Intraduodenal Administration Of Glucose Research Articles

Effect of intracerebroventricular infusion of insulin on glucose-dependent insulinotropic peptide in dogs

Glucose-dependent insulinotropic polypeptide (GIP), is an incretin with important role in glucose homeostasis and energy conservation. Thus far, the neural/hormonal mechanisms involved in the regulation of GIP secretion, have not yet been fully elucidated. The aim of this study was to evaluate a possible effect of intracerebroventricular administration of insulin in a centrally mediated regulation of GIP. Methods: Twenty-four adult dogs were used in this study. In group 1 the animals received a bolus icv infusion of regular insulin in a total volume of 50 μl or an equivalent amount of artificial cerebrospinal fluid (aCSF). In group 2 the animals received a continuous icv infusion of insulin or aCSF over a 3-h period. In group 3 the experiment of group 2 was repeated with a simultaneous intraduodenal infusion of a glucose load through the Mann–Bollman fistula. Blood samples were taken from cannulation of a hind limb vein at −15, 0, 5, 10, 15, 30, 45, 60, 90, 120, 150 and 180 min after infusions. Plasma levels of glucose, insulin and GIP were assayed. Results: Insulin levels were increased significantly in group 2 and 3 while GIP secretion was partly inhibited after icv administration of insulin and intraduodenal administration of glucose in the 3rd group. Conclusions: It is suggested that the hypothalamic insulin signaling contributes to plasma insulin levels and possibly exerts a negative regulation of GIP secretion after glucose load.

Glucose tolerance and gastric emptying in thyrotoxic rats

To clarify the contribution of gastrointestinal function to impaired oral glucose tolerance in hyperthyroidism, gastric emptying rate and portal and peripheral blood glucose responses to intragastric or intraduodenal glucose administration were investigated in experimental thyrotoxic rats. Glucose absorption from perfused intestine of thyrotoxic rats was also examined. Thyrotoxicosis was induced by subcutaneous (SC) thyroxine injection (50 μg/kg/d) for seven days. In intragastric glucose tolerance test, although insulin and glucagon responses were not significantly altered, increments in portal and peripheral blood glucose were significantly higher in thyrotoxic rats than in controls at 30 minutes. This phenomenon was almost normalized by the preadministration of phentolamine (2 mg/kg SC). In intraduodenal glucose tolerance test, blood glucose, insulin, and glucagon responses were similar in thyrotoxic and control rats. Gastric emptying rate in thyrotoxic rats was significantly higher than that in controls at 30 minutes, and that was also normalized by phentolamine administration. Absorption of glucose from perfused intestine was similar in thyrotoxic and control rats. These results suggest that an altered glucose tolerance to intragastric glucose load in thyrotoxic rats may primarily be due to rapid gastric emptying induced by increased α-adrenoceptor responses, and that glucose absorption from small intestine was not increased in short-term thyrotoxic rats.

Rates of lactate appearance and disappearance and brain lactate balance after oral glucose in the dog.

After glucose ingestion, arterial lactate concentrations increase. Although it is presumed that this is due to an increase in lactate production, rates of lactate appearance have not been measured after oral glucose nor has the major site of its production been identified. Since brain takes up a substantial portion of an oral glucose load but does not store appreciable amounts of glucose, it is possible that brain could be an important site for postprandial lactate formation. Therefore, to investigate the contribution of the brain to the increase in arterial lactate after glucose ingestion and to determine whether changes in lactate appearance or disappearance were predominantly involved, we measured lactate fluxes and brain lactate balance in dogs after intraduodenal administration of glucose (1.6 g/kg). Although systemic lactate appearance increased significantly after glucose administration (from 22 +/- 3 to 33 +/- 9 umole/kg/min, P less than 0.05), brain lactate output did not change (0.62 +/- 0.5 vs 0.74 +/- 0.5 umole/min). We conclude that after glucose ingestion, arterial lactate increases as a result of an increase in the rate of lactate appearance and that brain does not make a significant contribution to this.

Effect of upper abdominal autonomic denervation on glucagon secretion after intraduodenal glucose administration in dogs

Effect of upper abdominal autonomic denervation on glucagon secretion after intraduodenal glucose administration in dogs

Response of plasma glicentin to intraduodenal administration of glucose in piglets

Controversial results concerning the secretion of glicentin prompted us to investigate the response of circulating glicentin to intraduodenal administration of glucose in piglets. A 20% solution of glucose (2 g/kg) was administered into the duodenum of six piglets in a fully conscious state. As blood glucose rose, plasma insulin increased to a peak of 21 +/- 4 microU/ml. Plasma glucagon, determined by C-terminal-specific antiserum, was 70 +/- 30 pg/ml at fasting and slightly increased after the glucose load. Plasma immunoreactive glucagon measured by cross-reacting glucagon antiserum increased from the baseline of 1563 +/- 260 to a peak of 4738 +/- 415 pg/ml at 120 min. Plasma glicentin determined by antiserum R 64 was 463 +/- 81 pmol/l at baseline and reached a peak level of 1081 +/- 174 pmol/l at 90 min. The percent changes of plasma glucagon from the fasting level measured by cross-reacting antiserum and glicentin were 296 and 233%, respectively. There was a significant correlation between plasma glucagon measured by cross-reacting antiserum and glicentin (r = 0.817, P less than 0.001). Chromatography of plasma obtained during glucose load revealed the heterogeneity of glicentin. It can be concluded from the present study that glicentin is clearly secreted in response to intraluminal administration of glucose.

The failure of truncal vagotomy to affect motilin release in dogs

To elucidate the relationship between vagus nerve and motilin release, we have studied the influence of truncal vagotomy with pyloroplasty (TV) on motilin release in the fasting state and for 120 min following an intraduodenal administration of 10 g glucose in a 50-ml water solution or 5 g soybean oil. TV did not influence the intermittent fluctuation or concentration of plasma motilin in the fasting state. Intraduodenal glucose administration inhibited motilin release, but this was not affected by TV. Intraduodenal fat administration accelerated motilin release, but this effect also was not affected by TV. These results suggest that motilin secretion in the fasting state and after nutrient ingestion is not influenced by TV.

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.

Somatostatin and the intestinal transport of glucose and other nutrients in the anaesthetised rat.

The effects of somatostatin on oral glucose tolerance and on intestinal absorption of glucose and other nutrients have been studied in anaesthetised rats. Intravenous somatostatin (0.1-0.6 nmol/min) increased the rate of gastric emptying. After intraduodenal administration of glucose, the rise in peripheral plasma levels of the sugar was delayed, but finally exaggerated by somatostatin, which inhibited the insulin response. Absorption was evaluated by measuring the disappearance of radioactive nutrients from the lumen of a 'tied duodenojejunal loop'. At a luminal concentration of 4 mmol/l of 3-0-methylglucose, neither disappearance of the sugar from the lumen nor its appearance in plasma was affected by somatostatin. Passive transport of 3-0-methylglucose (100 mmol/l) was not significantly modified by somatostatin, although the appearance of the labelled tracer in plasma was delayed. Somatostatin had no significant effect on absorption of galactose (4 mmol/l), sucrose (40 mmol/l), leucine (4 mmol/l) or palmitate (0.1 and 0.4 mmol/l). These results show that somatostatin delays appearance of ingested sugars in peripheral plasma without direct effect on the absorption sites; this delay may result from changes in intestinal motility, enzyme secretion and splanchnic blood flow.

The effect of caerulein or cholecystokinin on pancreatic endocrine and exocrine secretion in the isolated perfused rat pancreas (author's transl)

Since Meade et al. reported the insulinotropic effects of the extracts of intestinal mucosa, many investigators have shown that cholecystokinin (CCK) is one of the gastrointestinal hormones stimulating insulin secretion. Contrary to these observations, Rabinovitch et al. observed no effect of pure preparations of CCK on insulin secretion and also pointed out that only crude preparations of CCK had a stimulating action on the β cell of the pancreatic islet. Recently, the insulinotropic effect previously attributed to CCK has been suggested to be due to contaminating gastric inhibitory polypeptide (GIP) present in crude preparations of CCK, not to CCK itself. Moreover, GIP has been demonstrated to potentiate the glucose-stimulated insulin release and had been found to be released by the intraduodenal administration of glucose and protein. More recently, synthetic octapeptide of CCK and synthetic caerulein, of which C-terminal pentapeptide was identical to that of CCK, have also been shown to stimulate insulin and glucagon secretion. However, it was difficult to discuss whether the insulinotropic action of these peptides administered exogenously was physiological or not because the plasma levels of CCK to which effects of exogenous CCK should be compared are unknown. The present study was, therefore, undertaken to make clear whether physiological concentrations of highly purified natural porcine CCK or synthetic caerulein have an insulinotropic effect in the isolated perfused rat pancreas. Since the well-known physiological action of CCK is its activity to increase secretion of amylase by the pancreas, insulinotropic effects of these peptides were investigated by paying attention to pancreatic exocrine secretion.Wistar strain male rats weighing 250-300g were used in all experiments. The pancreases were isolated according to the technique of Kanno and perfused with a Krebs Ringer bicarbonate buffer containing 4.6% Dextran T-70 and 0.25% bovine serum albumin. The effects of caerulein of the doses ranging from 0.01 to 100 ng/ml and CCK from 0.1 to 250 mU/ml were studied in the presence of 50,100,150 and 200 mg/dl glucose in the perfusion medium. Insulin (IRI) and glucagon (IRG) levels in the portal effluent were determined by radioimmunoassay using polyethylene glycol and charcoaled dextran with antiserum 30 K, respectively. Amylase activity in the pancreatic juice was assayed by a chromogenic method with blue-dyed starch polymer.In the presence of 50 mg/dl glucose, IRI and IRG releases were stimulated only with high doses of CCK or caerulein, i.e., more than 50mU/ml or 1 ng/ml. Moreover, the IRI and IRG responses to any doses were over in 5 min despite the prolonged infusion of the peptides. On the other hand, IRI and IRG releasing doses of CCK or caerulein resulted in lower rates of release of fluid and amylase when compared with those stimulated by the maximally effective dose of CCK or caerulein.The possibility that IRI stimulation by pure natural porcine CCK might depend, at least in part, on the contaminating GIP can be excluded under this experimental system where a glucose concentration of 50 mg/dl was used, because an infusion of GIP at a concentration of 5 ng/ml known to be effective at 100 mg/dl glucose, has been revealed to be ineffective at 80 mg/di glucose. Moreover, the concentration of GIP may be less than the threshold dose to stimulate IRI release at 50 mg/di glucose, even if highly purified preparations of CCK from G.I.H. Laboratory may have contained 10% (actually 1 to 2%) by weight of GIP. The concentration of GIP in the 50 mU/ml CCK could be calculated as 1.43 ng/ml (CCK; 3500 Units = 1 mg). Similarities between the effects of synthetic caerulein, certainly free of GIP and other contaminated peptides,

Chromatographic pattern of gut glucagon-like immunoreactivity (GLI) in plasma before and during glucose absorption.

In this work we have studied the chromatographic pattern on Bio-Gel P-30 columns of the glucagon-like immunoreactivity (GLI) present in unextracted plasma from normal dogs in the basal state and after intraduodenal administration of glucose. Basal plasma GLI, measured by R-8 antiserum, was distributed in four distinct fractions, whose approximate molecular weights were: greater than 30000 delta (Fraction I), 10000 delta (Fraction II), 3500 delta (Fraction III) and 2000 delta (Fraction IV). Fraction I accounted for the highest percent of total immunoreactivity. The increase in plasma GLI during glucose absorption was due to a significant increase of Fraction II, which may well correspond to tissue GLI Peak I, while no significant changes were evident in the other three fractions. The fact that tissue Peak I (or plasma Fraction II) ssems to be the factor secreted during glucose absorption puts the material/s of this molecular size in the first place for further investigation.

The effect of somatostatin on the response of GLI to the intraduodenal administration of glucose, protein, and fat.

The effects of somatostatin on GLI release during the absorption of intraduodenally administered glucose, casein hydrolysate and longchain triglycerides were studied in conscious dogs. Whereas, after an intraduodenal glucose load, GLI rose promptly in saline-infused control experiments to a peak of 5 ng/ml (SEM +/- 4) in 60 minutes, significantly lower values were observed during somatostatin infusion (P less than 0.025 -- 0.05). A similar reduction in the magnitude of the GLI response to intraduodenally administered casein hydrolysate (P less than 0.05) and fat (p less than 0.05) was observed.

THE RELATIONSHIP BETWEEN FOOD, GASTRO-INTESTINAL HORMONES AND CALCITONIN SECRETION

SUMMARY The role of calcitonin (CT) in postprandial calcium homeostasis and the possibility of a gastroentero-thyroid C-cell system was studied in young pigs. When pigs were fasted for more than 36 h and then fed, the plasma calcium concentration decreased by 6·1% over a period of 60–120 min after a meal. Since in thyroidectomized pigs the plasma calcium concentration increased by 7·2% when they were fed after a fast of 36 h it is suggested that increased CT secretion assists in the control of postprandial hypercalcaemia. Direct measurement of CT in peripheral plasma supported this suggestion. Because the plasma calcium concentration in an intact pig on a normal feeding regime does not change after a meal, the possibility of the involvement of one or more humoral factors in the stimulation of thyroid C-cells was investigated. Exogenous gastrin and endogenous gastrin stimulated by meat extract were both previously shown by us to increase CT secretion rate. This observation has now been extended to include other stimuli to endogenous gastrin, e.g. glycine and gastric distension. Furthermore, partially purified enteroglucagon increased CT secretion rate from perfused thyroid glands, isolated in situ. Stimulation of endogenous entero-glucagon by the intraduodenal administration of glucose, and probable stimulation of endogenous pancreozymin by intraduodenal fat, were both associated with an increased CT secretion rate from the thyroid gland. These results support the concept of a gastroentero-thyroid C-cell system which serves to stimulate CT secretion and thus to protect the skeleton from excessive bone resorption during periods of dietary sufficiency.

Effect of intraduodenal glucose administration on hepatic extraction of insulin in the anesthetized dog.

Extraction of insulin by the liver after administration of glucose in the duodenum has been studied in fourteen anesthetized dogs. Plasma insulin and glucose were measured in the portal vein hepatic vein and hepatic artery. During the control period 40+/-3% of the approximately 11 mU of insulin presented to the liver/min was removed during a single transhepatic passage. Within 5 min after glucose administration, the amount of insulin reaching the liver increased significantly. In some animals this increase preceded any significant increase in the glucose concentration of the femoral artery. After glucose administration, hepatic extraction of insulin remained unchanged in five animals and rose significantly in nine. In five of the latter animals, the increase may have been more apparent than real due to nonrepresentative sampling of hepatic venous blood. However, for the whole group of animals, comparison of arterial insulin levels with the amount of insulin delivered to the liver suggested a transient increase in insulin extraction between 5 and 50 min after glucose administration. In no animal was there a decrease in the proportion of insulin extracted by the liver after glucose administration. The results indicate that the extraction process is not saturable at physiological insulin levels. Prior to glucose administration, net hepatic glucose output averaged between 30 and 40 mg/min. After glucose administration, the liver began to take up glucose and there was a significant correlation between hepatic glucose uptake and the amount of insulin reaching the liver. However, since the amount of glucose presented to the liver also increased, it is not established that the insulin was responsible for the change in hepatic carbohydrate metabolism. The data demonstrate an increase in the absolute amount of insulin extracted by the liver after glucose administration and an important role for the liver in regulating peripheral insulin concentrations.

Effect of trauma on serum insulin levels in rabbits.

Serum insulin levels were measured following the infusion of glucose orally, and intraduodenally after exposing the duodenum by surgery. Oral administration of glucose produced a marked rise in insulin levels whereas intraduodenal infusion of glucose in operated animals was not associated with any increase in serum insulin level. Reserpine treatment of animals prior to the operation and the intraduodenal administration of glucose, did not abolish this failure of insulin level to rise following the intraduodenal infusion of glucose. These findings suggest that the failure of serum insulin levels to increase following the intraduodenal infusion of glucose in operated animals was not due solely to enhanced release of catecholamines.

Comparison of secretin response to oral intraduodenal or intravenous glucose administration.

Previous studies of the pancreatic exocrine response to intraduodenal glucose administration have not demonstrated the release of secretin; consequently, the importance of secretin in the enteric insulin release mechanism has been questioned.

Characterization of the responses of circulating glucagon-like immunoreactivity to intraduodenal and intravenous administration of glucose

The effects of ingested and infused glucose upon circulating glucagon-like immunoreactivity (GLI) were compared in 14 triply catheterized conscious dogs. Within 60 min after the intraduodenal administration of 2 g/kg of glucose, the mean level of glucagon-like immunoreactivity in the vena caval plasma more than doubled, whereas after intravenous infusion of the same dose over a 90 min period no change in the mean vena caval level was observed; during glucose infusion mean glucagon-like immunoreactivity in the pancreatic venous effluent declined, suggesting that hyperglycemia suppresses rather than stimulates pancreatic glucagon secretion. To determine if the rise in glucagon-like immunoreactivity that occurs during glucose absorption was of pancreatic origin, the effect of pancreatectomy performed 1 hr after the intraduodenal administration of glucose was determined. Although circulating insulin disappeared after resection of the pancreas, the level of glucagon-like immunoreactivity continued to rise, establishing its extrapancreatic origin. In other experiments, measurements of Glucagon-like immunoreactivity in plasma obtained simultaneously from pancreaticoduodenal and mesenteric veins and from the vena cava revealed the increment after intraduodenal glucose loading to be greatest in the mesenteric vein in 8 of 12 experiments, favoring the gut as the likely source of the rise. To characterize gut glucagon-like immunoreactivity, acid-alcohol extracts of canine jejunum were compared with similar glucagon-containing extracts of canine pancreas with respect to certain physical and biological properties. On a G-25 Sephadex column the elution volume of the jejunal immunoreactivity was found to be smaller than that of glucagon, which suggested a molecular size at least twice that of pancreatic glucagon. Furthermore, the in vivo and in vitro biological activities of the eluates containing jejunal glucagon-like immunoreactivity appeared to differ from those of eluates containing pancreatic glucagon. The jejunal material lacked hyperglycemic activity when injected endoportally into dogs, was devoid of glycogenolytic activity in the isolated perfused rat liver, and did not increase hepatic 3',5' cyclic adenylate in the perfused liver; however, like glucagon it appeared to stimulate insulin release. It seems quite clear the material in intestinal extracts either is a different substance or a different form from that of true pancreatic glucagon, although it crossreacts in the radioimmunoassay with antibodies to glucagon. It is concluded, (a) that hyperglycemia does not stimulate and probably suppresses the secretion of pancreatic glucagon; (b) that during intestinal absorption of glucose, a rise in glucagon-like immunoreactivity occurs; (c) this immunoreactivity is derived from an extrapancreatic site, probably the gut; (d) that the glucagon-like immunoreactivity extractable from jejunum is not the same as pancreatic glucagon but is a larger molecule devoid of hyperglycemic and glycogenolytic activity, a cross-reactant in radioimmunoassay for glucagon; and (e) that the eluate in which jejunal immunoreactivity is contained can stimulate insulin release in conscious dogs.