination of GIP in type 2 diabetics, like GLP-1 is likely to be normal. Studies of GIP secretion in type I diabetes are few, but reduced GIP secretion has been described in newly diagnosed type I diabetics. J Clin Endocrinol Metab. 1983 Jun;56(6):1306-12. Although GIP secretion in response to meals is normal in diabetics, GIP induced secretion of insulin is defective in diabetes. This is observed to be predominantly a defective stimulation of the late phase of insulin response (20-120 minutes) J Clin Endocrinol Metab. 2003 Oct;88(10):4897-903, despite a normal early response. The cause of this defective GIP signalling remains to be explained. A primary genetic cause seems less likely as euglycaemic first degree relatives of type 2 diabetics have normal GIP-induced insulin responses. Metabolism. 2003 Dec;52(12):1579-85. Paucity of GIP receptors due to down-regulation is a possible explanation, Diabetes. 2001 May;50(5):1004-11. but has not been clarified in humans. The glucagon stimulatory effect of GIP as well as the lack of effect on gastric emptying along with defective insulinotropic signalling makes GIP less likely to be useful as an anti-diabetic treatment modality compared to GLP-1. Development of GIP analogues (Tyr1-modified analogues Diabetes. 1999 Apr;48(4):758-65 and Ala2-substituted analogues Diabetes. 2002 Mar;51(3):652-61) suggest that GIP modulation could contribute to diabetes management. Tyr1 modified analogues seem to be more effective than Ala2 substituted analogues. Tyr1modified analogues have been shown to stimulate insulin secretion with significant reduction in glycaemia (1.5-2 fold) in obese diabetic ob/ob mice. Biochem J. 2002 Nov 1;367(Pt 3):913-20. |
GIP and Obesity
Obese patients have increased fasting concentrations of GIP as well as an early enhanced postprandial GIP response compared to lean subjects. J Clin Endocrinol Metab. 2003 Jun;88(6):2706-13. GIP receptor knock out prevents development of obesity and insulin resistance in ob/ob rats despite high fat feeding. Nat Med. 2002 Jul;8(7):738-42. although with decreased insulin response and hyperglycaemia. Feeding behaviour in these rodents was unaffected. In fact, DPP-IV resistant GIP-receptor antagonists with half life > 24 hours have been developed (Pro3 GIP) which inhibits cAMP formation in response to GIP, Biochem Biophys Res Commun. 2002 Feb 8;290(5):1420-6. without affecting cAMP formation stimulated by GLP-1.Diabetologia. 2003 Feb;46(2):222-30 Pro3 GIP thus inhibits GIP-induced insulin secretion by up to 86%. GIP receptor antagonists may have a part to play in future obesity treatment although the implications of GIP-blockade on carbohydrate and lipid metabolism might well restrict its evolution into a therapeutic agent for obesity in the near future. |