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E J Freyse

Publications and source records attributed to E J Freyse.

At least 19 recordsLinked to original sources
PubMed1990

Insulin therapy on the peritoneal route: effects on glucose control in experimental insulin dependent diabetes.

To quantitate the degree of glycemic control in relation to insulin doses required on the peritoneal route of administration, insulin dependent diabetic dogs instrumented with chronic peritoneal and venous catheters and with access devices for serial peritoneal injections, were treated with regular insulin at random order as follows: (1) subcutaneous injections, (2) peritoneal injections, (3) continuous intravenous infusion, (4) continuous peritoneal infusion. Metabolic profiles were taken over 24 h after an average duration of treatment of 2 weeks and were compared to data obtained in nondiabetic animals. Insulin doses and postprandial increase in peripheral insulinemia were higher and glycemic control was worse on peritoneal vs. subcutaneous injection therapy. Glycemic control and insulin doses were identical between peritoneal and intravenous infusion regimes. Hyperinsulinemia was only seen during nighttime in intravenously infused animals. It is concluded that in accordance with the fast pharmacokinetics of peritoneally administered insulin, sufficient glycemic and insulinemic control can only be obtained on the peritoneal route, when the insulin is applied by means of pumps.

Alanine↗
PubMed1989

Whole body glucose metabolism in experimental insulin-dependent diabetes after initiation or termination of insulin administration.

To investigate the kinetics in glucose metabolism, diabetic dogs were infused with double labelled glucose either when they were connected to an artificial beta cell after overnight insulin withdrawal (study I) or when they were disconnected from insulin supply after excellent metabolic control (study II). Fourteen hours after the last insulin injection, the animals had three-fold elevated rates of appearance Ra and of disappearance Rd of glucose in relation to non-diabetic controls; the metabolic clearance rate was reduced, glucose carbon recirculation was slightly elevated, and the % lactate from glucose was not altered. Glucosuria contributed approximately 30% to the elevated glucose turnover. In study I, Ra was normalized within 45 min after insulin supply but Rd increased transiently before returning to normal. In study II, plasma insulin was zero 30 min after termination of insulin supply. Ra increased immediately; Rd decreased slightly but increased thereafter. Lactate was elevated under all conditions. Its production from glucose increased slightly after initiation of insulin action. Glucose carbon recirculation was reduced to subnormal values when the animals were euglycemic but hyperinsulinemic.--It is concluded that even short intervals of relative lack of insulin action followed by restoration of glucose homeostasis, may induce wasting of substrates.

Animals↗
PubMed1989

Wick technique: reference method for implanted glucose sensors.

The control of function of experimentally implanted glucose sensors needs an independent reference method. Employing saline-impregnated cotton threads, an implanted wick-technique was adopted in dogs to obtain analytical specimen from the subcutaneous interstitial fluid compartment. By measuring the contents of potassium, calcium, and hemoglobin, the centrifuged wick fluid was validated to contain the interstitial concentrations of solutes after an equilibration time of approximately 15 min. Between 2 and 25 mmol/L, the steady state subcutaneous glucose concentration is nearly identical to circulating glycemia. Slow alterations, as during an oral glucose tolerance test, (OGTT) are well paralleled by the levels in the wick fluid. During alterations, however, a distinct delay is observed. The wick-based glucose levels are mirrored by the output of electrochemical sensors implanted at the same site. This method may be used in checking implanted sensors that can otherwise not be calibrated in situ.

Animals↗
PubMed1988

Intraindividual comparison of pharmacokinetics of insulin after intravenous, portal, subcutaneous and peritoneal administration.

To compare the kinetics of praehepatic and of posthepatic administered insulin, short term insulin deprived diabetic dogs were sequentially injected with 200 mU/kg of a monocomponent porcine insulin using either the intravenous, portal, subcutaneous or peritoneal route. After peritoneal insulin was applied, the peripheral plasma insulin levels increased immediately, their maxima were in the same range as after subcutaneous injection but the duration of elevation was shorter. There were portal-peripheral insulin-quotients greater than 1 after peritoneal and portal insulin administration but quotients less than 1 after subcutaneous and intravenous application. The time constant of insulin elimination was identical regardless of whether the praehepatic or the posthepatic route was used for application. The effectiveness of the administered insulin dose on blood glucose was found to be dependent on the posthepatic elevation of plasma insulin and its duration. The decrease in glycemia was initially identical in all tests but, on the whole, it was smaller after the two intravascular routes were used because of the shorter duration of elevated insulin levels. It is concluded that in an optimized management of insulin-dependent diabetes, the regime (doses and intervals or algorithms) must be adapted to the pharmacokinetic implications of the employed route of application.

Animals↗
PubMed1988

Absence of effect of heparin on insulin secretion.

Bioartificial pancreatic devices containing isolated islets of Langerhans have been designed, in which the blood of the recipient circulates in contact with an artificial membrane, protecting the islets against immune rejection. This system assumes that heparin, required to prevent blood clotting, does not alter insulin secretion. However, heparin has been reported to inhibit in vitro insulin secretion by rat islets and to suppress in vivo insulin secretion in dogs. Therefore, the following evaluation was made on the effect of different heparin preparations on insulin secretion. (a) Isolated rat islets of Langerhans were perfused or incubated in the absence or presence of 20 micrograms/ml heparin; insulin secretion in response to a stimulation by glucose 20 mM was not altered by the presence of heparin. (b) Insulin secretion by an insulin-secreting cell line (RINm5F) in response to leucine and theophylline was not suppressed by heparin up to 100 micrograms/ml concentration. However, an inhibitory effect was observed at 200 micrograms/ml, which is 100 times higher than the heparin concentration commonly used for therapeutic use. (c) Neither in normal rats nor in dogs did heparin alter portal plasma insulin levels and the increase in plasma insulin following an intravenous injection of glucose. In conclusion, these data do not confirm the formerly observed inhibitory effect of heparin, which can therefore be used for the in vivo evaluation of a bioartificial pancreas.

Animals↗
PubMed1987

The effect of prehepatic insulin administration on alanine flux rates in diabetic dogs.

The in vivo flux rates of glucose (6-3H-glucose) and of alanine (U-14C-alanine) were measured in insulin-dependent chronically diabetic dogs which were infused with insulin employing a bedside-type artificial B cell and either the peripheral or the portal venous route. In comparison with non-diabetic control animals the diabetic dogs had near-normal patterns of glucose metabolism and pancreatic glucagon regardless of the route of insulin administration. They also showed reduced basal portal but moderately elevated peripheral insulin levels on peripheral and near-normal peripheral values on portal insulin infusion. Both concentration and production rates of alanine were reduced on peripheral (0.142 +/- 0.016 mmol/l, 4.73 +/- 0.49 mumol.kg-1.min-1, p less than 0.05) but normal on portal insulin (0.206 +/- 0.030 mmol/l, 6.33 +/- 0.63 mumol.kg-1.min-1). The alanine clearance was slightly elevated or normal in the diabetic dogs, and the glucose production from alanine showed a strongly delayed response to an exogenous glucose load on either route of insulin administration. It is concluded that the peripheral hyperinsulinism during posthepatic insulin administration stimulates glucose utilisation to a normal extent, but inhibits the provision of amino groups in resting muscle. Alanine synthesis is thereby reduced, and the carbon moieties are shunted from glucose into circulating lactate. Long-term studies are needed to elucidate the role of the liver under these conditions.

Alanine↗
PubMed1987

Assessment of subcutaneous glucose concentration: validation of the wick technique as a reference for implanted electrochemical sensors in normal and diabetic dogs.

Employing saline-impregnated cotton threads, an implanted-wick technique was adopted in dogs to obtain specimen from the subcutaneous interstitial compartment in order to estimate its glucose concentration. By measuring the protein, potassium and haemoglobin contents, the centrifuged wick fluid was shown to contain the interstitial concentration of solutes after an equilibration time of approximately 15 min. In normal and in diabetic animals the steady state subcutaneous glucose concentration was almost identical to the circulating glucose level when ranged between 2 and 25 mmol/l. Slow alterations in the circulating glucose profile such as those which appear during an oral glucose tolerance test are closely mirrored by the respective levels in the wick fluid. Fast alterations, however, show deviations. The wick-based glucose levels are well paralleled by the current of Clark type glucose oxidase sensors implanted at the same site. Since, on the basis of in vitro calibrations the sensor outputs have only indicated apparent tissue glucose concentrations of between 70 and 90% of glycaemia, another reference is needed for calibration. Under steady state conditions, the wick method, and on this basis in routine measurements the blood glucose concentration, may be recommended as a reference of implanted sensors which can otherwise not be calibrated in situ.

Animals↗
PubMed1985

Alterations in alanine metabolism in diabetic dogs during short-term treatment with an artificial B cell.

The flux rates of plasma glucose and alanine were studied isotopically (6-3H-glucose and U-14C-alanine simultaneously) in resting chronically diabetic dogs during short-term treatment with an artificial B cell where the insulin was infused into a peripheral vein. Despite perfect blood glucose control and normal glucose flux rates, the concentration and rates of appearance and disappearance of alanine were significantly elevated in the diabetic animals before, during and after an exogenous glucose load. The incorporation of the carbon moiety of alanine into circulating glucose was also increased, but diminished to a near-normal extent when exogenous glucose was given. The plasma clearance rates for alanine in the diabetic dogs were normal throughout the study. It is concluded that normal blood glucose control in diabetes does not necessarily mean normalization of the entire metabolic network. On the basis of peripheral hyperinsulinaemia alanine formation from glucose and branched chain amino acids is elevated in muscle. This may explain increased flux of alanine despite normal blood glucose control.

Alanine↗
PubMed1985

Daily glucose and insulin rhythms in diabetic dogs on the artificial beta cell.

The circadian periods of plasma glucose, insulin and alpha-amino nitrogen (alpha-AN) were studied in fed and fasting normal and diabetic dogs which were fed either beef or beef supplemented with carbohydrates (CH). The diabetics were either withdrawn from insulin supply or treated with an artificial beta cell (ABC) or infused a constant insulin dose (CI).--There was a significant daily glucose rhythm in normal fasting animals and in fasting diabetics on CI or on insulin withdrawal. In the fed controls, the phase of the rhythms depends on carbohydrate content of food. In CH-free fed controls the insulin maxima were related to alpha-AN but in CH-fed controls they were related to glycemia. Due to the mechanism of ABC-provided insulin dosage, the phases of glucose and of insulin oscillations were correlated in all diabetics on ABC. Thus even if the mean glucose level is normalized by ABC the intrinsic phase relations remain altered.--It is concluded that the daily glucose periodicity is based on endogenous rhythms in glucose production and utilization and is essentially independent of current insulin provision. But it is governed by the meals as main "Zeitgebers" and modified by the actual insulin supply.

Amines↗
PubMed1985

In vivo comparison of different algorithms for the artificial beta-cell.

Using an extracorporeal artificial beta-cell in chronically diabetic dogs, the effects of four different mathematical models of glucose-controlled insulin dosage were compared: the Biostator algorithm (quadratic equation), Toronto algorithm (hyperbolic tangent function), Karlsburg algorithm (modified first-order derivative controller), and Ilmenau algorithm (second-order linear difference equation). The constants of all formulas implemented for the artificial beta-cell were obtained by regression analysis of paired blood glucose and plasma insulin data from normal control animals. Thus, they were biologically equivalent for all formulas. The patterns of blood glucose, insulin doses, and plasma insulin before, during, and after an intravenous glucose infusion test performed during the glucose-controlled insulin infusion showed no significant differences between the experimental groups subjected to the different algorithms. However, in no case were really normal blood glucose response curves restored by the artificial beta-cell. This might be due, first, to the fact that the algorithm parameters were not adapted to the actual individual insulin responsiveness, second, to the unphysiological peripheral venous route of insulin administration, and, third, to the lack of appropriate adaptation of the animals to normoglycemia.

Animals↗
PubMed1985

Canine C-peptide for characterization of experimental diabetes in dogs.

Radioimmunoassay of canine C-peptide (CCP) was developed for the characterization of endogenous beta cell function in experimentally diabetic dogs. The animals were rendered diabetic by subtotal pancreatectomy and intrasurgical infusion of 2 mg kg-1 streptozotocin into the superior pancreaticoduodenal artery. After an average duration of diabetes of 5 months the animals showed zero peripheral venous fasting CCP levels with no response to feeding, OGTT/i.v. glucagon loading or i.v. glucose tolerance testing. The data on CCP levels were entirely coincident with simultaneously measured plasma IRI levels. In non-diabetic control animals there were clear-cut CCP increases after all stimuli. The experimental model provided an IDDM-type diabetes without toxic symptoms but with sufficient exocrine pancreatic function. The comparison showed that plasma IRI analyses would also allow a reliable characterization of insulinogenic functions in these animals.

Animals↗
PubMed1984

Modelling the glucose-insulin system as a basis for the artificial beta cell.

The control constants for glucose-dependent insulin dosage in diabetic dogs were determined from test results in the opened system on the basis of a global blood glucose plasma-insulin control model. The controlled plant of the model consisted of the glucose and insulin subsystems; the entire insulin providing process was considered to be the controlling element, and the glucose-dependent insulin dose estimation, the controller. The constants obtained were employed in the extracorporeal artificial beta cell. The structure of the model and the numerical values of its state variables were verified by the prediction of blood glucose responses to intravenous glucose loads and by the correspondence between glucose balances and insulin doses as calculates and those as observed in diabetic animals. The application of the optimum control constant estimates in feedback-controlled insulin infusions provides improved blood glucose patterns but unchanged needs for insulin in comparison to the application of standard control parameters.

Animals↗
PubMed1984

Tracer kinetic studies of glucose and alanine metabolism in diabetic dogs on the artificial beta cell.

The in vivo glucose turnover was investigated employing [6-3H]glucose and [U-14C] glucose or [6-3H]glucose and [U-14C]alanine. Fasting chronically diabetic dogs at rest during short-term treatment with a bedside artificial beta cell were compared with normal animals in a glycemic steady state before, during, and after an i.v. load of unlabelled glucose. The insulin was infused into a peripheral vein. During the glucose-controlled insulin infusion glycemia was perfectly normalized, the concentrations of lactate and alanine remained elevated, pancreatic glucagon returned to normal, and the peripheral insulin levels were normal or slightly elevated in the diabetic dogs. Also the glucose turnover was in the normal range but the recirculation of the carbon label (i.e. the Cori cycle activity) was reduced. The alanine turnover and gluconeogenesis from alanine remained increased both in the basal state and during the glucose load. It is concluded that due to the absence of the physiological portosystemic insulin gradient, complete restoration of the physiological metabolic rates and control relations is not possible even if the blood glucose patterns are fully normalized.

Alanine↗
PubMed1983

Absorption rates of subcutaneously injected insulin in the dog as calculated from the plasma insulin levels by means of a simple mathematical model.

The appearance rate of insulin (calculated insulin secretion rate) in the circulating blood after subcutaneous injection was estimated in diabetic dogs from serial measurements of immunoreactive insulin concentrations using a simple mathematical model based on the insulin half-life and the distribution space. In the case of highly purified monocomponent porcine insulin, maximum concentrations occurred after 30-60 min. The duration of insulin appearance was dose-dependent and the rate of appearance could be described by a bi-exponential function. It was linearly dose-dependent but the effect on glycaemia showed saturation kinetics. The action of the injected dose on the fasting glycaemia diminished when the appearance rate became less than 0.3 mU X kg-1 X min-1. Fractional dose recovery was between 70% and 90% and was not different between depot and regular insulin. Appearance kinetics were not significantly affected by the initial glycaemia. The model presented provides a means for quantitative characterization of different insulin preparations.

Absorption↗
PubMed1983

Glucose metabolism studied isotopically in diabetic dogs: effect of restoration of peripheral normoinsulinaemia by the artificial B cell.

Normoglycaemia, peripheral normoinsulinaemia, and normoglucagonaemia were restored acutely in chronically diabetic dogs, using an extracorporal artificial B cell with peripheral venous insulin administration. Glucose metabolism was analysed by a non-steady-state tracer technique with double-labelled glucose (6-3H- and U-14C-glucose), and the incorporation of the 14C label into plasma lactate was determined. In the basal state, glucose turnover rates were not different from those in non-diabetic controls; but recirculation of the glucose-C label through the Cori cycle, and lactate labelling from glucose utilization were decreased. The glycaemic response to an intravenous infusion of non-labelled glucose was distinctly enhanced. This was based on a reduction in the rates of glucose disappearance. Its rates of appearance (total endogenous glucose production) were, however, suppressed to a normal extent by the exogenous glucose. Accordingly carbon recycling was nearly totally suppressed during the glucose infusion as in the controls. It is concluded that metabolic recompensation in these fasting, resting diabetic dogs remained incomplete because the interval of normoinsulinaemia, which obviously applied only to the peripheral circulation, was not long enough.

Animals↗