Effect Of Gastric Inhibitory Polypeptide Research Articles

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.

Effects of gastric inhibitory polypeptide on leucine- and arginine-stimulated insulin release.

Insulin release stimulated by single amino acids, with and without gastric inhibitory polypeptide (GIP), was studied in vivo in anesthetized rats and in vitro in collagenase-digested isolated rat pancreatic islets. Insulin release in vivo during a 15-min intravenous infusion of leucine (0.97 mM) or arginine (0.97 mM) with GIP (17 ng/min) was greater than with infusion of either amino acid or GIP alone. Serum immunoreactive GIP was in the physiological range, and serum glucose showed no significant change in these studies. In contrast, insulin release did not occur with valine infused alone or with GIP. Insulin release in vitro by isolated islets was greater during a 45-min incubation period with leucine (5-20 mM) or arginine (20 mM) plus GIP (10 ng to 10 micrograms/ml) than with either amino acid alone. This effect that occurred in the absence of glucose could not be demonstrated with low concentrations of leucine (1.5 mM) or with 20 mM valine. In vitro insulin release during paired perfusion studies of isolated islets was greater with leucine (20 mM) plus GIP (50 ng/min) than with leucine alone, and augmentation of insulin release by GIP was demonstrable in both the early and late phases of insulin release. From these results it is concluded that insulin release is greater, both in vivo and in vitro, after leucine or arginine plus GIP than with either amino acid or GIP alone. This effect appears to be specific for the insulinotropic amino acids tested, does not appear to be glucose dependent, and can be demonstrated in both the early and late phases of insulin release.

Effects of secretin and gastric inhibitory polypeptide on human pancreatic growth hormone-releasing factor(1–40)-stimulated growth hormone levels in the rat

Synthetic human pancreatic growth hormone-releasing factor containing 40 amino acids ([hpGRF (1–40)]-OH) significantly stimulated plasma growth hormone (GH) levels in both sodium pentobarbital and urethane anesthetized rats. Synthetic secretin, gastric inhibitory polypeptide (GIP), and glucagon significantly decreased plasma GH levels while synthetic vasoactive intestinal peptide (VIP) had no effect. Secretin and GIP also altered the in vivo plasma GH response to [hpGRF(1–40)]-OH. Whether this effect is the result of an interaction at the pituitary level or is due to an extra-pituitary effect of secretin and GIP awaits further study.

Natural purified porcine gastric inhibitory polypeptide (GIP) stimulates exocrine pancreas secretion due to contamination with a cholecystokinin-like substance

The effects of purified natural gastric inhibitory polypeptide-enterogastrone III (GIP-EG III) and a fraction which is further purified by high pressure liquid chromatography (GIP-HPLC) were investigated on the endocrine and exocrine isolated perfused pancreas of rats. At the dose of 5 ng/ml used for both GIP preparations, only GIP-EG III significantly stimulated volume and amylase secretion of the exocrine pancreas. The response of insulin release to stimulation by GIP-EG III or GIP-HPLC was not significantly different. In the presence of cholecystokinin-octapeptide (CCK-8) at a concentration which gave half-maximal stimulation of amylase secretion, GIP-EG III almost doubled the response of the exocrine pancreas, whereas GIP-HPLC had no additional effect. CCK-8 alone significantly increased total insulin output under hyperglycemic conditions. We conclude that porcine GIP purified by gel chromatography contains a CCK-like substance which can be removed by further purification on high pressure liquid chromatography without affecting the insulinotropic activity. Some of the reported effects of GIP could be due to contamination.

Interaction of gastric inhibitory polypeptide (GIP) and cholecystokinin (CCK-8) with basal and stimulated insulin secretion in mice.

The interaction of GIP and CCK-8 with basal insulin secretion and with insulin release induced by glucose or by the beta-adrenoceptor agonist L-isopropylnoradrenaline (L-IPNA) was studied in mice. GIP and CCK-8, when injected in threshold doses not affecting basal insulin secretion, did markedly enhance basal insulin release when given simultaneously. Maximal doses of the two peptides, on the other hand, did not potentiate each other's action, but displayed a pure additive effect on insulin secretion. Insulin release induced by a half-maximal dose of glucose was slightly potentiated by the threshold dose of GIP and markedly potentiated by the maximal dose i.e. the effect was greater than the algebraic sum of the individual actions. CCK-8 was without potentiating effect at both dose levels. The combination of GIP and CCK-8 did not display the potentiating effect of GIP alone on glucose-stimulated insulin release. However, an additive action was observed at both dose levels. Insulin release stimulated by a half-maximal dose of L-IPNA was not affected by either GIP or CCK-8 at the threshold doses. The combination of the two peptides and L-IPNA, however, displayed a lower response than that expected from an additive effect. Similarly, at the high dose level of the peptides, the combination of GIP plus CCK-8 and L-IPNA as well as CCK-8 alone plus L-IPNA displayed a lower insulin response than that expected from an additive effect. GIP alone plus L-IPNA gave the expected additive effect. The results show that interactions between different gastrointestinal polypeptides with insulin release may greatly change the expected effect exerted by any individually tested peptide, and that the action of the peptides on stimulated insulin secretion is highly dependent on the nature of the secretagogue. Such complex interactions must be borne in mind in the search for the incretin factor(s).

Effect of GIP on the secretion of insulin and somatostatin and the accumulation of cyclic AMP in vitro in the rat.

The effects of gastric inhibitory polypeptide (GIP) on insulin secretion as well as on the intra-islet accumulation of [3H]cyclic AMP were investigated in isolated pancreatic islets of the rat. In the presence of 6.7 mmol/l of glucose, 3.0 and 30 nmol/l of GIP induced both insulin and [3H]cyclic AMP responses, while lower and higher concentrations of the peptide were ineffective. A coupling of the two parameters was also found with regard to interaction between glucose and GIP. Thus while 30 nmol/l of GIP was stimulatory together with 6.7, 16.7 or 33.3 mmol/l of glucose, the peptide stimulated neither insulin release, nor the accumulation of [3H]cyclic AMP in the presence of a low concentration of glucose (3.3 mmol/l). The concomittant release of insulin and somatostatin was studied in the perfused pancreas in order to assess a possible influence by somatostatin on the dose-response pattern for GIP-induced insulin release. In this preparation 1.0 to 10 nmol/l of GIP stimulated insulin and somatostatin secretion; however while these concentrations were equipotent on insulin release, 10 nmol/l of GIP stimulated somatostatin release more than 1 nmol/l, indicating differences in dose-response curves for the GIP-induced stimulation of the two hormones. It is concluded that 1) modulation of GIP-induced insulin release is coupled to changes in cyclc AMP response in the islet, 2) GIP-induced somatostatin secretion may influence the concomittant insulin response.

Interaction of gastric inhibitory polypeptide and arginine with glucose in the perfused pancreas of rats treated with triiodothyronine.

Chronic treatment of rats with triiodothyronine (T3) resulted in suppression of insulin release from the isolated pancreas when perfused with 8.6 mM glucose. This inhibition could be partially overcome by 16 mM glucose but the insulin release was still significantly reduced. Arginine and gastric inhibitory polypeptide (GIP) induced an insulinotropic action in both control and significantly reduced. Arginine and gastric inhibitory polypeptide (GIP) induced an insulinotropic action in both control and T3-treated preparations. This was achieved in the latter, in the absence of a second phase of insulin secretion to glucose. The insulinotropic effect of both arginine and GIP was abolished by mannoheptulose in both control and T3-treated animals.

Effect of gastric inhibitory polypeptide on plasma levels of chylomicron triglycerides in dogs.

To determine whether gastric inhibitory polypeptide (GIP) promotes the clearance of chylomicron triglycerides (TG) from the circulation in dogs, chyle collected from donor dogs via a thoracic duct fistula was infused at a rate of 2 ml/min i.v. into normal recipient dogs during an infusion of either porcine GIP (1 microgram/kg per h) or saline as a control. In the GIP-infused dogs the rise in plasma TG was significantly below that of the control animals [mean peak of 36 +/- 4 mg/dl vs. 82 +/- 18 mg/dl (P less than 0.05)]. It is concluded that GIP exerts an effect upon the removal of chylomicron TG from the blood. The results suggest that GIP may play a physiologic role in the disposition of ingested fat.

GIP-like immunoreactivity in glucagon cells. Interactions between GIP and glucagon on insulin release.

In the present study the cellular and subcellular distribution of immunoreactive glucagon and GIP (gastric inhibitory polypeptide) were studied in the mouse. Furthermore, the effects of pure GIP and glucagon on basal and stimulated insulin secretion were investigated. Immunohistochemistry revealed that immunoreactive GIP occurred in the pancreatic glucagon cells and in endocrine cells, also displaying glucagon immunoreactivity, scattered along the small and large intestines. Electron immunocytochemistry revealed that the GIP-like material and glucagon coexisted in the secretory granules of the pancreatic glucagon cells. Pure porcine GIP and glucagon both stimulated basal insulin release. When equipotent doses of the peptides were given together, the two peptides antagonized each other's effect. Both peptides potentiated glucose- and carbachol-induced insulin release. When equipotent doses of the two peptides were given together prior to the administration of each of these secretagogues their effects on insulin release were additive.

Secretory effects of gastric inhibitory polypeptide on the isolated perfused porcine pancreas.

The effect of gastric inhibitory polypeptide (GIP) in physiological concentrations (250, 500, 1,000 and 2,000 pg/ml) upon endocrine and exocrine secretion from the isolated perfused porcine pancreas was studied at various glucose concentrations in the perfusate. GIP increased insulin release in a dose-dependent manner. The sensitivity of the beta-cells to GIP was glucose independent. No effect was observed on glucagon or exocrine secretion regardless of the glucose concentration in the perfusate. We conclude that GIP is powerful insulin-stimulator even in low physiological concentrations in the presence of glucose concentrations comparable to those seen during an oral glucose load, which makes GIP to one of the strongest incretin candidates known, i.e. the factor(s) contributing to the augmented insulin response after ingestion of glucose.

The effect of gastric inhibitory polypeptide (GIP) on gastric acid secretion in dogs

Inhibitory effects of gastric inhibitory polypeptide (GIP) on tetragastrin-stimulated gastric acid secretion were studied in five dogs prepared with both Heidenhain fundic pouches and simple gastric fistulae. In the first series of experiments graded doses of GIP, doubling from 0.25 to 2.0 microgram/kg-hr, were given intravenously with a background infusion of 4.0 microgram/kg-hr tetragastrin. In the second experiments graded doses of tetragastrin, doubling from 1.0 to 8.0 microgram/kg-hr, were given intravenously with an additional infusion of 0.5 microgram/kg-hr of GIP. GIP inhibited dose-dependently gastric acid secretion from Heidenhain pouches, but not from simple fistulae. Lineweaver-Burk and Dowd-Riggs transformations of dose-response data obtained with tetragastrin alone and tetragastrin plus GIP showed similar D50 (the dose required for half-maximal response). This indicates that GIP acts as a noncompetitive inhibitor of tetragastrin on acid secretion from the denervated stomach. GIP, however, had no inhibitory effects on acid secretion from the innervated stomach. The cause of this paradoxical effect of GIP remains unknown.

Nervous control of gastro-pancreatic somatostatin secretion in pigs

The influence of the autonomic nervous system on the secretion of somatostatin from the antral and the fundic parts of the stomach and from the pancreas of the pig was investigated in experiments involving electrical stimulation of the vagal nerves and the splanchnic nerves in (1) intact, anesthetized pigs and (2) isolated perfused preparations of (a) antrum with intact vagal supply, (b) pancreas with intact vagal supply, (c) pancreas with intact sympathetic supply. The results clearly demonstrated that parasympathetic activity inhibits D-cell function in all gastro-pancreatic tissues; antral gastrin secretion was inversely correlated to somatostatin secretion and it is suggested that antral D-cell secretion participates in the control of gastrin secretion; the inhibitory effect of Gastric Inhibitory Polypeptide (GIP) as well as intraluminal HCl on gastrin secretion may be exerted via the stimulatory effect of both on somatostatin secretion. The sympathetic innervation of the pancreas is also clearly inhibitory to the pancreatic somatostatin secretion, whereas sympathetic nervous activity influences little the gastric somatostatin release.

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.

Effect of gastric inhibitory polypeptide on pentagastrin-stimulated acid secretion in man.

Eight male subjects were given pentagastrin by intravenous infusion in doses of 25, 74, 222, 667, and 2000 ng/kg/hr, each dose for 30 min. On another day the same subjects were given the same doses of pentagastrin while gastric inhibitory polypeptide (GIP) was being infused intravenously in a dose of 2 microgram/kg/hr. At the 222 ng/kg/hr dose of pentagastrin, acid output was significantly lower with GIP; at all other doses of pentagastrin, acid output did not differ significantly in tests with and without GIP. Pepsin output in the tests with and without GIP did not differ significantly at any dose of pentagastrin. Plasma concentration of GIP, measured by radioimmunoassay, showed a mean +/- SE plateau level of 7.4 +/- 1.4 ng/ml during GIP infusion and 0.4 +/- 0.1 ng/ml peak level after a standard meal. We conclude that the increase in blood concentration of GIP produced by feeding is probably inadequate to cause significant inhibition of gastric acid or pepsin secretion in man.

Gastric inhibitory polypeptide enhanced lipoprotein lipase activity in cultured preadipocytes.

Fat feeding stimulated the release of gastric inhibitory polypeptide (GIP) without concomitant insulin secretion. Since antilipolytic effects of GIP have been demonstrated and the uptake of triglyceride fatty acid by adipose tissue postprandially is a process reciprocally regulated with lipolysis, a stimulatory role of GIP on adipose tissue lipoprotein lipase activity may be present. After cultured preadipocytes were incubated for 2 h with GIP, the release of lipoprotein lipase activity into the culture medium and the total cellular activity present in acetone-ether powders of cells were measured. GIP stimulated significant increases in the lipoprotein lipase activity released into the culture medium and in cells. A dose response relationship was strongest for the effect of GIP on the enzyme activity in extracts of acetone-ether powders of the cells. The increased lipoprotein lipase activity produced by GIP could provide a mechanisms for clearance of chylomicron triglyceride after feeding in man.

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.

Interaction of gastric inhibitory polypeptide, glucose, and arginine on insulin and glucagon secretion from the perfused rat pancreas.

Gastric inhibitory polypeptide (GIP) produced an increase in immunoreactive insulin (IRI) and immunoreactive glucagon (IRG) release from the isolated perfused rat pancreas. The magnitude of both effects was shown to be dependent on the prevailing glucose concentration. GIP stimulated IRG release at glucose concentrations less than 5.5 mM and IRI release at glucose levels greater than 5.5 mM. Arginine"stimulated IRG secretion in the presence of low glucose (2.7 mM) was potentiated by GIP. In contrast, GIP augmented arginine-stimulated insulin release only in the presence of arginine concentrations of (less than 20 mM, producing no further increase over a maximal arginine stimulus. The glucagonotropic effect of GIP in the presence of arginine was found to be suppressed by glucose, with the opposite effect observed with insulin release. It was concluded that the endocrine pancreatic action of GIP depends to a great degree on existing levels of modulating nutrients in the blood.

Insulin release from isolated rat pancreatic islets induced by α-ketoisocaproic acid, L-leucine, D-glucose or D-glyceraldehyde: Effect of gastric inhibitory polypeptide or glucagon

There are major differences in the insulin-releasing capacity of α-ketoisocaproic acid, L-leucine, D-glucose or D-glyceraldehyde. This applies to the threshold concentration, the maximal effective dose and the order of potency. At low concentrations α-ketoisocaproic acid and D-glyceraldehyde are more effective than glucose. Leucine is the weakest, α-ketoisocaproic acid the most effective stimulator. Only D-glyceraldehyde impairs insulin release at high concentrations. Gastric inhibitory polypeptide and glycagon potentiate the effect of glucose, α-ketoisocaproic acid or D-glyceraldehyde, but not of leucine. Potentiation is similar in magnitude, resulting in a shift of the dose/response curves to the left. In addition, glucagon potentiates the action of the maximal effective glucose concentration. It is suggested that the different capacities of four substances initiating insulin release reflect differences in their mode of action. Since the potentiators, gastric inhibitory polypeptide and glucagon, amplify insulin release in a rather similar way, their mode of action might be analogous.

The Effect of Gastric Inhibitory Polypeptide on Human Jejunal Water and Electrolyte Transport

Using a triple-lumen gut perfusion technique, the net flux of water and electrolytes in the jejunum of 5 healthy volunteers was measured before, during and after an intravenous infusion of gastric inhibitory polypeptide (GIP). The dose of GIP used (1 mug/min for 30 mins) has previously been shown to raise serum GIP levels to physiological levels achieved in normal subjects after a meal. During GIP infusion, net water Na, K, and HCO3 absorption was significantly reduced and chloride flux was switched from absorption to secretion when compared to pre- and post-GIP control periods (p less than 0.001).

Characteristics of inhibition of gastric secretion by secretin.

Characteristics of inhibition of gastric secretion by secretin.