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Biomedical subjects

A Vølund

Publications and source records attributed to A Vølund.

At least 37 records · Page 2Linked to original sources
PubMed1994

Perinatal determinants among children who later develop IDDM.

OBJECTIVE: The aim of this study was to investigate whether children who develop insulin-dependent diabetes mellitus (IDDM) differ in some aspects from a matched control group at the time of birth. RESEARCH DESIGN AND METHODS: We studied all children who were born in Denmark during the period 1973-1977 and admitted to a Danish hospital with a diagnosis of IDDM during 1978-1989. The study was conducted by combining two nationwide registries, The National Patient Registry and The Birth Registry. RESULTS: The criteria were fulfilled by 837 children. Data regarding the age of the parents, the number of previous pregnancies of the mother, the month of birth, and the birth weight and length of the children who developed IDDM were compared with the data of an age- and sex-matched control group of 837 children without IDDM. We did not detect any significant differences between the two groups with respect to the parameters studied. CONCLUSIONS: No differences in perinatal determinants could be demonstrated among Danish children who develop IDDM compared with children without diabetes.

Adolescent↗
PubMed1993

Dose-response testing with nickel sulphate using the TRUE test in nickel-sensitive individuals. Multiple nickel sulphate patch-test reactions do not cause an 'angry back'.

The aim of this study was to employ the TRUE test assay to confirm the presence or absence of the 'angry back' phenomenon, i.e. that a strong positive patch-test reaction heightens adjacent patch-test response. In addition, we wished to establish the dose-response relationship for nickel sulphate patch tests among nickel-sensitive patients. Seventy-two nickel-sensitive patients, 36 in Odense and 36 in Stockholm, were tested with a 10-step nickel sulphate dilution series (TRUE test) and two placebo patches. The position of the patches was rotated, to provide a balanced spatial distribution of the different concentrations. Readings were performed blind. The results were analysed by means of polynomial multiple-regression methods and a logistic dose-response model. Half the patients (38/72) had a threshold patch-test concentration for nickel sulphate in the range of 3-0.3 microgram/cm2. The 'angry back' phenomenon was not apparent in this study, as the spill-over effect was not statistically significant. Strong reactions to high concentrations of nickel sulphate did not enhance the response to adjacent lower concentrations of nickel sulphate.

Dermatitis, Allergic Contact↗
PubMed1993

Pancreatic beta-cell function and glucose metabolism in human segmental pancreas and kidney transplantation.

beta-Cell function and glucose metabolism were studied in eight insulin-dependent diabetic recipients of combined segmental pancreas and kidney transplant with peripheral insulin delivery (Px), in eight nondiabetic kidney-transplant individuals (Kx), and in eight normal subjects (Ns) after three consecutive mixed meals. All subjects had normal fasting plasma glucose, but increased basal levels of C-peptide were demonstrated in the transplant groups (P < 0.05 relative to Ns). Postprandial hyperglycemia was increased 14% in Kx and 32% in Px (P < 0.05), whereas compared with Ns postprandial C-peptide levels were increased three- and twofold, respectively, in Kx and Px (P < 0.05). Compared with Ns basal insulin secretion rate (combined model) was increased 2-fold in Kx and 1.4-fold in Px (P < 0.05). Maximal insulin secretion rate was reduced 25% in Px compared with Kx (P < 0.05) but not different from that of Ns (P NS). Also, maximal insulin secretion rate occurred later in Px than in controls (Tmax: Px 50 min, Kx 30 min, and Ns 32 min; P < 0.05). The total integrated insulin secretion was increased 1.4-fold in Px compared with Ns (P < 0.05) but decreased 1.4-fold compared with Kx (P < 0.05). Fasting and postprandial proinsulin-to-C-peptide molar ratios were inappropriately increased in Px compared with Kx and Ns. Basal hepatic glucose production was increased 43% in Px and 33% in Kx compared with Ns (P < 0.05). Postprandial total systemic glucose appearance was similar in all three groups, whereas peripheral glucose disposal was 15% reduced in Px (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Chemical stability of insulin. 1. Hydrolytic degradation during storage of pharmaceutical preparations.

Hydrolysis of insulin has been studied during storage of various preparations at different temperatures. Insulin deteriorates rapidly in acid solutions due to extensive deamidation at residue AsnA21. In neutral formulations deamidation takes place at residue AsnB3 at a substantially reduced rate under formation of a mixture of isoAsp and Asp derivatives. The rate of hydrolysis at B3 is independent of the strength of the preparation, and in most cases the species of insulin, but varies with storage temperature and formulation. Total transformation at B3 is considerably reduced when insulin is in the crystalline as compared to the amorphous or soluble state, indicating that formation of the rate-limiting cyclic imide decreases when the flexibility of the tertiary structure is reduced. Neutral solutions containing phenol showed reduced deamidation probably because of a stabilizing effect of phenol on the tertiary structure (alpha-helix formation) around the deamidating residue, resulting in a reduced probability for formation of the intermediate imide. The ratio of isoAsp/Asp derivative was independent of time and temperature, suggesting a pathway involving only intermediate imide formation, without any direct side-chain hydrolysis. However, increasing formation of Asp relative to isoAsp derivative was observed with decreasing flexibility of the insulin three-dimensional structure in the formulation. In certain crystalline suspensions a cleavage of the peptide bond A8-A9 was observed. Formation of this split product is species dependent: bovine greater than porcine greater than human insulin. The hydrolytic cleavage of the peptide backbone takes place only in preparations containing rhombohedral crystals in addition to free zinc ions.

Drug Stability↗
PubMed1992

Placebo-controlled comparison of captopril, metoprolol, and hydrochlorothiazide therapy in non-insulin-dependent diabetic patients with primary hypertension.

The antihypertensive effect of captopril, metoprolol, and hydrochlorothiazide was compared in 23 non-insulin-dependent (NIDDM) diabetic patients less than or equal to 75 years of age, with borderline to moderate primary hypertension. In a double blind, placebo-controlled cross-over trial the patients were treated with 25 to 50 mg captopril, 50 to 100 mg metoprolol, 12.5 to 25 mg hydrochlorothiazide, and placebo, each given twice daily for 8 weeks. Antidiabetic treatment remained unchanged during the study. After receiving placebo for a 4 week run-in period, arterial blood pressure was 168/101 +/- 93/10 (mean +/- SEM) mm Hg. Diastolic blood pressure was lowered significantly during all active treatment periods compared to the placebo value of 97 +/- 2 mm Hg: captopril, 92 +/- 1 mm Hg; metoprolol, 90 +/- 1 mm Hg; hydrochlorothiazide, 91 +/- 1 mm Hg. Metabolic variables were not significantly altered by captopril and metoprolol, while hydrochlorothiazide treatment increased hemoglobin A1c from 7.5 +/- 0.3 to 8.2 +/- 0.4% (P less than .001), decreased high-density lipoprotein-cholesterol from 1.19 +/- 0.08 to 1.10 +/- 0.06 mmol/L (P less than .05). Glomerular filtration rate, urinary albumin excretion, orthostatic blood pressure response, and digital systolic blood pressure in the lower limb remained unchanged during the active treatment periods. The frequency of subjective adverse effects was acceptable during active treatment and not significantly different compared to placebo. We conclude that antihypertensive treatment for 8 weeks with captopril or metoprolol in NIDDM patients is well-tolerated and causes no deterioration in metabolic control and kidney function, while hydrochlorothiazide causes a slight deterioration in glycemic control and lipid profile.

Aged↗
PubMed1992

Relationship between insulin injection regimen and metabolic control in young Danish type 1 diabetic patients. The Danish Study Group of Diabetes in Childhood.

In 1987 and 1989 nationwide screening for HbA1c was carried out in Denmark. Twenty-one paediatric departments treating children with diabetes participated in the first study and twenty-two in the second. During this 2-year period metabolic control deteriorated despite the fact that the use of multiple injection regimens increased from 39% to 54%. The possible reasons for the deterioration in metabolic control were examined in the 429 children (> or = 9 years, 1987) and adolescents (< 18.8 years, 1989) who participated in both studies. All had diabetes duration of greater than one year (1987) and all were treated by the same departments during the study period. The children were divided into three subgroups according to injection regimen. Group A (n = 128) received twice-daily insulin injections; group B (n = 171) were on multiple injections (three or more) while group C (n = 130) shifted from twice-daily insulin to multiple injections during the 2-year period. A deterioration of blood glucose control as assessed by HbA1c was observed in all three treatment groups. For group C the 2-year increase in daily insulin dose was more pronounced for males (19%) than for females (6%). Body mass index increased significantly in all treatment groups during the study period. The 1989 mean levels were higher in group B (males 20.6 kg m-2, females 22.0 kg m-2) than group A (males 19.3 kg m-2, p = 0.002; females 20.7 kg m-2, p = 0.000003) and group C (males 19.4 kg m-2, p = 0.0005; females 20.7 kg m-2, p = 0.008).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Influence of portal delivery of insulin on intracellular glucose and lipid metabolism.

We have investigated whether portal delivery of insulin as a result of intrahepatic islet cell autografts would prevent the development of metabolic alterations. Seven pancreatectomized dogs received islet autografts transplanted into the liver through the portal vein (PD). One year after transplantation, their intravenous glucose tolerance and insulin responses were similar to age-matched control (C) dogs (n = 5). Also, normal triglyceride content in arterial smooth muscle and striated muscle was observed in the dogs with portal insulin delivery in contrast to the substantial increases we observed in pancreatectomized dogs (n = 7) with pancreatic autografts that drained into the systemic circulation (SD). In these dogs, the tissue samples were taken at the age of 3 to 4 years. Triglyceride content (mean +/- SEM) in the aorta was 4.9 +/- 1.2 versus 2.6 +/- 0.6 versus 20.7 +/- 8.0 mumol/g (P less than .01) in C, PD, and SD models, respectively. The corresponding values for triglyceride content in striated muscles were 29.1 +/- 1.2, 25.9 +/- 1.5, and 171.4 +/- 46.6 mumol/g (P less than .01). Glucose-6-phosphate dehydrogenase (G-6-PDH) and malic enzyme, key enzymes for lipid synthesis, were also normal in the PD model, in contrast to the fivefold increased activity of these enzymes in the SD model (P less than .01). The glycolytic enzymes, hexokinase (HK) and phosphofructokinase (PFK), were normal compared with the decreased values in the SD. These data indicate that it is possible to normalize glucose and lipid metabolism in arterial walls by portal delivery of insulin, following intrahepatic islet cell transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

In vitro and in vivo potency of insulin analogues designed for clinical use.

Analogues of human insulin designed to have improved absorption properties after subcutaneous injection have been prepared by recombinant DNA technology. Five rapidly absorbed analogues, being predominantly in mono- or di-meric states in the pharmaceutical preparation, and a hexameric analogue with very low solubility at neutral pH and slow absorption, were studied. Receptor binding assays with HEP-G2 cells showed overall agreement with mouse free adipocyte assays. Two analogues, B28Asp and A21Gly + B27Arg + B30Thr-NH2, had nearly the same molar in vitro potency as human insulin. Another two showed increased adipocyte potency and receptor binding, B10Asp 194% and 333% and A8His + B4His + B10Glu + B27His 575% and 511%, while B9Asp + B27Glu showed 29% and 18% and the B25Asp analogue only 0.12% and 0.05% potency. Bioassays in mice or rabbits of the analogues except B25Asp showed that they had the same in vivo potency as human insulin 1.00 IU = 6.00 nmol. Thus the variation had the same in vivo potency as human insulin 1.00 IU = 6.00 nmol. Thus the variation in in vivo potency reflects the differences in receptor binding affinity. Relative to human insulin a low concentration is sufficient for a high affinity analogue to produce a given receptor complex formation and metabolic response. In conclusion, human insulin and analogues with markedly different in vitro potencies were equipotent in terms of hypoglycaemic effect. This is in agreement with the concept that elimination of insulin from blood and its subsequent degradation is mediated by insulin receptors.

Adipose Tissue↗
PubMed1991

Intravenous insulin infusion to simulate subcutaneous absorption. Bioavailability and metabolic sequelae.

OBJECTIVE: To determine the bioavailability and bioactivity of subcutaneously injected insulin. RESEARCH DESIGN AND METHODS: A randomized block design with six male mongrel dogs as subjects. In protocol 1, purified pork insulin was infused intravenously to simulate the pattern of appearance in the blood that would have been expected from subcutaneous injection. Three intravenous doses (0.05, 0.10, and 0.15 U/kg) were infused on separate days in a pattern (0-300 min) designed to approximately simulate the absorption rate of subcutaneously injected insulin. In protocol 2, interscapular subcutaneous injections of pork insulin at 0.10 U/kg were made. RESULTS: Integrated insulin, decrement in plasma glucose, and maximal glucose clearance for subcutaneous injection experiments were similar to intravenous infusion of equal dose (P greater than 0.10) but significantly different from low-dose infusions (P less than 0.025). Similar results were observed for hepatic glucose output and glucose uptake. Hypoglycemia elicited counterregulatory responses that appeared to be under a threshold differentiated at a plasma glucose of approximately 3 mM. Integrated insulin was plotted against insulin dose to create dose-response curves for intravenous data. The curve was then used to predict the actual appearance rate of insulin in plasma for subcutaneous injection. The estimated bioavailability of subcutaneous insulin was 103.0 +/- 10.5% of the injected dose. CONCLUSIONS: We concluded that, in dogs, insulin delivered subcutaneously in the interscapular area is not significantly degraded before absorption, resulting in metabolic effects equal to intravenous insulin infusion of equivalent dose.

Animals↗
PubMed1991

Absorption kinetics and action profiles of subcutaneously administered insulin analogues (AspB9GluB27, AspB10, AspB28) in healthy subjects.

OBJECTIVE: The subcutaneous absorption and resulting changes in plasma insulin or analogue, glucose, C-peptide, and blood intermediary metabolite concentrations after subcutaneous bolus injection of three soluble human insulin analogues (AspB9GluB27, monomeric; AspB28, mixture of monomers and dimers; and AspB10, dimeric) and soluble human insulin were evaluated. RESEARCH DESIGN AND METHODS: Fasting healthy male volunteers (n = 7) were studied on five occasions 1 wk apart randomly receiving 0.6 nmol.kg-1 s.c. 125I-labeled AspB10 or soluble human insulin (Novolin R, Novo, Copenhagen); 1st study and 0.6 nmol.kg-1 s.c. 125I-labeled AspB28, AspB9GluB27 or soluble human insulin (2nd study). Residual radioactivity at the injection site was measured over 8 h with frequent venous sampling for plasma immunoreactive insulin or analogue, glucose, C-peptide, and blood intermediary metabolite concentrations. RESULTS: The three analogues were absorbed 2-3 times faster than human insulin. The mean +/- SE time to 50% residual radioactivity was 94 +/- 6 min for AspB10 compared with 184 +/- 10 min for human insulin (P less than 0.001), 83 +/- 8 min for AspB28 (P less than 0.005), and 63 +/- 9 min for AspB9GluB27 (P less than 0.001) compared with 182 +/- 21 min for human insulin. delta Peak plasma insulin analogue levels were significantly higher after each analogue than after human insulin (P less than 0.005). With all three analogues, the mean hypoglycemic nadir occurred earlier at 61-65 min postinjection compared with 201-210 min for the reference human insulins (P less than 0.005). The magnitude of the hypoglycemic nadir was greater after AspB9GluB27 (P less than 0.05) and AspB28 (P less than 0.001) compared with human insulin. There was a significantly faster onset and offset of responses in C-peptide and intermediary metabolite levels after the analogues than after human insulin (P less than 0.05). CONCLUSIONS: The rapid absorption and biological actions of these analogues offer potential therapeutic advantages over the current short-acting neutral soluble insulins.

3-Hydroxybutyric Acid↗
PubMed1991

Subcutaneous insulin absorption explained by insulin's physicochemical properties. Evidence from absorption studies of soluble human insulin and insulin analogues in humans.

OBJECTIVE: To study the influence of molecular aggregation on rates of subcutaneous insulin absorption and to attempt to elucidate the mechanism of absorption of conventional soluble human insulin in humans. RESEARCH DESIGN AND METHODS: Seven healthy male volunteers aged 22-43 yr and not receiving any drugs comprised the study. This study consisted of a single-blind randomized comparison of equimolar dosages of 125I-labeled forms of soluble hexameric 2 Zn2+ human insulin and human insulin analogues with differing association states at pharmaceutical concentrations (AspB10, dimeric; AspB28, mixture of monomers and dimers; AspB9, GluB27, monomeric). After an overnight fast and a basal period of 1 h, 0.6 nmol/kg of either 125I-labeled human soluble insulin (Actrapid HM U-100) or 125I-labeled analogue was injected subcutaneously on 4 separate days 1 wk apart. Absorption was assessed by measurement of residual radioactivity at the injection site by external gamma-counting. RESULTS: The mean +/- SE initial fractional disappearance rates for the four preparations were 20.7 +/- 1.9 (hexameric soluble human insulin), 44.4 +/- 2.5 (dimeric analogue AspB10), 50.6 +/- 3.9 (analogue AspB28), and 67.4 +/- 7.4%/h (monomeric analogue AspB9, GluB27). Absorption of the dimeric analogue was significantly faster than that of hexameric human insulin (P less than 0.001); absorption of monomeric insulin analogue AspB9, GluB27 was significantly faster than that of dimeric analogue AspB10 (P less than 0.01). There was an inverse linear correlation between association state and the initial fractional disappearance rates (r = -0.98, P less than 0.02). Analysis of the disappearance data on a log linear scale showed that only the monomeric analogue had a monoexponential course throughout. Two phases in the rates of absorption were identified for the dimer and three for hexameric human insulin. The fractional disappearance rates (%/h) calculated by log linear regression analysis were monomer 73.3 +/- 6.8; dimer 44.4 +/- 2.5 from 0 to 2 h and 68.9 +/- 3.5 from 2.5 h onward; and hexameric insulin 20.7 +/- 1.9 from 0 to 2 h, 45.6 +/- 5.0 from 2.5 to 5 h, and 70.6 +/- 6.3 from 5 h onward. CONCLUSIONS: Association state is a major determinant of rates of absorption of insulin and insulin analogues. The lag phase and the subsequent increasing rate of subcutaneous soluble insulin absorption can be explained by the associated state of native insulin in pharmaceutical formulation and its progressive dissociation into smaller units during the absorption process.

Absorption↗
PubMed1991

Comparison of subcutaneous soluble human insulin and insulin analogues (AspB9, GluB27; AspB10; AspB28) on meal-related plasma glucose excursions in type I diabetic subjects.

OBJECTIVE: To compare postprandial glucose excursions and plasma free insulin-analogue levels after subcutaneous injection of three novel human insulin analogues (AspB10; AspB9, GluB27; and AspB28) with those after injection of soluble human insulin (Actrapid HM U-100). RESEARCH DESIGN AND METHODS: Six male subjects with insulin-dependent diabetes, at least 1 wk apart and after an overnight fast and basal insulin infusion, received 72 nmol (approximately 12 U) s.c. of soluble human insulin 30 min before, or 72 nmol of each of the three analogues immediately before, a standard 500-kcal meal. RESULTS: Mean basal glucoses were similar on the 4 study days. Compared to human insulin (6.3 +/- 0.8 mM), mean +/- SE peak incremental glucose rises were similar after analogues AspB10 (5.4 +/- 0.8 mM) and AspB9, GluB27 (5.4 +/- 0.7 mM) and significantly lower after analogue AspB28 (3.6 +/- 1.2 mM, P less than 0.02). Relative to soluble human insulin (100% +/- SE21), incremental areas under the glucose curve between 0 and 240 min were 79% +/- 34 (AspB10, NS), 70% +/- 29 (AspB9, GluB27, NS), and 43% +/- 23 (AspB28, P less than 0.02). Basal plasma free insulin levels were similar on the 4 study days. Plasma free insulin-analogue levels rose rapidly to peak 30 min after injection at 308 +/- 44 pM (AspB10); 1231 +/- 190 pM (AspB9, GluB27) and 414 +/- 42 pM (AspB28) and were significantly higher than corresponding (i.e., 30 min postmeal) plasma free insulin levels of 157 +/- 15 pM (P less than 0.02 in each case). CONCLUSIONS: Plasma profiles of the insulin analogues were more physiological than that of human insulin after subcutaneous injection. All three analogues given immediately before the meal are at least as effective as soluble human insulin given 30 min earlier. These analogues are promising potential candidates for short-acting insulins of the future.

Adult↗
PubMed1991

Nitrendipine once or twice daily in hypertensive non-insulin-dependent diabetes mellitus.

Twenty (12 male, 8 female) hypertensive patients were recruited into the study; their mean (+/- SD) sitting blood pressure (BP) was 166 +/- 13/101 +/- 4 mm Hg, age 59.6 +/- 5.8 years, weight 83.4 +/- 14.2 kg, and glycosylated hemoglobin (HbA1) 9.9 +/- 2.6%. After a run-in period of 4 weeks, patients were randomized to receive nitrendipine once or twice daily, with 15 patients completing the 12-week study period. Prior to treatment with nitrendipine, the patients subsequently treated on a twice-daily regimen had a higher sitting systolic BP (SBP) of 173 +/- 15 mm Hg compared to the once-daily patient group at 159 +/- 7 mm Hg (p less than 0.05). There were no differences between the two treatment groups in weight or diabetes control. Once-daily nitrendipine effectively reduced the sitting SBP and diastolic BP (DBP), i.e., SBP fell from 159 +/- 7 to 147 +/- 12 mm Hg (p less than 0.05) and DBP fell from 100 +/- 4 to 86.3 +/- 8 mm Hg (p less than 0.001). Nonsignificant reductions in weight from 81.5 +/- 11.3 to 80.9 +/- 11.2 kg and HbA1 from 9.8 +/- 3.3 to 8.4 +/- 1.3% were also seen. Similarly, with twice-daily nitrendipine, a significant (p less than 0.01) fall in sitting systolic BP from 173 +/- 15 to 148 +/- 9 mm Hg and DBP 103 +/- 4 to 85 +/- 8 mm Hg was also achieved. Little or no change was observed in weight or glycemic control in this patient group.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1990

Monomeric insulins and their experimental and clinical implications.

Due to the inherent pharmacokinetic properties of available insulins, normoglycemia is rarely, if ever, achieved in insulin-dependent diabetic patients without compromising their quality of life. Subcutaneous insulin absorption is influenced by many factors, among which the associated state of insulin (hexameric) in pharmaceutical formulation may be of importance. This review describes the development of a series of human insulin analogues with reduced tendency to self-association that, because of more rapid absorption, are better suited to meal-related therapy. DNA technology has made it possible to prepare insulins that remain dimeric or even monomeric at high concentration by introducing one or a few amino acid substitutions into human insulin. These analogues were characterized and used for elucidating the mechanisms involved in subcutaneous absorption and were investigated in preliminary clinical studies. Their relative receptor binding and in vitro potency (free-fat cell assay), ranging from 0.05 to 600% relative to human insulin, were strongly correlated (r = 0.97). In vivo, most of the analogues exhibited approximately 100% activity, explainable by a dominating receptor-mediated clearance. This was confirmed by clamp studies in which correlation between receptor binding and clearance was observed. Thus, an analogue with reduced binding and clearance gives higher circulating concentrations, counterbalancing the reduced potency at the cellular level. Absorption studies in pigs revealed a strong inverse correlation (r = 0.96) between the rate of subcutaneous absorption and the mean association state of the insulin analogues. These studies also demonstrated that monomeric insulins were absorbed three times faster than human insulin. In healthy subjects, rates of disappearance from subcutis were two to three times faster for dimeric and monomeric analogues than for human insulin. Concomitantly, a more rapid rise in plasma insulin concentration and an earlier hypoglycemic response with the analogues were observed. The monomeric insulin had no lag phase and followed a monoexponential course throughout the absorption process. In contrast, two phases in rate of absorption were identified for the dimer and three for the normal hexameric human insulin. The initial lag phase and the subsequent accelerated absorption of soluble insulin can now be explained by the associated state of native insulin in pharmaceutical formulation and its progressive dissociation into smaller units during the absorption process. In the light of these results, the effects of insulin concentration, injected volume, temperature, and massage on the absorption process are now also understood.(ABSTRACT TRUNCATED AT 400 WORDS)

Diabetes Mellitus, Type 1↗