Endogenous Gastric Inhibitory Polypeptide Research Articles

Abstract 18394: Gastric Inhibitory Polypeptide is Associated with Metabolic Disorder and Cardiovascular Disease Independent of Glucose in Humans

Background - Emerging animal studies have reported the beneficial effect of interrupting gastric inhibitory polypeptide (GIP) receptor signaling in metabolic disorders including extreme fat deposition with insulin resistance and glucose intolerance. These results propose the hypothesis that hyper GIP secretion may contribute to the development of cardiovascular disease (CVD) in humans. However, most studies have focused on incretin responses to glucose loading, and the association between endogenous GIP levels and cardiometabolic disorders has not been well defined in humans. Methods and Results - To examine the association between fasting GIP and cardiometabolic disorders or CVD independent of plasma glucose (PG) levels, we analysed 300 non-diabetic subjects. Furthermore we performed in vitro functional analysis using human macrophage cells. Simple regression analysis demonstrated that the fasting total GIP was correlated with cardiometabolic disorders such as waist to hip ratio, hyperinsulinemia, and HOMA-IR. ANCOVA and logistic analysis after adjustment for age, gender, BMI, smoking, HOMA-IR, hypertension, LDL cholesterol, HDL cholesterol, eGFR and PG, revealed that fasting GIP was increased in the subjects with CVD than non-CVD (53.7 ± 32.2 v.s. 28.2 ± 18.1, p <0.01), and each tertile increase in fasting GIP was associated with the prevalence of CVD (odds ratio 3.12 per tertile, 95% CI 1.73 to 5.62; p <0.01). Furthermore, molecular analysis revealed that GIP receptor was present in human monocyte/macrophage, T-lymphocyte, and human carotid atherosclerotic lesion. In vitro analysis revealed that GIP stimulation up-regulated gene expression of interleukin 6, CC chemokine receptor (CCR) 2, CCR5, and scavenger receptor type A in human THP-1 macrophages. Conclusions - These results suggest that oversecretion of GIP may contribute to cardiometabolic disorder, resulting in the development of CVD independent of PG in humans.

Understanding the Incretin Effect

It is well known that the incretin effect contributes as much as half of the insulin secretory response to oral glucose load and that this effect is reduced along with worsening glucose tolerance in those with type 2 diabetes. Gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the two primary incretin hormones secreted from the intestine after the ingestion of glucose and other nutrients (1–3). In type 2 diabetes patients, the insulinotropic action of GIP is diminished, whereas that of GLP-1 is substantially preserved, although secretion of the latter appears to be diminished (4, 5). Thus, methods of enhancement of circulating concentrations of GLP-1 and/or GLP-1 receptor signaling have been established as therapeutic strategies in type 2 diabetes. GLP-1 receptor agonists and dipeptidyl-peptidase-4 (DPP-4) inhibitors are now widely and successfully used for this condition. DPP-4 inhibitors augment endogenous active GIP and GLP-1 concentrations. In this therapeutic strategy, DPP-4 inhibitors are expected to enhance the incretin effect by raising plasma concentrations of active incretin hormones. The study in this issue of JCEM by Vardarli et al. (6) assesses the incretin effect after treatment with the DPP-4 inhibitor vildagliptin in patients with type 2 diabetes. Subjects were recruited into a double-blind, two-way crossover study (order randomized) to evaluate the incretin effect under treatment with vildagliptin (100 mg once daily) or placebo. Under both treatments, an oral 75-g glucose load was performed on d 12, and on d 13 isoglycemic glucose infusion was administered to reproduce glucose excursions after oral glucose load. The glucose excursions after oral and iv glucose administration matched well. Vildagliptin reduced the integrated incremental glucose concentration during oral glucose load by 15.8%. Moreover, as expected, the ratio of integrated incremental responses of insulin, C-peptide, and insulin secretion rates over glycemic excursions was significantly enhanced under vildagliptin treatment. Surprisingly, however, the numerical incretin effect (based on insulin, C-peptide concentrations, and insulin secretion rates measured after oral and iv glucose testing) did not differ between vildagliptin and placebo. To further elucidate these findings, the authors show that the insulin secretory response to glucose is enhanced with vildagliptin treatment not only by oral load but also after iv load, contributing to the numerical similarity of the calculated incretin effects. This raises several questions regarding calculation of the incretin effect and its purported physiological basis. Oral glucose load was shown to produce a greater insulin response than iv injection of glucose in the 1960s (7, 8), and the incretin effect was defined as the difference in -cell secretory response to oral or iv glucose stimuli (9–11). The calculation was based on the assumption that after oral glucose administration, -cells are stimulated by the elevated plasma glucose as well as by the additional stimulation of incretin hormones not activated during iv glucose loading. Vardarli et al. (6) have now demonstrated that there is a minor rise in the intact GLP-1 concentration during iv glucose administrationafter vildagliptin exposure. Furthermore, this rise may underlie the enhanced insulin secretory response after iv glucose load that results in the substantial insulin response used in calculating the incretin effect. Vildagliptin was found not to change the numerical incretin effect compared with placebo. The authors discuss the relationship between the amount of iv glucose administration needed to obtain isoglycemia and the incretin effect calculated by insulin, C-peptide concentrations, and insulin secretion rates. The more that the incretin effect is reduced, the more glucose needs to be administered iv to reproduce the glucose ex-

Gastric inhibitory polypeptide does not inhibit gastric emptying in humans

The insulinotropic gut hormone gastric inhibitory polypeptide (GIP) has been demonstrated to inhibit gastric acid secretion and was proposed to possess "enterogastrone" activity. GIP effects on gastric emptying have not yet been studied. Fifteen healthy male volunteers (23.9 +/- 3.3 yr, body mass index 23.7 +/- 2.3 kg/m(2)) were studied with the intravenous infusion of GIP (2 pmol.kg(-1).min(-1)) or placebo, each administered to the volunteers on separate occasions from -30 to 360 min in the fasting state. At 0 min, a solid test meal (250 kcal containing [(13)C]sodium octanoate) was served. Gastric emptying was calculated from the (13)CO(2) exhalation rates in breath samples collected over 360 min. Venous blood was drawn in 30-min intervals for the determination of glucose, insulin, C-peptide, and GIP (total and intact). Statistical calculations were made by use of repeated-measures ANOVA and one-way ANOVA. During the infusion, GIP rose to steady-state concentrations of 159 +/- 15 pmol/l for total and 34 +/- 4 pmol/l for intact GIP (P < 0.0001). Meal ingestion further increased GIP concentrations in both groups, reaching peak levels of 265 +/- 20 and 82 +/- 9 pmol/l for total and 67 +/- 7 and 31 +/- 9 pmol/l for intact GIP during the administration of GIP and placebo, respectively (P < 0.0001). There were no differences in glucose, insulin, and C-peptide between the experiments with the infusion of GIP or placebo. Gastric half-emptying times were 120 +/- 9 and 120 +/- 18 min (P = 1.0, with GIP and placebo, respectively). The time pattern of gastric emptying was similar in the two groups (P = 0.98). Endogenous GIP secretion, as derived from the incremental area under the curve of plasma GIP concentrations in the placebo experiments, did not correlate to gastric half-emptying times (r(2) = 0.15, P = 0.15 for intact GIP; r(2) = 0.21, P = 0.086 for total GIP). We conclude that gastric emptying does not appear to be influenced by GIP. The secretion of GIP after meal ingestion is not suppressed by its exogenous administration. The lack of effect of GIP on gastric emptying underlines the differences between GIP and the second incretin glucagon-like peptide 1.

Absence of hepatic extraction of gastric inhibitory polypeptide in conscious dogs.

Fractional hepatic extraction of gastric inhibitory polypeptide was examined in conscious unrestrained dogs with catheters in the portal vein, hepatic vein, and the carotid artery and Doppler flow probes on the portal vein and hepatic artery. Following a control period, endogenous gastric inhibitory polypeptide was stimulated by oral administration of glucose with and without prior infusion of atropine. In other experiments, gastric inhibitory polypeptide (20 ng/kg/min) was infused into the portal system in association with peripheral infusion of glucose. In none of these experiments was it possible to demonstrate any significant fractional hepatic extraction of gastric inhibitory polypeptide.

Endogenous Gastric Inhibitory Polypeptide (GIP) Does Not Affect Removal of Triacylglycerol from Plasma in Man

Endogenous Gastric Inhibitory Polypeptide (GIP) Does Not Affect Removal of Triacylglycerol from Plasma in Man

Effects of exogenous and endogenous gastric inhibitory polypeptide in obese hyperglycaemic (ob/ob) mice

Gastric inhibitory polypeptide, also commonly referred to as glucose-dependent insulinotropic polypeptide or GIP, is a 42 amino acid hormone synthesized and released by the Kcells of the small intestine in response to nutrients. Previous studies have shown that plasma GIP concentrations are inordinately raised in obese hyperglycaemic (oblob) mice, and that oral administration of carbohydrate, protein and especially fat evokes marked plasma GIP responses (Flatt et al., 1983a; P. R. Flatt, C. J. Bailey, P. Kwasowski, T. Page & V. Marks, unpublished work). Overfeeding, K-cell hyperplasia and insensitivity of these cells to suppression by endogenous insulin are envisaged to generate the hypergipaemia (Flatt et al., 1983a,b). Since GIP is a recognized component of the entero-insular axis (Brown, 1982), the raised concentrations in ob/ob mice suggest an important pathogenic role in the promotion of hyperinsulinaemia and related metabolic abnormalities of the ob/ob syndrome (Flatt et al., 1983~). The present study examines the insulinotropic action of exogenous and endogenous GIP in relation to the prevailing hyperglycaemia in ob/ob mice. Obese (oblob) mice from the Aston colony were supplied with a standard pellet diet and maintained as described previously (Flatt & Bailey, 1981a; Bailey et al., 1982). The mice were used at 10-12 weeks of age and starved for 18 h before experimentation. The insulin response to exogenous GIP was examined by intraperitoneal administration of porcine GIP (40pg/kg) (Professor J. C. Brown, University of British Columbia, Canada) together with either glucose (2g/kg) or an equivalent volume of saline (O.l54mmol/l NaC1). Blood samples for determination of plasma concentrations of glucose, insulin and GIP were taken from the cut tail-tips of conscious mice at 0, 5, 15, and 30min. Plasma disappearance of GIP was followed until 180min. The insulin response to endogenous GIP was examined by oral administration of fat (Intralipid, 870mg/kg) followed at 30min by an intraperitoneal injection of either glucose (2g/kg) or an equivalent volume of saline (0.154mmol/l NaCl). Blood samples for plasma glucose, insulin and GIP determination were taken at 0, 30, 60, and 90min. Insulin and GIP were measured by radioimmunoassay (Flatt et al., 1983~). Statistical evaluation was made by Student’s t-test. As shown in Fig. la, intraperitoneal administration of GIP with saline evoked a marked but transient plasma insulin response. Plasma glucose concentrations (not illustrated) were not significantly changed, being within the range 7-l0mmol/l. When GIP was administered with

Lack of effect of exogenous or endogenous gastric inhibitory polypeptide on the elimination rate of Intralipid in man.

Six healthy subjects were studied by means of an intravenous fat tolerance test on three occasions, in the fasting state, in the postprandial state, and during an intravenous infusion of gastric inhibitory polypeptide (GIP). No effects on the elimination rate of Intralipid were seen either by endogenous or exogenous GIP.

Gastric inhibitory polypeptide (GIP) release by actively transported, structurally similar carbohydrates.

Six awake adult dogs prepared with a duodenocutaneous fistula were infused intraduodenally with one of the following solutions: 3% saline, 10% glucose, 20% glucose, 20% galactose, 20% fructose, 20% mannose, 20% sorbitol, 20% maltose, 20% lactose, or 20% sucrose. Both 10 and 20% glucose stimulated GIP release, and the response appeared to be dose related. Actively transported galactose (C-4 epimer) stimulated GIP release, but less than glucose. Fructose (C-2 keto sugar) which is absorbed by facilitated transport did not stimulate GIP release. Mannose (C-2 epimer) which is passively absorbed by diffusion did not release GIP. Sorbitol (reduced alcohol of glucose) which is not absorbed did not release GIP. Of the disaccharides tested, only maltose stimulated the release of GIP. The results suggest that structural integrity of the glucose molecule from the C-1 to C-4 carbon atoms, a free aldehyde group on the C-1 carbon atom, and a cyclic structure are all necessary for both the active transport of glucose and the release of endogenous GIP. It would appear that structurally similar receptors exist for both the active transport of glucose and for the release of GIP.

Effect of endogenous gastric inhibitory polypeptide (GIP) on the removal of triacylglycerol in dogs

In order to clarify the effect of endogenous gastric inhibitory polypeptide (GIP) upon lipid metabolism, the removal of intravenously administered triacylglycerol was investigated following an oral glucose or galactose load in dogs. After an overnight fast, the triacylglycerol emulsion was infused at a constant rate of 1 ml/min for 90 min, and glucose, galactose or tap water was orally administered at 30 min. Blood glucose increased after the glucose load but it did not change following the galactose load or water ingestion. Plasma insulin increased after the glucose load but did not change after galactose or tap water ingestion. Plasma glucagon did not show any discernible change in the three experimental groups. Plasma GIP increased following the glucose or galactose load to 4360 or 1653 pg/ml, respectively. Plasma triacylglycerol increased to the same levels at 30 min in the three experimental groups. The peak levels of plasma triacylglycerol and integrated plasma triacylglycerol for 150 min did not differ in the three groups. Moreover, there was no difference in the removal rate of plasma triacylglycerol following the withdrawal of the fat emulsion. It is concluded from the present study that endogenously released GIP does not elicit any effect upon triacylglycerol removal.

Role of endogenous gastric inhibitory polypeptide (GIP) for inhibition of gastric secretion by fat and hypertonic glucose in the dog : S.J. Konturek, N. Kwiecień, T. Radecki, R. Ebert and W. Creutzfeldt. Institute of Physiology, Medical Academy of Kraków, Poland, and Department of Medicine, University of Göttingen, West Germany

Role of endogenous gastric inhibitory polypeptide (GIP) for inhibition of gastric secretion by fat and hypertonic glucose in the dog : S.J. Konturek, N. Kwiecień, T. Radecki, R. Ebert and W. Creutzfeldt. Institute of Physiology, Medical Academy of Kraków, Poland, and Department of Medicine, University of Göttingen, West Germany

The role of endogenous gastric inhibitory polypeptide in the enteroinsular axis.

In order to elucidate the relationship between the release of gastric inhibitory polypeptide (GIP) and insulin, we compared plasma GIP and insulin concentration responses to meal ingestion in normal subjects and patients with various surgical modifications of the food pathway. Nine patients with Billroth I partial gastrectomy (BI), 7 patients with Billroth II partial gastrectomy (BII), and 6 patients with total gastrectomy (TG) were tested. In BI patients the increase in blood glucose was similar to that in normal subjects, but the response was significantly greater in BII and TG patients. In TG patients blood glucose rose significantly higher in response to a standard meal than in all other groups. In BI patients the mean peak GIP level after meal ingestion was significantly higher than in normal subjects. In BII and TG patients an extremely exaggerated GIP response after the meal was observed. The insulin response to feeding was increased only in the BII and TG patients. Since the insulin response was enhanced only when both the glucose and GIP responses were magnified, we conclude that endogenous GIP is a glucose-dependent insulinotropic factor. In addition, from the fact that meal-stimulated GIP release is most marked in patients with total gastrectomy, we conclude that the direct contact of food with the GIP-producing cells is a strong mechanical or chemical stimulus for GIP release.

Gastric inhibitory polypeptide (GIP) and insulin release after small-bowel resection in man.

Fifteen patients in whom various parts of the small intestine had been resected because of Crohn's disease or mesenteric thrombosis and 10 healthy volunteers were studied. A 50-g oral glucose load (OGTT) and an intravenous glucose infusion giving the same plasma glucose profile as the OGTT were carried out to study (a) the relation between the plasma gastric inhibitory polypeptide (GIP) levels after oral glucose and the length and nature of the intestinal residues and (b) the importance of endogenous GIP as an incretin in man. The magnitude of the increase in plasma GIP after oral glucose load was positively correlated to the length of residual jejunum. The incretin effect was positively correlated to the length of residual intestine. Patients with preserved ileal residues had larger incretin effects than patients with less than 150 cm jejunal residues and no ileal residues, although the integrated increases in plasma GIP after oral glucose were equal. Compared with healthy volunteers, the patients with more than 150 cm residual jejunum had significantly higher increases in plasma GIP and normal incretin effects. The GIP release and the incretin effect in patients with preserved ileal residues were normal. The incretin effect of the patients with less than 150 cm jejunum was significantly subnormal in spite of a normal GIP release. These findings indicate that the upper intestine releases GIP after oral glucose and that other as yet unknown intestinal hormonal factors act as incretins in concert with GIP.

The association between endogenous gastric inhibitory polypeptide release and suppression of gastric acid output following intraduodenal fat stimulation

The association between endogenous gastric inhibitory polypeptide release and suppression of gastric acid output following intraduodenal fat stimulation

Gastric inhibitory polypeptide (GIP) release and incretin effect after oral glucose in obesity and after jejunoileal bypass.

Twelve morbidly obese patients and 17 patients treated for obesity by jejunoileal shunt operation were studied. A 50-g oral glucose load (OGTT) and an intravenous glucose infusion were carried out to study a) the relation between the plasma gastric inhibitory polypeptide (GIP) levels after oral glucose and the type of jejunoileal bypass performed and b) the importance of endogenous GIP as an incretin in man. The GIP release during OGTT and incretin effect were normal in the obese patients. After jejunoileal shunt, measuring 48 cm and with a ratio of 3:1 between the jejunal and ileal segments, the GIP release and the incretin effect were significantly reduced. Incremental increase in plasma GIP and OGTT was significantly correlated to the incretin effect in these patients. After jejunoileal shunt with the reverse ratio of proximal and distal intestine the incretin effect was significantly higher in spite of a comparable GIP release. Five patients after ileoascendostomia for familial hypercholesterolemia had significantly supernormal GIP release during OGTT but normal incretin effect. The findings indicate the insulinotropic effect of GIP and are in accordance with the concept that incretins other than GIP are released from the distal intestine.

Mannitol and glucose: effects on gastric acid secretion and endogenous gastric inhibitory polypeptide (GIP).

Serum gastric inhibitory polypeptide was measured in dogs prepared with Heidenhain pouches and Mann-Bollman fistulae following the intraduodenal (ID) infusion of isotonic saline, 20% glucose, or 20% mannitol. Following ID 20% glucose, serum GIP concentrations rose significantly (P less than 0.05) between 30 and 120 min and there was a significant inhibition (P less than 0.05) of acid secretion in the Heidenhain pouches between 15 and 75 min. A good correlation (r = 0.925) was found between the rise in serum GIP and the inhibition of acid secretion. Although neither ID isotonic saline nor 20% mannitol stimulated GIP release, the latter produced a significant (P less than 0.05) inhibition of acid secretion between 60 and 105 min. We conclude: (1) the inhibitory effect of acid secretion following ID glucose is mediated in part by the release of endogenous GIP; (2) glucose and mannitol probably inhibit gastric acid secretion by different mechanisms.

Effect of gastric inhibitory polypeptide on lower esophageal sphincter pressure in cats

The effect of gastric inhibitory polypeptide on lower esophageal sphincter pressure was studied in cats to determine whether the effect was similar to that of its structurally related hormones, secretin, glucagon, and vasoactive intestinal peptide. Five healthy cats without endoscopic evidence of esophagitis were manometrically evaluated for 75 min using triple lumen open-tipped constantly perfused catheters. Exogenous gastric inhibitory polypeptide, 0.2 μg per kg per min, alone significantly decreased (P < 0.05) basal sphincter pressure within 15 min of administration to a maximum lowering of sphincter pressure of −13.8 ± 3.8 mm Hg at 45 min. Maximum mean serum gastric inhibitory polypeptide concentration, 428 ± 47 pg per ml, occurred at 15 min. Exogenous gastric inhibitory polypeptide also decreased lower esophageal sphincter pressure at all time periods (P < 0.02) when given during a constant pentagastrin infusion, 0.5 μg per kg per hr. Endogenous gastric inhibitory polypeptide was released by intraduodenal 20% glucose bolus injection or constant perfusion. After bolus glucose administration, serum gastric inhibitory polypeptide concentrations increased from undetectable values to a mean peak concentration of 657 ± 78 pg per ml at 15 min. Maximum lowering of lower esophageal sphincter pressure, −15.8 ± 3.5 mm Hg, coincided with the peak gastric inhibitory polypeptide concentrations. After pentagastrin infusion plus a 30-min intraduodenal glucose perfusion, mean serum gastric inhibitory polypeptide concentration reached a maximum of 600 ± 58 pg per ml at 30 min and remained elevated at 75 min (440 ± 39 pg per ml). These increases in serum gastric inhibitory polypeptide levels were associated with significant decrements in lower esophageal sphincter pressure with the maximum lowering occurring between 45 and 75 min (−14 to −16 mm Hg). We conclude that gastric inhibitory polypeptide lowers both basal and pentagastrin-stimulated lower esophageal sphincter pressure in cats.

The effect of endogenous gastric inhibitory polypeptide on glucose-induced insulin secretion in mild diabetes.

Diabetic subjects have previously been found to have increased secretion of immunoreactive gastric inhibitory polypeptide (IR-GIP) in response to oral glucose or triglyceride compared with normal subjects. In the present study, a group of 19 diabetics was selected with milder glucose intolerance (fasting plasma glucose = 109 mg. per deciliter) than those reported previously. In these diabetics no enhancement of IRGIP responses was found to either 75 gm. oral glucose or 50 ml. oral corn oil when compared with 13 subjects with normal carbohydrate tolerance. Some of the subjects were obese and, when assessed independently from glucose tolerance, obesity was associated with higher integrated IRGIP responses to oral glucose but not to oral corn oil. The degree of obesity (92 to 154 per cent ideal body weight) did not correlate with fasting or stimulated IRGIP responses of the 32 subjects. One hour after ingestion of 50 ml. corn oil, when IRGIP concentrations were maximal but glucose and insulin remained unaffected, the diabetic subjects showed increased relative acute-phase insulin secretion to a 20 gm. pulse of intravenous glucose compared with that from a glucose pulse alone (p &amp;lt; 0.01). Subjects with normal carbohydrate tolerance had no increase in relative acute insulin response to glucose after triglyceride priming. The relative second-phase insulin response (10 to 30 min.) increased significantly with triglyceride priming in both diabetics (p &amp;lt; 0.01) and nondiabetics (p &amp;lt; 0.05). Although glucose disappearance rates (Kg) correlated with relative insulin responses, the increase in insulin secretion with triglyceride priming was not associated with an increase in Kg. Although obese subjects show increased stimulated GIP responses to oral glucose, patients with mild diabetes have normal GIP secretion to oral glucose and to triglyceride, but show a GIP-associated increase in both phases of glucose-induced insulin secretion.

Localization of Gastric Inhibitory Polypeptide Release by Intestinal Glucose Perfusion in Man

To determine the site of endogenous release of gastric inhibitory polypeptide (GIP), glucose perfusions (556 mmoles per liter) of duodenum, proximal jejunum, midjejunum, and ileum were performed in human volunteers using an occluding balloon perfusion technique. Preperfusion GIP concentrations were below assay sensitivity (125 pg per ml) in all subjects. After glucose perfusion, maximal serum GIP concentrations for the four groups were: duodenum, 1383 +/- 152 pg per ml; proximal jejunum, 904 +/- 87 pg per ml; midjejunum, 545 +/- 91 pg per ml, and ileum 305 +/- 38 pg per ml. Integrated GIP secretion was significantly greater with duodenal perfusion (111 +/- 21 ng-min ml-1) d proximal jejunal perfusion (69 +/- 5 ng-min ml-1), as compared to either midjejunal (47 +/- 7 ng-min ml-1) or ileal (25 +/- 6 ng-min ml-1) perfusions. Peak serum insulin concentrations and integrated insulin secretion were also significantly greater with perfusion of the duodenum or proximal jejunum. Serum glucose concentrations, integrated serum glucose, and glucose absorption were similar for the four areas perfused. The results of this study indicate that the proximal small intestine is the primary site of endogenous GIP release in man, but that smaller quantities are also released by the distal small bowel.