Glucose Distribution Space Research Articles

Peri‐operative iv fluids in diabetic patients – don’t forget the salt

Peri‐operative iv fluids in diabetic patients – don’t forget the salt

Kinetics of glucose transport and sequestration in lactating bovine mammary glands measured in vivo with a paired indicator/nutrient dilution technique

To quantify kinetics of mammary glucose utilization in vivo, 24 paired glucose and extracellular indicator (p-aminohippuric acid) dilution curves across intact bovine mammary glands were obtained after bolus injections into the external iliac artery. Dilution curves were analyzed using a compartmental capillary, convolution integration model. Four candidate submodels of glucose transport and metabolism in capillary supply zones were fit to the glucose dilution curves and evaluated. Model I, with one extracellular compartment for glucose and first-order unidirectional uptake, failed, indicating that efflux of glucose from the intracellular space could not be ignored. Model II, with first-order exchanges between extracellular and intracellular compartments and sequestration from the latter, was overdefined because unidirectional clearance of glucose was at least five times the blood flow rate and 20 times the net clearance rate. Model III, combining extracellular and intracellular space into one compartment, was superior in its goodness-of-fit to curves and identifiability of parameters. Michaelis-Menten parameters of sequestration were not identifiable. Parameters of the optimal compartmental capillary, convolution integration model were applicable to both the dynamics of injected glucose dilution and the steady-state background arteriovenous difference of glucose. Glucose sequestration followed first-order kinetics between 0 and 7 mM extracellular glucose with an average rate constant of 0.006 s(-1) or a clearance of 44 ml/s. The ratio of intracellular to extracellular glucose distribution space was 0.34, which is considerably lower than the expected intracellular volume and suggests an intracellular occlusion compartment with which extracellular glucose rapidly exchanges.

Monensin and Growth Hormone Effects on Glucose Metabolism in the Prepartum Cow

Twenty-seven multiparous Holstein dairy cows were used to evaluate the singular and combined effects of somatotropin and monensin treatments during the late dry period on postpartum metabolism and production. Treatments were 1) control, 2) injection of exogenous bovine somatotropin (bST); 3) total mixed rations topdressed with 300mg of monensin/d, and 4) monensin and somatotropin in combination, during the last 28 d before expected parturition. A 500-mg subcutaneous injection of sustained-release somatotropin was administered at d-28 and -14 relative to expected calving. Glucose kinetics was evaluated on d 15 before expected calving date using a tracer dose of 45mg of U-13C-labeled glucose. Jugular blood was sampled 20 times during 8h after tracer injection. Intake of DM was 1.9% of BW, and daily feed was supplied in six equal meals before the glucose kinetic assay. The CONSAM simulation program, which assumes a two-compartment model, was used to analyze the glucose 13C enrichment curves with time. Average glucose distribution space, glucose mass, and glucose residence time in compartment 1 were increased in monensin-treated cows and were decreased in bST-treated cows. On the day of the glucose kinetic assay, blood concentrations of glucose, NEFA, and urea were similar among treatments. The changes in glucose pool and distribution space suggest that monensin increases propionate supply and bST facilitates glucose flow into glucose consuming organs. It is concluded that dairy cows might benefit from a combined application of monensin and bST before parturition.

Minimal model of food absorption in the gut

Of the physiological subsystems involved in glucose metabolism, all have now been modelled with continuous-time compartmental models except the gut. To address this omission, three progressively more complex models of the conversion of food by the gut into the rate of appearance of glucose in plasma were identified, using two different sample input foods which were tested on a type 1 diabetic patient. The minimal model that achieved a reasonable match with measured values had one compartment. Two model parameters specific to the food modelled were glycaemic value (grams of glucose per gram of food), and the fractional turnover rate, corresponding to a combination of the gastric emptying time constant and other rate limiting metabolic processes. Parameters specific to the individual were compartmental volumes, specifically for the glucose distribution space. It was only possible to achieve an adequate model prediction with a one compartmental model by explicitly incorporating transport delay into the model. By combining this model with models of insulin production and glucose disposal, the glycaemic response of an identified food may also be predicted for patients with type 2 diabetes mellitus. This predicted responses, along with the predicted response for bread or glucose, enables calculation of the Glycaemic Index for the food from its glycaemic value, time constant, and transport delay, along with the insulin production and glucose disposal model parameters for the individual patient. These three minimal model parameters therefore embody all the information of the Glycaemic Index, and more, allowing a continuous prediction of the effect of eating a given food over time. Together with a means of combining the parameters of individual foods into a combination set for a composite meal, this minimal model could enable diabetic patients to predict the time course of glycaemic action for a meal and to adjust treatment accordingly.

Direct Measurement of the λ of the Lumped Constant of the Deoxyglucose Method in Rat Brain: Determination of λ and Lumped Constant from Tissue Glucose Concentration or Equilibrium Brain/Plasma Distribution Ratio for Methylglucose

Steady-state distribution spaces of 2-[14C]deoxyglucose ([14C]DG), glucose, and 3-O-[14C]methylglucose at various concentrations of glucose in brain and plasma ranging from hypoglycemic to hyperglycemic levels have been determined by direct chemical analyses in the brains of conscious rats. The hexose concentrations were measured chemically in freeze-blown brain extracted with ethanol to avoid the degradation of acid-labile products of [14C]DG back to free [14C]DG that has been found to occur with the more commonly used perchloric acid extraction of brain. Corrections were also made for nonphosphorylatable, labeled products of [14C]DG found in the nonacidic fractions of the brain extracts, which were previously included with the assayed [14C]DG, and for the contribution of the hexose contents in the blood in the brain, which was found to be particularly critical for the determination of the glucose distribution space, especially in hypoglycemic states. From the measured contents of the hexoses in brain and plasma, the relationships of the tissue concentrations and distribution spaces of each of the hexoses and of the lambda (i.e., ratio of tissue distribution space of DG to that of glucose) of the DG method to the tissue glucose concentration were derived. The lambda was then quantitatively related to the measured equilibrium ratio for [14C]methylglucose over the full range of brain and plasma glucose levels. By combining these new data with the values for the lumped constant, the factor that converts the rate of DG phosphorylation to glucose phosphorylation, previously determined in rats over the same range of plasma glucose levels, the phosphorylation coefficient was calculated and the lumped constant graphed as a function of the measured distribution space in brain for [14C]methylglucose.

Glucose turnover during pregnancy in anaesthetized post-absorptive rats.

During pregnancy the decline in blood [glucose] does not result from the increased distribution space of glucose. The absolute rate of glucose turnover increases in late pregnancy in parallel with the rise in the mass of the conceptus. Nevertheless, glucose turnover per kg body wt. is not increased in late pregnancy, since the lower blood [glucose] decreases glucose utilization by maternal tissues.

Carbohydrate metabolism in the rat epididymis: evidence that glucose is taken up by tissue slices and isolated cells by a process of facilitated transport.

An examination has been made of factors which influence the rate at which exogenous glucose is utilized by tissue slices and isolated cells prepared from the epididymis of rats with ligated efferent ducts. The uptake of exogenous glucose by tissue slices was unaffected by the addition of testosterone, dihydrotestosterone or carnitine but was reduced by theophylline and, in the caput epididymidis, was stimulated by insulin. Mannose was also utilized by epididymal tissue but fructose and galactose were utilized little, if at all. Galactose, arabinose and 1–0-methylglucose were ineffective in altering the rate at which exogenous glucose was taken up by isolated cells, whereas 3–0-methylglucose, 5-thio-D-glucose and 2-deoxy-D-glucose reduced the rate of glucose uptake, as did phloridzin and phloretin which inhibit membrane transport of hexoses in other tissues. The reduced rate of glucose uptake by epididymal cells in the presence of the nonmetabolizable sugar, 3–0-methylglucose, was shown to be due to competitive inhibition. By comparing the distribution space of glucose in isolated cells with that of substances which are normally excluded from entry into cells, it was evident that the extra- and intracellular concentrations of glucose were greatly displaced from equilibrium values. It is concluded that glucose enters epididymal cells with difficulty but that uptake occurs by a process of facilitated transport.

Evaluation of a 'true' fractional removal rate of glucose in man by bolus and simulated-ramp increase of glucose.

An infusion method designed to produce a gradual ramplike rise in plasma glucose levels in man showed that the observed slope of the ramp was not significantly different from the calculated slope only when both of the following parameters were used: 1. When the glucose disappearance rate coefficient (k) was calculated by an incremental method in which the fasting plasma glucose level was subtracted from each plasma glucose value obtained during a standard rapid intravenous glucose tolerance test. This proved to be superior to a contrasting method in which absolute glucose values are used for the semilogarithmic plot of glucose concentration versus time. 2. When the dilution technic was used to estimate directly the volume distribution of glucose rather than relying on standard reference tables that predict glucose distribution space in man. By using these two parameters obtained during standard intravenous glucose tolerance testing, we have shown that it is possible to calculate the rate of glucose infusion required to achieve successfully in man a ramp of plasma glucose of any desired steepness and to characterize the consequent insulin secretion. This simulated ramp increase of glucose provides a potentially useful tool for investigation of the dynamics of islet-cell function in man.

Disturbances in glucose metabolism in patients with liver damage due to paracetamol overdose.

1. Intravenous glucose tolerance test were performed in fourteen patients with mild or moderate liver damage due to paracetamol overdose. 2. In patients managed conservatively there was glucose intolerance associated with a diminished early insulin response to glucose, suggesting inadequate nutrition in the period between the overdose and the glucose tolerance test. 3. Patients given intravenous glucose supplements to maintain nutrition were also glucose intolerant and, in these, insulin responses to glucose were normal. The decreased fractional disappearance rate was partly due to an increase in glucose distribution space and partly due to a decrease in absolute glucose disappearance rate. 4. Impaired gluconeogenesis was suggested by mild fasting hypoglycaemia in four patients and raised fasting blood lactate concentrations. Serum growth hormone concentrations showed a paradoxical increase after glucose. 5. All these variables had returned to normal in four patients re-tested after recovery.

Glucose metabolism in rat skeletal muscle at rest. Effect of starvation, diabetes, ketone bodies and free fatty acids.

The influence of starvation, diabetic ketoacidosis, ketone bodies and free fatty acids on glucose metabolism in resting skeletal muscle was studied in the isolated perfused rat hindquarter perparation and in intact rats. In the hindquarter preparation, the provision of 1.3 mM oleate, 1 mM octanoate or 2 mM acetoacetate did not alter the uptake of glucose in the presence of insulin. In contrast, glucose uptake in the presence of insulin was significantly depressed in hindquarters of rats with diabetic ketosis. In fed, fasted and diabetic rats the distribution space of glucose in skeletal muscle in vivo ranged between 15 to 20 per cent (extracellular space, 18 to 20 per cent), indicating that transport into the cell and not phosphorylation was rate-limiting for glucose uptake. The administration of glucose and insulin did not increase the glucose distribution space in fed or fasted rats; however, it caused a marked increase in tissue lactate in the fasted group, suggesting inhibition of pyruvate oxidation. The concentrations of hexose monophosphates in skeletal muscle freeze-clamped in vivo were very similar in the three groups, indicating phosphofructokinase was not inhibited in the fasted or diabetic rats. There were also no major differences in the concentrations of citrate, glycerolphosphate, ATP, ADP and AMP: the concentration of acetyl CoA was increased in both forty-eight hour fasted and diabetic rats and free CoA was diminished in the diabetic rats. Tissue glycogen waslower in fasted and diabetic than in fed rats. The data suggest that in resting skeletal muscle there is no inhibition of glucose metabolism by exogenous fatty acids and ketone bodies anaiagous to that which occurs in heart and diaphragm. The rate limiting step in glucose uptake appears to be its transport into the cell which is inhibited in rats with diabetic ketosis. Glucose metabolism at the level of pyruvate dehydrogenase may be inhibited in skeletal muscle during fasting and diabetes as a result of changes in the concentrations of acetyl CoA and CoA.

Effects of infusion of octanoate on glucose concentration in plasma and the rates of glucose production and utilization in dogs.

The effects of intravenously administeredsodium octanoate, an 8-carbon saturated fatty acid, on glucose turnover were investigated in 16 healthy dogs by 2 isotope dilution technics: the method of successive measured injections of glucose-U-C14 (14 dogs) and the procedure of priming injection-continuous infusion (2 dogs). The results obtained with both technics were similar. Intravenous administration of octanoate, with or without albumin, in amounts which produced a mean maximal increase of 4.3 mEq./L. in plasma FFA levels decreased significantly plasma glucose concentration by an average of 25 mg./100 ml., and decreased also the rates of plasma glucose appearance (production) and disappearance (utilization) by approximately 30 and 24 per cent of control values, respectively. Furthermore, the intermixing glucose mass was decreased significantly by about 34 per cent of control values during infusion of octanoate in saline. The apparent distribution space of glucose was not altered. The effect on glucose production, primarily the hepatic release of glucose, occurred within 3 minutes of starting the octanoate infusion and was quantitatively greater than the effect on glucose utilization by tissues accounting thereby for the decrements in the intermixing mass and plasma concentration of glucose. The possible mechanisms by which octanoate alters glucose turnover are discussed. Finally, intravenously administered octanoate produced no changes in plasma cholesterol and triglyceride concentrations. The effects of intravenously administeredsodium octanoate, an 8-carbon saturated fatty acid, on glucose turnover were investigated in 16 healthy dogs by 2 isotope dilution technics: the method of successive measured injections of glucose-U-C14 (14 dogs) and the procedure of priming injection-continuous infusion (2 dogs). The results obtained with both technics were similar. Intravenous administration of octanoate, with or without albumin, in amounts which produced a mean maximal increase of 4.3 mEq./L. in plasma FFA levels decreased significantly plasma glucose concentration by an average of 25 mg./100 ml., and decreased also the rates of plasma glucose appearance (production) and disappearance (utilization) by approximately 30 and 24 per cent of control values, respectively. Furthermore, the intermixing glucose mass was decreased significantly by about 34 per cent of control values during infusion of octanoate in saline. The apparent distribution space of glucose was not altered. The effect on glucose production, primarily the hepatic release of glucose, occurred within 3 minutes of starting the octanoate infusion and was quantitatively greater than the effect on glucose utilization by tissues accounting thereby for the decrements in the intermixing mass and plasma concentration of glucose. The possible mechanisms by which octanoate alters glucose turnover are discussed. Finally, intravenously administered octanoate produced no changes in plasma cholesterol and triglyceride concentrations.

Effect of adrenal steroids on glucose kinetics in normal and diabetic dogs.

The rates of endogenous glucose production, utilization, the amount of the intermixing glucose (“pool”) and the apparent distribution space were measured in conscious, trained normal and depancreatized dogs by the method of successive measured injections of tracer. During the intravenous infusion of hydrocortisone or methylprednisolone both the rates of glucose production and utilization fell in normal dogs. Since the same effect was obtained during the infusion of hydrocortisone in depancreatized dogs this effect of adrenal steroids does not seem to be due to an extra release of insulin. In normal dogs, daily injections of 4 mg. per kilogram of methylprednisolone for one week significantly increased the rates of glucose production and utilization and also the amount of intermixing glucose and the apparent glucose space, without any significant change in the concentration of glucose in the blood plasma. Prolongation of methylprednisolone treatment for a second week caused a further increase in all four parameters again with no change in plasma glucose level. The intravenous infusion of glucose was found to diminish the rate of endogenous glucose production to the same degree before as after one week of methylprednisolone treatment. In diabetic dogs deprived of insulin, two daily injections of methylprednisolone increased the rate of glucose production and the plasma concentration but not the apparent distribution space of glucose. These experiments indicate that in dogs the homeostasis of plasma glucose level is maintained in spite of markedly increased gluconeo genesis if pancreatic function is unimpaired.

Rates of production, utilization, accumulation and apparent distribution space of glucose. Effects of insulin in dogs using a validated tracer method.

Rates of production, utilization, accumulation and apparent distribution space of glucose. Effects of insulin in dogs using a validated tracer method.

Abrupt and delayed effects of insulin on the distribution space of glucose in the dog.

IT has been proposed that insulin increases the permeability of cell membranes of animals to glucose1. If this is so, an increase induced by insulin in the volume through which glucose can disperse could occur as a result of the addition of intra-cellular spaces to those through which glucose is distributed without the added insulin. The method of successive tracer injections2 provides a means for determining, at each injection time, the amount of glucose which intermixes rapidly with the plasma glucose. From this value the corresponding apparent volume or space of distribution can be calculated, assuming that the concentration of plasma glucose is uniform throughout the volume. In this communication these procedures were used to determine the immediate and later effects of injection of insulin and of infusion of insulin on the glucose distribution space of the dog.

Effect of insulin on free glucose content of rat diaphragm in vitro.

Effect of insulin on free glucose content of rat diaphragm in vitro.

Action of insulin on transfer of sugars across cell barriers; common chemical configuration of substances responsive to action of the hormone.

Action of insulin on transfer of sugars across cell barriers; common chemical configuration of substances responsive to action of the hormone.