Acute hyperglycemia slows gastric emptying, but its effects on small intestinal motor activity and glucose absorption are unknown. In type 2 diabetes, the postprandial secretion of glucose-dependent insulinotropic polypeptide (GIP) is preserved, but that of glucagon-like peptide-1 (GLP-1) is possibly reduced; whether the latter is secondary to hyperglycemia or diabetes per se is unknown.

The aim was to investigate the effects of acute hyperglycemia on duodenal motility and flow events, glucose absorption, and incretin hormone secretion.

Nine healthy volunteers were studied on two occasions. A combined manometry/impedance catheter was positioned in the duodenum. Blood glucose was clamped at either 9 mmol/liter (hyperglycemia) or 5 mmol/liter (euglycemia) throughout the study. Manometry and impedance recordings continued between T=-10 min and T=180 min. Between T=0 and 60 min, an intraduodenal glucose infusion was given (approximately 3 kcal/min), together with 14C-labeled 3-O-methylglucose (3-OMG) to evaluate glucose absorption.

Hyperglycemia had no effect on duodenal pressure waves or flow events during the 60 min of intraduodenal glucose infusion, when compared to euglycemia. During hyperglycemia, there was an increase in plasma GIP (P<0.05) and 14C-3-OMG (P<0.05) but no effect on GLP-1 concentrations in response to the intraduodenal infusion, compared to euglycemia.

Acute hyperglycemia in the physiological range has no effect on duodenal pressure waves and flow events but is associated with increased GIP secretion and rate of glucose absorption in response to intraduodenal glucose.

Postprandial glycaemia is now recognised as the major determinant of average glycaemic control in type 2 diabetes, as assessed by glycated haemoglobin. Therefore, an understanding of the factors influencing both the rise in blood glucose and insulin secretion after a meal is fundamental to the development of dietary and pharmacological approaches to optimise glycaemic control. The gastrointestinal tract regulates the rate at which carbohydrate and other nutrients are absorbed and is the source of regulatory peptides that stimulate pancreatic insulin secretion in the setting of elevated blood glucose levels. This article highlights the importance of the gastrointestinal tract in insulin secretion and glucose homeostasis and discusses potential strategies directed at modification of gastrointestinal function in order to improve glycaemic control in the management of diabetes.

Recent evidence has highlighted the impact of glycemic control on the incidence and progression of diabetic micro- and macrovascular complications, and on cardiovascular risk in the non-diabetic population. Postprandial blood glucose concentrations make a major contribution to overall glycemic control, and are determined in part by upper gastrointestinal function. Conversely, poor glycemic control has an acute, reversible effect on gastrointestinal motility. Insights into the mechanisms by which the gut contributes to glycemia have given rise to a number of novel dietary and pharmacological strategies designed to lower postprandial blood glucose concentrations.

Small intestinal glucose absorption is increased in animal models of diabetes mellitus, but little data are available in humans. Small intestinal motility is reported to be frequently abnormal in patients with diabetes and could potentially affect glucose absorption. Our aim was to evaluate small intestinal glucose absorption and duodenal motor responses to intraduodenal nutrients, in patients with type 1 diabetes and controls.

Eight type 1 patients (two with autonomic neuropathy) and nine controls were studied during euglycemia. A manometric catheter was positioned across the pylorus, and nutrient infused intraduodenally (90 kcal over 30 min), followed by a bolus of 3-O-methylglucose (3-OMG). Blood was sampled to measure glucose and 3-OMG concentrations.

During nutrient infusion, the number of duodenal waves did not differ between patients and controls. After the infusion, patients with diabetes had more propagated duodenal wave sequences (p < 0.05). The area under the plasma 3-OMG curve did not differ between the groups but correlated with both the blood glucose concentration at the time of 3-OMG administration (r = 0.64, p < 0.005) and the number of duodenal waves (r = 0.52, p < 0.05) and antegrade propagated duodenal sequences (r = 0.51, p < 0.05) preceding the 3-OMG bolus.

During euglycemia, duodenal motor responses to small intestinal nutrient are comparable in patients with relatively uncomplicated type 1 diabetes and healthy subjects, but duodenal motility after nutrient infusion is increased in patients. Small intestinal glucose absorption is similar in patients and controls, but may be dependent on the blood glucose concentration and duodenal motor activity.

The effect of hyperglycaemia on sugar transport was studied by comparing transepithelial permeation and tissue content of 3-O-methyl-D-glucose (3-O-MG), beta-methyl-D-glucoside (beta-MDG) and D-glucose in isolated mucosae of guinea-pig jejunum mounted in a flux chamber. Sugars were administered either to the luminal or the blood side of mucosae prepared either from normal animals or those maintained in a hyperglycaemic state by I.V. glucose infusion for 12 h. In control animals, absorptive sugar fluxes increased in the order glucose greater than beta-MDG greater than 3-O-MG. Only beta-MDG was accumulated in the tissue beyond the medium concentration. Permeation of 3-O-MG and beta-MDG in the direction blood-to-lumen was mainly paracellular as indicated by the strict correlation with the simultaneous permeation of polyethylene glycol (mol. wt. 900). Luminal addition of 10(-3) M-phlorhizin increased permeation and decreased tissue content of beta-MDG and D-glucose when administered on the blood side, suggesting that these sugars are recaptured at the brush border even from vigorously mixed solutions. For flux coefficient calculation the preparation was regarded as a three-compartment system. With all three sugars, the influx coefficient was higher at the luminal, but lower at the basolateral membrane than the corresponding efflux coefficient. 3-O-MG displayed the highest basolateral influx coefficient of all three sugars, being even higher than its luminal influx coefficient. The luminal influx coefficient of beta-MDG was 22 times greater, and its basolateral efflux coefficient 2.5 times less than the corresponding values for 3-O-MG, resulting in cellular beta-MDG accumulation. D-Glucose was suited best for transepithelial transport, having a luminal influx coefficient only 1.6 times less, and a basolateral efflux coefficient almost 10 times greater than those for beta-MDG. Prolonged hyperglycaemia increased the lumen-to-blood permeation of all three sugars 1.3-2-fold. No significant differences in tissue content to control values were observed after 45 min (3-O-MG, D-glucose) or 90 min (beta-MDG) incubation. Therefore, flux coefficients increased by the same factors in luminal and basolateral membranes, i.e. 1.7, 1.3 and 1.7 for 3-O-MG, beta-MDG and D-glucose, respectively. These results indicate that changes in both the luminal and basolateral membranes play a role in the increase of sugar transport in hyperglycaemia and that a regulatory mechanism might exist between the transport systems located in both membranes.(ABSTRACT TRUNCATED AT 400 WORDS)

It was observed previously (Cs aky , T.Z. and Fischer, E. (1981) Diabetes 30, 568-574), that sustained hyperglycemia enhances the intestinal transport of aldohexoses ; on the other hand, hyperfructosemia affects primarily the transport of fructose. The present study examines in detail the hyperketosemia -induced intestinal ketose transport. Intravenously infused 3-O- methylfructose produces marked 3-O- methylfructosemia without concomitant hyperglycemia; in such animals the intestinal transport of both fructose and 3-O- methylfructose increased. The hyperketosemia -induced increased ketose transport was inhibited by phloretin but only if placed on the serosal compartment. Phlorizin affects neither the basal nor the induced intestinal ketohexose transport. The enhancement of the intestinal ketohexose transport is not sodium-dependent and is not inhibited by ouabain.

The sodium-dependency of both the saturable and non-saturable components of glucose and galactose absorption across the rat jejunum in vivo has been determined. The non-saturable process appears to be unaffected by sodium removal but when Na+ concentrations in the lumenal fluid are progressively reduced from 143 mM to 0 mM the Jmax for active absorption is greatly decreased. In a separate study these two components of glucose transport were further investigated using intravenous sugar infusion to modify the transepithelial sugar concentration gradient. When identical glucose concentrations were present in plasma and intestinal lumen, the reduction in glucose absorption was fully accounted for by the elimination of the non-saturable component from the overall absorptive process. Together, these observations can be interpreted as further evidence for the existence of at least two absorption processes in vivo. The implication for analysing results from experimental studies of intestinal sugar absorption in vivo is discussed.

Hyperglycemia produced by intravenous infusion of glucose cause, in the everted jejunum of rat, an increase of net transintestinal transport of glucose, Na and water without modifying their cell concentration. The concentration of glucose in the fluid pouring out at the serosal side is higher than the calculated intracellular concentration, especially in the experiments in which the serosal compartment is initially empty. This fact could be explained by the possible existence of an active extrusion mechanism in the basolateral membrane of the enterocyte.

A study of the three-dimensional structure of the upper jejunal mucosa in diabetics has been carried out. The structural findings were related to 14C-L-phenylalanine uptake in vitro, sucrase activity in mucosal homogenates, and the enzyme content of the absorptive cells as measured cytophotometrically. A low grade mucosal transformation of the sprue-type was found, which was associated with decreased sucrase activity, and with no reduction in phenylalanine accumulation. On the other hand the specific activities of alkaline phosphatase, non-specific esterase, and succinic dehydrogenase in the surface cells remained unchanged.

The villous tissue hyperosmolality created by the intestinal countercurrent multiplier has been proposed to be of importance for fluid transport across the intestinal epithelium in vivo. This study was performed to test this hypothesis. Net transport of fluid and electrolytes (sodium, potassium and chloride), as well as unidirectional fluxes of water and sodium were determined in the small intestine of the cat. The villous osmolality was altered by varying the composition of sodium and glucose in the isotonic solutions perfusing the intestinal lumen. Net transport of fluid was correlated to tissue osmolality mainly due to an increase of the unidirectional flux of water from lumen to tissue with augmented tissue osmolality. The results are thus consistent with the view that the intestinal countercurrent multiplier is of essential importance for net water transport. A correlation was found between net water and net sodium intestinal transport. A similar correlation was also demonstrated between net sodium and net chloride absorption rates in the jejunum while in the ileum net loss of sodium into the intestinal lumen was not accompanied by any corresponding loss of chloride ions. This observation suggests the presence of a sodium independent transport mechanism for chloride in the ilium but not in the jejunum.

1. The utilization of some metabolic fuels has been measured in vitro in a preparation of rat jejunum to which the substrates were supplied via the perfusate flowing through the vascular bed. 2. In jejunum from 48 hr-fasted rats, the combined rates of utilization of 1 mM-acetoacetate and 2mM-D-3-hydroxybutyrate are similar to that of 7.5 mM-glucose. 3. The utilization of glucose is reduced in jejunum from animals fasted for 48 hr (45--63% reduction) and also from animals after 3--6 days of diabetes induced by streptozotocin (29% reduction). The addition of ketone bodies or of Na-oleate to the vascular perfusate does not reduce the utilization of glucose by the jejunum of either fed or 48 hr fasted rats. 4. Ketone bodies in the vascular perfusate reduce the oxidation of glucose by the jejunum of fed rats. In the jejunum of 48 hr-fasted rats, ketone bodies completely inhibit the oxidation of glucose so that all the glucose utilized by the tissue is converted to lactate. 5. The findings are discussed in relation to other work and it is concluded that substrates for the oxidative metabolism of the jejunum of fasted rats are likely to be ketone bodies, glutamine and fatty acids; at the same time the utilization of glucose is reduced and its oxidation completely abolished.