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Biomedical subjects

A Vølund

Publications and source records attributed to A Vølund.

At least 55 records · Page 3Linked to original sources
PubMed1988

Carbohydrate and lipid metabolism of skeletal muscle in type 2 diabetic patients.

Peripheral hyperinsulinaemia is the cause of metabolic changes that might contribute to the high incidence of macrovascular disease in patients with diabetes mellitus. In order to test this hypothesis muscle biopsies from 12 Type 2 diabetic patients and 14 age and sex matched non-diabetic patients, undergoing minor surgery, were obtained. The diabetic patients had significantly elevated fasting serum insulin (0.29 +/- 0.05 vs 0.06 +/- 0.03 nmol-1) and glucose (8.3 +/- 1.5 vs 4.6 +/- 0.5 mmol-1) and HbA1 levels (8.4 +/- 0.4 vs 5.0 +/- 0.2 per cent). The fasting and 2-h postprandial C-peptide levels were 0.99 +/- 0.25 vs 0.39 +/- 0.12 and 3.12 +/- 0.75 vs 1.09 +/- 0.34 nmol/l, respectively. The diabetic patients showed a marked elevation of triglyceride in the striated muscle biopsies compared to the non-diabetic controls (290 +/- 52 vs 48 +/- 6 mumol/g wet weight, p less than 0.001). Moreover, the activities of glucose-6-phosphate dehydrogenase (0.25 +/- 0.03 vs 0.13 +/- 0.01 U/g wet weight) and malic enzyme (0.15 +/- 0.01 vs 0.05 +/- 0.01 U/g wet weight), necessary for lipid synthesis, were significantly increased (both p less than 0.001) in the diabetic patients while the glycolytic enzymes, hexokinase (0.65 +/- 0.09 vs 1.82 +/- 0.11 U/g wet weight), pyruvate kinase (7.3 +/- 0.9 vs 13.2 +/- 0.9 U/g wet weight), phosphofructokinase (1.3 +/- 0.2 vs 2.6 +/- 0.2 U/g wet weight), and alpha-glycerophosphate dehydrogenase (7.3 +/- 0.5 vs 12.5 +/- 0.7 U/g wet weight) were decreased (all p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1988

Application of a biokinetic model for prediction and assessment of glycated haemoglobins in diabetic patients.

An improved biokinetic model describing the haemoglobin A1c ketoamine fraction (HbA1c), and the haemoglobin A1d aldimine fraction (HbA1d), as a function of preceding blood glucose levels has been studied. The model requires knowledge of the chemical reaction rate constants and the life span of the erythrocytes. Calculated HbA1c corresponding to constant blood glucose levels was about 6% lower than previously found using a simplified method of calculation. The predicted variations in the glycated haemoglobins in response to simulated variations in the glucose concentration were, however, similar to the improved and the simplified model calculations. Thus, HbA1d reached a new steady state level within 24 h and HbA1c within 4 weeks after sudden change in glucose concentration. When the blood glucose concentration was simulated by sine waves with periods from 2 to 60 days it was observed that the HbA1d varied in parallel with the glucose concentration with a time delay of about 2 h, whereas the HbA1c was almost constant with periods less than 7 days. Haemoglobin A1c predicted from observed blood glucose levels in diabetic patients followed over several weeks varied in parallel with measured HbA1c. However, the measured values were systematically higher than the calculated. This could be due to an underestimation of the daily mean blood glucose levels used for calculation of HbA1c or to inaccurate estimates of the reaction rate constants. Based on the model it could be demonstrated that the HbA1c fraction corresponds to an exponentially weighted average of daily mean blood glucose levels over the preceding 4 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Glucose↗
PubMed1988

Retinopathy in newly presenting non-insulin-dependent (type 2) diabetic patients.

One hundred and twenty-nine (97 M, 32 F) previously untreated non-insulin-dependent diabetic patients were studied. Meal and glucose (75 g) tolerance tests were performed on two separate days with glucose, C-peptide and insulin levels estimated during each with the inclusion of growth hormone during the meal test. In addition glycosylated haemoglobin (HbA1) and plasma creatinine levels were determined. Clinical evaluation included detailed ophthalmological examination following mydriasis. Differences between retinopaths (n = 21) and non-retinopaths (n = 108) were FPG 13.7 vs 11.6 (mmol/l) (p less than 0.01); HbA1: 12.9 vs 11.3 (%) (p less than 0.01); BMI: 25.2 vs 29.4 (kg/m2) (p less than 0.001); age 56.8 vs 52.4 (yr) (ns); creatinine: 91.2 vs 88.4 (mumol/l) (ns); systolic blood pressure: 152.4 vs 143.9 mmHg (ns); diastolic blood pressure 87.9 vs 87.7 mmHg (ns); fasting growth hormone: 4.6 +/- 0.9 vs 2.4 +/- 0.3 (mU/1) (p less than 0.01). Multivariate logistic analysis however revealed that systolic blood pressure in conjunction with the insulin response gave the most significant correlation with retinopathy. No significant correlation was observed with age, sex, diastolic blood pressure, creatinine, family history or smoking. The effect of disease duration could not be evaluated. B-cell function appears central to microvascular complications in non-insulin dependent diabetes mellitus.

Blood Glucose↗
PubMed1987

Calculated pattern of intraportal insulin appearance without independent assessment of C-peptide kinetics.

Prehepatic beta-cell insulin release can be calculated with C-peptide measurements, but this requires independent determination of kinetics of C-peptide disappearance from plasma. We introduce an approach by which a prehepatic insulin release pattern is calculated from plasma insulin and C-peptide, without separate C-peptide kinetic analysis. Human insulin and C-peptide were infused intraportally into conscious dogs (n = 11) at equimolar rates; endogenous insulin and C-peptide release were suppressed with somatostatin (0.8 micrograms . kg-1 . min-1). Insulin and C-peptide were infused at basal and equimolar rates (range 19-72 pmol/min in dogs), and the infusions were slowly increased, in stepwise fashion, to a maximum at 60 min (range 152-613 pmol/min) and subsequently renormalized at either 85 (n = 6) or 195 (n = 5) min. Plasma insulin and C-peptide measurements were described simultaneously by a composite model of insulin and C-peptide plasma kinetics, with the molar intraportal appearance rate due to the infusion R(t) as an unknown input for both insulin and C-peptide catabolism. The model assumes one-compartment disappearance kinetics for both peptides. Fitting the model to the measured insulin and C-peptide data, we were able to compute the insulin-appearance pattern accurately for every experiment; calculated and actual secretion rates were highly correlated (r = .93-.97) and had very similar temporal patterns. Also calculated were the fractional disappearance rates for human insulin (t1/2 = 6.9 min) and C-peptide (t1/2 = 14 min) in the dog, as well as the C-peptide distribution volume (12.3 +/- 0.5% body wt).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Kinetics of trypsin catalysis in the industrial conversion of porcine insulin to human insulin.

The kinetics of coupling and transpeptidation reactions catalysed by trypsin were studied in media with low water contents to see whether the usual Michaelis-Menten kinetics applied under the unusual conditions used in peptide bond synthesis, to obtain information about the magnitude of rate constants and activation energies, and to gain insight into the mechanism of catalysis. Porcine insulin, des-(AlaB30)-porcine insulin, human insulin-ThrB30-OMe and human insulin-ThrB30(But)-OBut were used as substrates. Two threonine esters (Thr-OMe and Thr(But)-OBut) were used for transpeptidation and coupling. The reactions progressed according to first-order kinetics until about 35% conversion, and the experimental data were adequately explained by Michaelis-Menten kinetics. The rates of the coupling and transpeptidation reactions in media with low water contents were orders of magnitude below the rates of peptide bond hydrolysis by trypsin in water. It was not possible to approach saturation of the enzyme with substrate so determination of Km was impossible, but for each substrate a value larger than 0.1 M was estimated from the Lineweaver-Burk plot. The rate of release of alanine from porcine insulin depended on the type of threonine ester present; for example, Thr-OMe inhibited the reaction. Coupling occurred faster than transpeptidation. However, in the medium used, the activation energies for the two reactions were similar (about 50 kJ/mol), so the difference in reaction rates is probably due to different transmission coefficients in the activated transition states. Computer simulations enabled us to obtain quantitative descriptions of the reaction progress curves from fitted rate constants.

Alanine↗
PubMed1985

Biological potency of porcine, bovine and human insulins in the rabbit bioassay system.

Potency determination of porcine, bovine and human insulins relative to the International Standard in the pharmacopoeial rabbit bioassay system requires that the log-dose response curves are parallel. Furthermore, the same relative potency should be obtained independent of how the hypoglycaemic response is defined. The results of 508 rabbit blood glucose assays have been analyzed by new multivariate statistical methods. No deviations from parallelism of the log-dose response curves were detected. However, the potencies showed significant variation depending on the blood sampling times. Pure porcine and human (semisynthetic and biosynthetic) insulin potencies decreased by 12% and 18%, respectively, from the 30-min to the 2.5-h response, whereas bovine insulin potencies increased by 9%. Since the standard is a 52:48 mixture of bovine and porcine insulins, these results could be due to porcine and human insulins having a quicker onset and shorter duration of hypoglycaemic effect than bovine insulin. This was confirmed in assays of bovine relative to porcine insulin and by direct comparison of mean blood glucose curves. It is concluded that there is a response time-dependent variation in potency when the test and standard insulin have a different species composition. Hence, pure species insulin standards - a porcine, a bovine and a human standard - are needed for assay of the three insulins.

Animals↗
PubMed1985

The subcutaneous absorption of human and bovine ultralente insulin formulations.

The subcutaneous absorption of 125I-labelled semisynthetic human ultralente insulin was compared with that of 125I-labelled beef ultralente in eight insulin-dependent diabetic patients using a balanced cross-over design. In randomized order, 6 U of human ultralente was given in the thigh and in the abdominal wall while 24 U was given in the contralateral thigh and 6 U of bovine ultralente in the abdominal wall. On a second occasion the injection sites of human and bovine ultralente were reversed. Human ultralente was absorbed significantly faster than bovine ultralente. Thus, the 50% disappearance time of the radioactivity in the thigh was 15 +/- 3 h versus 44 +/- 9 h for the high dose, and 13 +/- 2 h versus 21 +/- 5 h for the small dose for human and bovine ultralente, respectively. Correspondingly, values for the abdomen (6U) were 9 +/- 1 h and 16 +/- 2 h. The difference between the absorption rates for 6 U and 24 U was statistically significant for bovine ultralente only. Human ultralente, but not bovine ultralente showed faster absorption from the abdomen than from the thigh. The absorption rate of human ultralente insulin, though faster than bovine ultralente insulin, makes it suitable as the basal insulin preparation for multiple insulin injection regimens.

Adult↗
PubMed1985

Induction of formaldehyde contact sensitivity: dose response relationship in the guinea pig maximization test.

The sensitizing potential of aqueous formaldehyde was evaluated with the guinea pig maximization test (GPMT) in two laboratories (Copenhagen and Stockholm) using different guinea pig strains. Six intradermal (0.01%-3%), and 6 topical (0.5%-20%) concentrations were used for induction, and formaldehyde 1% and 0.1% was used for challenge. The incidence of contact sensitivity depended on the intradermal, but not on the topical induction dose. Statistical analyses showed a non-monotonous (non-linear) dose response relationship. The estimated maximal sensitization rate in Copenhagen was 80% after intradermal induction with 0.65% formaldehyde; in Stockholm it was 84% after induction with 0.34%. The data from the two laboratories could be described by parallel displaced dose response curves suggesting that the guinea pig strain used in Stockholm was significantly more susceptible to formaldehyde than the strain used in Copenhagen. The EC50 (formaldehyde concentration at which 50% of the guinea pigs were sensitized) at the 72 h scoring and a 1% challenge concentration, was 0.061% in Copenhagen and 0.024% in Stockholm.

Administration, Topical↗
PubMed1984

Glucosylation of human haemoglobin A. Dynamic variation in HbA1c described by a biokinetic model.

The reaction kinetics for the reversible condensation of D-glucose and haemoglobin A through a labile haemoglobin A-aldimine adduct to HbA1c have been investigated using a biokinetic model. The specific rate constants obtained from in vitro experiments were included in the model which also took into account the removal of HbA1c by decay of erythrocytes. Using a sinusoidal variation in blood glucose a phase delay of about 2 hours was observed between the maximum blood glucose concentration and the maximum aldimine concentration. The mean haemoglobin A-aldimine concentration was independent of both the amplitude and frequency of the blood glucose oscillations and reached equilibrium concentration within 24 hours. The steady state relation between mean blood glucose and HbA1c was similar to the corresponding relation based on an irreversible formation of HbA1c. However, contrary to the irreversible model the steady state HbA1c concentration with the reversible model was reached 3 to 4 weeks after a change in blood glucose level. This finding is in agreement with clinical experience and indicates that in assessing continuous glycaemic control in diabetic patients haemoglobin A1c should be measured approximately every 3 to 4 weeks.

Blood Glucose↗
PubMed1984

Dose-dependent subcutaneous absorption of porcine, bovine and human NPH insulins.

The absorption of 125I-labelled porcine, bovine and human neutral protamine Hagedorn (NPH) insulins was compared in 40 diabetic patients after subcutaneous injections in the thighs using doses of 6 and 24 IU (40 IU/ml). Furthermore, the absorption of porcine NPH insulin was compared with bovine NPH insulin and porcine lente type insulin in the same dose (6 IU). All these intermediately acting insulins showed similar absorption rates when administered in the same dose. However, an increase in the injected dose from 6 to 24 IU resulted in a decrease of approximately 30% in the absorption rate of all NPH insulins.

Absorption↗
PubMed1984

Human Monotard insulin: dose-dependent subcutaneous absorption.

The aim was to study the effect of dose on subcutaneous absorption of semisynthetic human Lente-type insulin (Monotard HM) in IDDM patients. The absorption was evaluated by measurements of residual radioactivity of 125-I labelled insulin at the injection sites. In 9 patients, on consecutive days, 6, 12, 24 and 36 IU of Monotard HM was given subcutaneously. The residual radioactivity was measured up to 49 hr after injections. A dose-dependent absorption was found with significantly decreasing absorption rates for increasing doses. The times for 50% of initial activity to disappear were (doses given in parentheses): 9.0 hr (6 IU), 8.9 hr (12 IU), 10.9 hr (24 IU), 14.8 hr (36 IU).

Absorption↗
PubMed1983

Optimal sampling times for minimum variance of clearance determination.

1 Clearance of a substance that follows first order kinetics can be determined from multiple plasma concentrations (the standard method) or from only one plasma concentration and an assumed volume of distribution (the simplified method). 2 On the basis of statistical considerations it is shown that the variance of the clearance determined by the standard method has a minimum when the mean sampling time is equal to the reciprocal elimination constant. For the simplified method the variance of the clearance is minimal when the sampling time is equal to the reciprocal elimination constant multiplied by one plus the ratio between the squared coefficients of variation of the concentration and the volume of distribution. 3 The sampling times determined in this way are optimal in the sense that the variance of the clearance estimate will be larger for any alternative choice of the same number of sampling times. In practice, the optimal sampling times can only be determined approximately because the elimination constant is not known exactly. The loss in precision of the clearance estimation arising herefrom will be less if the elimination constant is underestimated than if it is overestimated to the same relative extent. 4 In theory, the simplified method with optimal sampling time will give a more precise clearance determination than the standard method, if the number of optimally spaced sampling times is less than one plus the ratio between the squared coefficients of variation of the concentration and volume of distribution. In studies where each subject serves as his own control and the coefficient of variation of the volume of distribution is relatively small the simplified method will be of higher precision unless the number of samples with the standard method is unusually large.

Humans↗
PubMed1982

A study of the comparative safety and efficacy of neutral soluble human (semi-synthetic) and porcine monocomponent insulin in non-diabetic subjects.

Neutral soluble human (semi-synthetic) and porcine insulin and diluting medium were administered subcutaneously in a randomized fashion to six fasting normal male subjects. The plasma glucose, C-peptide and insulin response was observed for a period of two hours before and six hours after injection of insulin (0.075 m/kg) into the anterior abdominal wall. The hypoglycaemic response was identical for the two insulins with the plasma glucose values reaching a nadir at 90--120 minutes and returning to within 10% of basal levels by six hours. Also similar peak plasma insulin values were achieved with human and porcine insulin by 50--60 minutes post-injection. The C-peptide response following the administration of both insulins suggested equal suppression of endogenous beta cell secretion. The two insulins were well tolerated with no immediate or delayed allergic reactions in any subject. These results suggest that human (semi-synthetic) and porcine soluble monocomponent insulins under the described experimental conditions are bioequivalent.

Adult↗
PubMed1981

Glucagon: structure-function relationships investigated by sequence deletions.

A series of glucagon analogues, des-(1-4)-glucagon, des-(5-9)-glucagon, des-(10-15)-glucagon, des-(16-21)-glucagon, des-(22-26)-glucagon and des-(27-29)-glucagon, were prepared by condensation of synthetic fragments and characterized biologically and immunologically. Fully synthetic glucagon was also characterized. The potencies with regard to glucagon receptor binding in purified rat liver plasma membranes were, in decreasing order: synthetic glucagon 108%, des-(1-4)-glucagon 5.7%, des-(27-29)-glucagon 0.92%, des-(5-9)-glucagon 0.47%, des-(10-15)-glucagon 0.0028%, des-(16-21)-glucagon 0.0017% and des-(22-26)-glucagon 0.00060% relative to that of natural porcine glucagon. Des-(27-29)-glucagon was the only analogue that activated the adenylate cyclase in rat liver plasma membranes or stimulated the lipolysis in isolated free fat cells from rat epididymal fat pad. The potencies were 0.16% and 0.20% of that of glucagon, respectively. Des-(1-4)-glucagon was a glucagon antagonist in the adenylate cyclase assay. The immunoreactivities of the glucagon analogues were determined with two commonly used anti-glucagon sera, K 5563 and K 4023, directed towards the C-terminus and some segment in the sequence 2-23, respectively. In the K 5563 assay, des-(27-29)-glucagon and des-(22-26)-glucagon had potencies of 0.0009% and less than 0.09% of that of glucagon, respectively. The remaining analogues had potencies varying from 45% to 141% of that of glucagon. In the K 4023 assay, the analogues showed a non-linear dilution effect. The combined results indicate a partition within the glucagon molecule with regard to receptor binding and adenylate cyclase activation. The region 10-26 appears to be the most important for receptor binding, whereas 1-4 is essential for adenylate cyclase activation. The C-terminal segment 27-29 is important for the maintenance of full receptor binding but non-essential for adenylate cyclase activation.

Adenylyl Cyclases↗
PubMed1980

Multivariate bioassay.

In a multivariate bioassay the response variable is r-dimensional and the dose variable is one-dimensional. Thus, the graph of the dose response relation is a curve in the (r+1)-dimensional space. The similarity requirement for a test and a standard is divided into two parts: (i) a condition of marginal similarity corresponding to the usual similarity or parallelism of each response variable considered separately; (ii) a condition that all response variables give the same relative potency. These conditions correspond to two nested hypotheses for which a T2- and an asymptotic likelihood ratio test, respectively, are presented for the case of a multivariate normal response distribution and a parallel-line dose response model. Equations for direct calculation of the maximum likelihood estimate of the relative potency have been obtained. An asymptotic confidence set for the common relative potency is derived. These methods have been applied to a twin cross-over assay of insulin by the rabbit blood sugar method, in which the measurements of the blood sugar concentration at intervals after the insulin administration were regarded as the multivariate response. In comparison with the usual univariate analysis, multivariate methods allow additional tests of basic assumptions and they appear to provide a more efficient utilization of experimental data, leading to improved potency estimates.

Animals↗