Immunoreactive Gastric Inhibitory Polypeptide Research Articles

Gastric inhibitory polypeptide release from a tumor-derived cell line.

A cell line derived from intestinal tumors of transgenic mice (STC-1) was subcloned to produce a stable line with approximately 30% immunoreactive gastric inhibitory polypeptide (irGIP)-containing cells (STC 6-14). High-performance liquid chromatography (HPLC) of STC 6-14 extracts indicated that the tumor cell-derived irGIP had the same retention time as synthetic porcine GIP-(1-42) (pGIP). Approximately 30% of the cells also contained immunoreactive somatostatin (irSS), which eluted as a single peak on HPLC, corresponding with SS-(1-14). On average, each well of extracted cells (5.0 x 10(5) cultured 4 days) contained 33.3 +/- 1.4 ng irGIP and 18.4 +/- 1.5 ng irSS. Basal release of irGIP in the presence of 5 mM glucose was 733 +/- 58 pg.ml cells-1.2h-1 (2.20 +/- 0.17% of total cell content; TCC) and doubled at 20 mM glucose (4.20 +/- 0.42% TCC). The response to glucose was augmented by addition of a SS neutralizing antibody (SOMA-10) and suppressed by 10 nM SS. Basal release of irSS in 5 mM glucose was 377 +/- 35 pg.ml cells-1.2h-1 (2.05 +/- 0.19% TCC) and was increased by glucose (> or = 15 mM) and the addition of pGIP (> or = 1 nM). The STC 6-14 cell line represents a model to study the synthesis, storage, and release of GIP and SS in a controlled environment.

Hepatic extraction of insulin after stimulation of secretion with oral glucose or parenteral nutrients

To determine whether hepatic extraction of insulin differs when glucose is administered by parenteral and physiologic routes, we studied responses to oral glucose and to intravenous (IV) infusion of glucose or glucose plus arginine in normal volunteers. As in earlier studies, when IV glucose infusions were empirically programmed to produce isoglycemic responses with 50 or 75 g oral glucose, ratios of integrated areas under concentration curves for immunoreactive C-peptide (CP) to insulin in the plasma were higher with IV than with oral glucose. Mean values ± standard errors for these ratios in paired experiments with 50 g oral glucose were 5.6 ± 0.66 compared with 8.3 ± 1.4 with IV glucose ( P < .03). With 75 g oral glucose, the corresponding values were 4.3 ± 0.38 and 7.8 ± 0.50 ( P < .001). These results suggest that hepatic extraction of insulin is diminished when insulin secretion is potentiated by enteroinsular mechanisms after oral glucose administration. To determine whether this phenomenon is related to the route of administration of glucose or to the enhancement of insulin secretion with oral glucose, programmed IV infusions of glucose were used to elicit excursions of plasma CP similar to those obtained after 50 g oral glucose, and programmed infusions of glucose plus arginine were used to elicit excursions of plasma CP similar to those obtained after 75 g oral glucose. Plasma levels of immunoreactive gastric inhibitory polypeptide (GIP) increased substantially after ingestion of 75 g glucose, but did not change during isoglycemic IV glucose infusions or during IV infusions of glucose plus arginine. Under these conditions, ratios of integrated areas under the concentration curves of CP to immunoreactive insulin (IRI) were not significantly different in either set of studies (5.10 ± 0.56 and 5.35 ± 0.61, 6.06 ± 0.47 and 5.41 ± 0.47, respectively). In these experiments with matching of plasma CP excursions, relative hyperglycemia resulted from IV infusion of glucose alone, but was avoided with IV infusion of glucose plus arginine. The results suggest that decreased hepatic extraction of insulin is associated with higher rates of secretion of the hormone, and indicate that this phenomenon is independent of route of delivery of the nutrient stimulus. It is concluded that modulation of hepatic extraction of insulin should not be regarded as an expression of the enteroinsular axis in response to absorption of glucose from the intestine.

Enteroendocrine peptides in a canine model of orthotopic jejunoileal autotransplantation.

The enteroendocrine cells of the small bowel provide a rich source of regulatory peptides involved in the modulation of gastrointestinal function. Recent work from our laboratory showed that in situ neural isolation (autotransplantation) of the jejunoileum produced marked changes in tissue expression of several neuropeptides. In the present study, we examined the influence of extrinsic innervation on the tissue expression of endocrine peptides localized to various regions of the gastrointestinal tract. Concentrations of immunoreactive gastric inhibitory polypeptide (GIP), neurotensin (NT) and peptide tyrosine tyrosine (PYY) in fasting plasma and regional tissue biopsies were determined before and at varying time points (2, 6, 12 weeks) after a model of canine orthotopic jejunoileal autotransplantation. GIP was not altered in plasma or tissue at any time point. Plasma concentrations of NT and PYY increased after autotransplantation. Following a decrease in tissue concentrations two weeks after autotransplantation, NT increased progressively from 2 to 6 to 12 weeks, reaching a maximal increase of 895% over baseline in proximal ileum. Tissue concentrations of PYY followed much the same pattern as NT, but these trends never achieved statistical significance. Chromatographic characterization of tissue biopsy extracts revealed molecular heterogeneity of NT-like immunoreactivity, while GIP and PYY immunoreactivity coeluted as single species with authentic standards. Taken together with our earlier observations, it appears that disruption of extrinsic and intrinsic neural continuity to the jejunoileum (autotransplantation) does not affect gut endocrine peptides such as GIP and PYY to the same extent as enteric neuropeptides. NT has been localized to neural as well as endocrine cells and is involved in the temporal adaptive response to autotransplantation.

Gastric inhibitory polypeptide (GIP) response in diabetes using a highly specific antiserum.

Gastric inhibitory polypeptide (GIP), a hormone secreted from the proximal small gut, is recognized as a major component of the enteroinsular axis. However, circulating levels of GIP in diabetes have been reported to be exaggerated, normal or decreased following glucose ingestion, which may be due to the presence of variable crossreacting immunoreactive GIP forms in the circulation. We have raised an antibody (S705) which recognizes only 5 kDa GIP. Using this antiserum we have measured circulating GIP levels in 18 healthy volunteers, and 13 Type 2 diabetic and 9 Type 1 diabetic patients following ingestion of 75 g glucose. As expected, blood glucose levels and blood insulin levels are significantly abnormal in the diabetic groups. On the other hand, circulating GIP levels at all time-points and integrated incremental GIP over 120 min were not different from the control group. However, we cannot exclude the possibility that apparently normal immunoreactive GIP levels in diabetes might conceal subtle alterations in biological activity which could play a role in the pathogenesis of the disease.

Endocrine-Metabolic Function in Remission-Phase IDDM During Administration of Cyclosporine

We have studied the endocrine-metabolic status of patients in non-insulin-receiving (NIR) remission of insulin-dependent diabetes mellitus (IDDM) within 6-60 mo of diagnosis during administration of cyclosporine, in comparison with nondiabetic subjects. IDDM patients in NIR remission were recognized when target glycemic control (plasma glucose and mean capillary blood glucose levels less than 7.8 mM before meals) was maintained without administration of insulin for at least 2 wk. In so-called isoglycemic tests, 50 g glucose was administered orally, and the glycemic curve was simulated in a subsequent study by programmed intravenous infusion of glucose. Under these conditions, the subjects with diabetes exhibited obvious glucose intolerance: acute beta-cell responses to intravenous glucose were virtually absent but significant, although subnormal responses were present after oral glucose. The responses of plasma immunoreactive gastric inhibitory polypeptide to oral glucose were normal. After bolus intravenous injections of glucose, the patients with diabetes again exhibited glucose intolerance; acute responses of immunoreactive insulin (IRI) and C-peptide were present, although grossly obtunded. On intravenous infusion of arginine (30 g in 30 min), the patients with diabetes showed substantial but subnormal increases in plasma IRI and C-peptide. Intravenous infusion of arginine elicited increments of plasma immunoreactive glucagon (IRGI) in both groups, and this response was slightly exaggerated in the patients with diabetes. On ingestion of a standard mixed meal (Sustacal) delivering 600 cal, there was a modest but significantly greater increase in plasma glucose levels in the diabetic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Stimulation of Glucagon Secretion by Gastric Inhibitory Polypeptide in Patients with Hepatic Cirrhosis and Hyperglucagonemia

Porcine gastric inhibitory polypeptide (GIP) was infused iv (120 micrograms in 60 min) in seven patients with biopsy-proven hepatic cirrhosis who had surgical porta-caval anastomoses and hyperglucagonemia in the postabsorptive state. The infusions resulted in elevation of blood levels of immunoreactive GIP into the upper range of those observed after ingestion of large mixed meals. This was accompanied by significant increments in immunoreactive glucagon (IRG) in the plasma. Similar infusions in two cirrhotic patients with surgical porta-caval anastomoses who had normal plasma IRG levels in the postabsorptive state had no effect on the plasma IRG level. Ingestion of triglyceride (60 g) in hyperglucagonemic cirrhotic patients with porta-caval anastomoses also resulted in elevation of plasma immunoreactive GIP, and this was again associated with significant elevation of the plasma IRG level. Chromatography studies showed that the increments in plasma IRG after the administration of GIP or triglyceride were largely accounted for by increases in pancreatic-type glucagon. There were no significant effects of administration of GIP or triglyceride on the blood levels of glucose or immunoreactive insulin. It is concluded that porcine GIP is glucagonotropic in patients with cirrhosis of the liver who show elevated levels of IRG in the plasma in the postabsorptive state. This effect is not due to diversion of portal blood to the systemic circulation and may be attributable to hypersensitivity of the alpha-cells to stimulation by GIP.

Effet de l'hypoxie sur les concentrations plasmatiques de gastrine et de polypeptide inhibiteur gastrique (GIP) chez le veau nouveau-né

Calves were subjected to experimental hypoxia from 0.5 to 4 h after birth. The plasma level of immunoreactive gastric inhibitory polypeptide was higher (P less than 0.05) than in control calves during hypoxia and 2 and 7 h later. However, the gastrin level was not lower during treatment and was higher (P less than 0.05) 3, 6, and 13 h later. Hypoxia could have changed circulating levels or degradation rates of these peptides and could have delayed abomasal emptying.

Suppression of insulin receptor binding by prolonged enteral or parenteral nutrient infusion in the rat: role of gastric inhibitory polypeptide

In the rat, prolonged enteral or parenteral alimentation with a high-carbohydrate diet results in hyperinsulinemia, which is substantially greater with the parenteral route. Supplementing the parenteral infusate with porcine gastric inhibitory polypeptide (GIP) to approximate plasma immunoreactive GIP levels achieved with enteral feeding further increases steady-state plasma insulin and glucose concentrations, suggesting insulin resistance. We examined the effects of sustained hyperinsulinemia elicited by continuous nutrient infusion on insulin binding to isolated rat adipocytes and the modification of this response by GIP. Compared with a baseline group, both enterally and parenterally alimented groups showed decreased insulin receptor binding affinity. However, despite substantially different steady-state plasma insulin levels, insulin binding was similar with either infusion route. Factors other than plasma insulin concentration alone therefore contribute to insulin receptor down-regulation during prolonged enteral alimentation. Supplementing the parenteral infusate with exogenous GIP resulted in a further reduction in insulin receptor affinity. Thus, adaptation to continuous nutrient infusion is characterized by insulin receptor down-regulation regardless of the route of nutrient delivery. An additional suppression of insulin receptor binding may in part be responsible for the insulin resistance elicited by prolonged exogenous GIP administration.

Lack of insulinotropic effect of endogenous and exogenous cholecystokinin in man.

Intraduodenal phenylalanine administration (333 mg/min over 60 min) released endogenous cholecystokinin in healthy young subjects as demonstrated radioimmunologically and by intraduodenal bilirubin and pancreatic enzyme output. Concomitantly, there was only a small increase over basal in circulating immunoreactive-insulin and immunoreactive-C-peptide concentrations. In healthy volunteers intraduodenal infusions of saline (10 ml/min), glucose (333 mg/min) or phenylalanine (333 mg/min) were performed for 60 min when plasma glucose was clamped at approximately 8 mmol/l. Phenylalanine enhanced immunoreactive-insulin and immunoreactive-C-peptide responses three-fold more than did the same amount of glucose. Immuno-reactive gastric inhibitory polypeptide responses were small and not different after glucose and phenylalanine administration. Immunoreactive cholecystokinin was significantly stimulated to 9.4 +/- 1.4 pmol/l only by intraduodenal phenylalanine. Plasma phenylalanine concentrations increased into the supraphysiological range (approximately 1.5 mmol/l). Intravenous infusions of phenylalanine achieving plasma concentrations of 1.2 mmol/l stimulated insulin secretion at elevated plasma glucose concentrations (approximately 8 mmol/l clamp experiments), but had no effect at basal plasma glucose concentrations. A small increase in cholecystokinin also was observed. Intravenous infusions of synthetic sulphated cholecystokinin-8 leading to plasma concentrations in the upper postprandial range (8-12 pmol/l) did not augment the immunoreactive-insulin or immunoreactive-C-peptide levels during hyperglycaemic clamp experiments, in the absence or presence of elevated plasma phenylalanine concentrations. It is concluded that the augmentation of the glucose-induced insulin release by intraduodenal administration of phenylalanine cannot be related to cholecystokinin release, but rather is explained by the combined effects of elevated glucose and phenylalanine concentrations. In man, cholecystokinin does not augment insulin secretion caused by moderate hyperglycaemia, elevations of phenylalanine concentrations, or combinations thereof.

Gastric Inhibitory Polypeptide in Newly Diagnosed Ketotic Type I (Insulin‐dependent) Diabetics

Plasma concentrations of 5,000 daltons (5 kDa) immunoreactive gastric inhibitory polypeptide (IR-GIP) were measured before and up to 16 hours after the start of low-dose insulin treatment in newly diagnosed ketotic type I (insulin-dependent) diabetics. Nine patients were non-fasting. Before insulin treatment mean IR-GIP was 31 +/- 6 pmol/l (range 9-65 pmol/l). Four patients had IR-GIP concentrations in the normal fasting range (10-25 pmol/l), and nine patients had concentrations below 35 pmol/l. The remaining patients had IR-GIP concentrations in the normal postprandial range. A meal eaten after the start of insulin treatment caused an increase in IR-GIP in all patients. All patients had beta-cell function as estimated by plasma C-peptide. Individual changes in C-peptide were significantly correlated to changes in blood glucose both after the meal (r = 0.80, p less than 0.01) and during insulin treatment (r = 0.85 +/- 0.04). No correlation could be found between IR-GIP and blood glucose, C-peptide or insulin concentrations. Newly diagnosed ketotic type I diabetics have IR-GIP concentrations within the normal postprandial level. Hypoinsulinaemia, hyperglycaemia, and hyperketonaemia do not by themselves increase 5 kDa IR-GIP markedly above normal fasting levels.

Heterogeneity of immunoreactive gastric inhibitory polypeptide in the plasma of newly diagnosed type 1 (insulin-dependent) diabetics.

The aim was to compare the three molecular forms of plasma immunoreactive gastric inhibitory polypeptide (IR-GIP) i.e. void volume (Vo), 8 and 5 kDa IR-GIP, found in type 1 diabetics with those found in normal subjects. Plasma from 6 non-fasting newly diagnosed ketotic type 1 diabetics obtained before and 1 h after a test meal given at start of insulin treatment, and before and 1 h after a test meal given after one and seven days of insulin treatment, respectively, was gel filtered and so was plasma from 6 normal subjects. The immunoreactivity in the effluents was measured with five different antisera. The elution positions of the three peaks were similar in controls and diabetics. With any given antiserum none of the components differed significantly as to amount of immunoreactivity between diabetics and controls, neither after the meals nor in the fasting state. The amount of Vo did not change in response to the meal, whereas the 8 and 5 kDa forms in the diabetics increased similarly to the increase in normals, also during ketosis. The Vo component did not differ significantly between diabetic and normal subjects, but it decreased significantly after start of insulin treatment. In the non-fasting, ketotic state before start of insulin treatment, no IR-GIP form was elevated significantly above normal postprandial levels. We conclude that the molecular forms of IR-GIP are similar in type 1 diabetics and normal subjects, but the molecular forms measured and their relative amounts vary according to which antiserum is used. The present study does not support that lack of insulin and ketosis markedly influence IR-GIP in plasma.

Immunoreactive gastric inhibitory polypeptide and K cell hyperplasia in obese hyperglycaemic (ob/ob) mice fed high fat and high carbohydrate cafeteria diets.

The effect of diet composition on plasma and intestinal concentrations of immunoreactive gastric inhibitory polypeptide (GIP) and intestinal K cell density was examined in obese hyperglycaemic (ob/ob) mice. The mice were reared from 3 to 11 weeks of age on either stock diet, a high fat (HF) cafeteria diet or a high carbohydrate (HC) cafeteria diet. The HF cafeteria diet increased the concentration of GIP in plasma (75%) and in the intestine (118%) and increased the density (54%) of GIP-secreting K cells in the upper jejunum compared with the stock diet. Plasma and intestinal GIP concentrations were not significantly altered by the HC cafeteria diet, although the density of K cells in the upper jejunum was increased (45%). The extent of hyperglycaemia and hyperinsulinaemia in ob/ob mice was not significantly altered by the HF and HC cafeteria diets. The results indicate that an increased amount of dietary fat chronically stimulates the production and secretion of GIP, and enhances intestinal K cell density in ob/ob mice.

Reduced incretin effect in type 2 (non-insulin-dependent) diabetes.

Integrated incremental immunoreactive insulin and connecting peptide responses to an oral glucose load of 50 g and an "isoglycaemic" intravenous glucose infusion, respectively, were measured in 14 Type 2 (non-insulin-dependent) diabetic patients and 8 age- and weight-matched metabolically healthy control subjects. Differences between responses to oral and intravenous glucose administration are attributed to factors other than glucose itself (incretin effect). Despite higher glucose increases, immunoreactive insulin and connecting peptide responses after oral glucose were delayed in diabetic patients. Integrated responses were not significantly different between both groups. However, during "isoglycaemic" intravenous infusion, insulin and connecting peptide responses were greater in diabetic patients than in control subjects as a consequence of the higher glycaemic stimulus. The contribution of incretin factors to total insulin responses was 72.8 +/- 6.9% (100% = response to oral load) in control subjects and 36.0 +/- 8.8% in diabetic patients (p less than or equal to 0.05). The contribution to connecting peptide responses was 58.4 +/- 7.6% in control subjects and 7.6 +/- 14.5% (p less than or equal to 0.05) in diabetic patients. Ratios of integrated insulin to connecting peptide responses suggest a reduced (hepatic) insulin extraction in control subjects after oral as compared to intravenous glucose. This was not the case in diabetic patients. Immunoreactive gastric inhibitory polypeptide responses were not different between control subjects and diabetic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of gastric inhibitory polypeptide in the response to prolonged parenteral or enteral alimentation in rats.

To examine the effects of long-term elevation of plasma gastric inhibitory polypeptide (GIP), the responses to parenteral (PA) or enteral (EA) alimentation were studied in conscious rats with duodenal and venous cannulae. A weight-maintaining liquid diet (84% as glucose, 16% as amino acids) was infused at a constant rate for 6 days by either route, and daily blood samples were taken. A subset of animals receiving PA also received porcine GIP with the infusate (PA plus GIP; plateau plasma immunoreactive GIP, IRGIP, 610 +/- 120 pg/ml). With PA, plasma IRGIP did not change from basal levels, whereas with EA IRGIP rose to virtual plateau levels (mean 530 +/- 110 pg/ml). In the steady state, plasma immunoreactive insulin (IRI) was significantly lower with EA (mean, 153 +/- 5 microU/ml) than with PA (mean, 226 +/- 15 microU/ml), which in turn was lower than with PA plus GIP (mean, 375 +/- 23 microU/ml, P less than 0.001 by ANOVA). A similar ranking of plasma glucose levels occurred in the steady state, with means of 113 +/- 7 (EA), 126 +/- 3 (PA), and 184 +/- 9 (PA plus GIP) mg/dl (P less than 0.001 by ANOVA). To assess the response to transient hyperglycemia in the steady state, an intravenous glucose bolus was given to each group on the fifth day. Peak plasma IRI levels did not differ among the three groups; however, the glucose disappearance rate was significantly slower with PA plus GIP compared with either EA or PA.(ABSTRACT TRUNCATED AT 250 WORDS)

Gastric Inhibitory Polypeptide (GIP) Responses After Oral Glucose Ingestion in Hyperthyroidism

Gastric inhibitory polypeptide (GIP) is a gastrointestinal hormone stimulated after oral nutrient ingestion, but not after intravenous nutrient administration. GIP stimulates insulin release in the presence of hyperglycemia and as such is considered a major enteroinsular hormone. Since elevated glucose and insulin levels are found in hyperthyroidism, we compared the GIP responses to oral glucose ingestion in 12 hyperthyroid patients and 10 age-matched controls. Seventy-five grams of oral glucose was ingested after overnight fasting and samples were obtained at 0, 30, 60, 90, 120, and 180 min for serum glucose and immunoreactive insulin (IRI) and GIP (IRGIP). The mean serum glucose levels in hyperthyroid subjects were significantly higher (P less than or equal to 0.05) at every time studied except at 180 min. At 60 min, peak mean glucose was 171 +/- 14 mg/dl versus 128 +/- 7 mg/dl in controls (P less than 0.02). Except for fasting, mean IRI levels were significantly higher (P less than 0.001) in hyperthyroid subjects than in controls at all times studied. At 60 min, IRI rose to a peak of 125 +/- 11 microU/ml in hyperthyroid subjects versus 50 +/- 9 microU/ml in controls (P less than 0.001). Mean fasting, stimulated, and incremental IRGIP levels were slightly higher but not statistically different in the hyperthyroid subjects versus controls. Glucose and IRI responses are exaggerated in hyperthyroidism after oral glucose ingestion. Even though GIP has insulinotropic action, its role in the hyperinsulinism found in hyperthyroid subjects appears to be minimal.

Immunoreactive gastric inhibitory polypeptide response to a meal during the first eighteen months after diagnosis of type 1 (insulin dependent) diabetes mellitus.

The changes in plasma concentrations of immunoreactive gastric inhibitory polypeptide (IR-GIP) in response to a standard meal were examined in 21 normal subjects and 15 Type 1 (insulin dependent) diabetic patients 7 days, 14 days, and 3, 6, 9, 12, and 18 months after time of diagnosis. During the first 4 tests significantly lower plasma IR-GIP concentrations were found in the diabetic patients after the standard meal. At 9 months and during the remaining tests there was no difference in IR-GIP concentrations between the diabetic and the normal subjects. The IR-GIP response was normalized faster if the diabetic patients were treated with initial short term intensive insulin therapy than if they were treated conventionally with 1 or 2 daily injections of insulin. beta-Cell function, evaluated by the C-peptide response to the meal, increased significantly during the first 3 months. After 3 months maximal beta-cell function was found while the corresponding IR-GIP responses were significantly lower than those of the normal subjects. Thereafter beta-cell function declined gradually and significantly, coinciding with the normalization of the IR-GIP response. No individual covariation between IR-GIP and beta-cell function during the 18 months was found in any patient. The IR-GIP response to a meal was diminished at the onset of Type 1 (insulin dependent) diabetes mellitus. After the start of insulin therapy the response improved, perhaps as a function of the quality of metabolic control, and within a year it was comparable to that of normal subjects. Lack of endogenous GIP therefore does not explain the diminished beta-cell function in Type 1 diabetes a few months after onset of the disease. No causal relationship between the changes in beta-cell function and IR-GIP during the first 18 months after the onset of the disease seems to exist.

Effect of serial test meals on plasma immunoreactive GIP in non-insulin dependent diabetic patients and non-diabetic controls.

Previous reports have shown considerable variation in postprandial gastric inhibitory polypeptide (GIP) response in non-insulin-dependent diabetic (NIDD) patients. One reason for this may be the use of different GIP antisera. Employing antiserum R65, which specifically reacts with the 5000-dalton GIP, we investigated the plasma GIP response to serial test meals in 11 NIDD patients and 11 age- and weight-matched non-diabetic controls. The postprandial GIP response was lower in the NIDD patients than in the non-diabetic controls (p less than 0.05). Although the serum insulin concentrations did not differ between diabetic and non-diabetic subjects, the insulin to glucose ratio was lower in the diabetics than in the non-diabetic subjects (p less than 0.05) indicating some degree of relative insulin deficiency in the diabetic patients. The data suggest that the GIP secretory capacity may be impaired in NIDD patients. Whether the impairment of GIP secretion is associated with impaired insulin secretion requires further investigation.

The Effects of Xylitol on Gastric Emptying and Secretion of Gastric Inhibitory Polypeptide in the Rat

The effects of xylitol on the rate of gastric emptying and plasma gastric inhibitory polypeptide secretion in the rat were studied to relate xylitol adaptation to these phenomena. Male Sprague-Dawley rats, weighing about 250–270 g, were either gradually adapted to 20% xylitol diets or given a basal diet. The animals were, after a 24-hour fast, given a 1.2 g/kg body weight dose of xylitol or glucose either alone or with a 99mTc-tin colloid marker to study gastric emptying by using a gamma camera. Blood was taken from the tail vein, and plasma was analyzed for immunoreactive gastric inhibitory polypeptide by using a double-antibody radioimmunoassay. Xylitol adaptation did not appear to have any effect on the secretion of gastric inhibitory polypeptide. However, adaptation of rats to 20% dietary xylitol appeared to change the rate of gastric emptying by decreasing it. Therefore, it was concluded that gastric emptying plays a role in the adaptation to high xylitol doses while gastric inhibitory polypeptide appears not to be involved.

The hepatic extraction of gastric inhibitory polypeptide and insulin.

The hepatic extractions of gastric inhibitory polypeptide (GIP) and insulin were determined using in vitro and in vivo methods to assess the role of the liver in GIP metabolism and the possible effect of GIP on the hepatic extraction of insulin. During in vitro studies using the isolated perfused rat liver, infusion of GIP (2000 pg/ml) alone and in combination with porcine insulin (200 microU/ml) resulted in negligible hepatic extraction of immunoreactive GIP (IR-GIP) in both fed and fasted animals during either physiologically euglycemic or hyperglycemic perfusions. Hepatic extraction of insulin, however, ranged from 26-36% in fasted animals and from 7-25% in fed animals. Hepatic extraction of insulin and net hepatic glucose appearance were minimally affected by GIP. In vivo studies in awake dogs were then performed, in which simultaneous portal and peripheral venous levels of IR-GIP, immunoreactive insulin (IRI), and glucose were assessed after intraduodenal glucose administration. The portal to peripheral (PORT/PERI) venous ratio of endogenous IRI and IR-GIP reflected the findings of the in vitro studies; the PORT/PERI ratio of IRI levels rose from a basal value of 1.9 +/- 0.3 to a peak of 3.7 +/- 0.9, while the PORT/PERI ratio of IR-GIP levels rose from a basal value of 1.0 +/- 0.1 to a peak of 1.4 +/- 0.2, then rapidly returned to 1.0. The in vivo data are consistent with a continuous hepatic extraction of 40-50% of the insulin entering the liver and a negligible hepatic extraction of IR-GIP. We conclude that hepatic extraction of GIP in vitro or in vivo is minimal. In addition, while the fed state of the animal before infusion can result in changes in the in vitro hepatic extraction of insulin, GIP does not mediate these changes.

Bethanechol prevents inhibition of gastric acid secretion by gastric inhibitory polypeptide.

Earlier studies of gastric inhibitory polypeptide (GIP) have shown that it is a powerful inhibitor of acid secretion in denervated gastric pouches. Other studies, however, have shown that it is a weak inhibitor in innervated stomach preparations. In this study we evaluated the inhibitory action of GIP in four dogs, each provided with both a vagally denervated (Heidenhain) pouch and a gastric fistula of the innervated stomach. The effect of intravenous infusion of pure porcine GIP (1 microgram X kg-1 X h-1) on pentagastrin dose response was studied with and without background infusion of bethanechol (25 micrograms X kg-1 X h-1). GIP powerfully inhibited pentagastrin-stimulated acid secretion from the Heidenhain pouch but not from the gastric fistula. The maximal inhibition was 76% for the Heidenhain pouch and 29% for the gastric fistula. Despite the attainment of high levels of circulating immunoreactive GIP (greater than 3,000 pg/ml) early after the onset of infusion of the peptide, inhibition occurred relatively late, suggesting that this action of GIP might be mediated by the release of some other substance(s). Background infusion of bethanechol totally abolished the inhibitory action of GIP in both the Heidenhain pouch and gastric fistula.