Åke Nordén

Ten-year Follow-up of Subjects with Impaired Glucose Tolerance: Prevention of Diabetes by Tolbutamide and Diet Regulation

In a diabetes detection survey carried out between 1962 and 1965, 2477 (1.1%) of 228,883 subjects had Clinistix-positive glucosuria after a carbohydrate-rich luncheon meal. Of these 2477, 578 displayed impaired tolerance to oral glucose without having manifest diabetes. From this group, 267 men were divided into five groups and subjected to the following treatments and controls: (a) diet regulation and 0.5 g tolbutamide t.i.d. (N = 49), annual oral glucose tolerance test (OGTT); (b) diet regulation and one placebo tablet t.i.d. (N = 48), annual OGTT; (c) diet regulation only (N = 50), annual OGTT; (d) no treatment (N = 61), annual OGTT; and (e) no treatment, OGTT at follow-up (N = 59 at follow-up). In addition, a control group was included comprised of men with normal OGTT (N = 52). At follow-up, 29% of those without diet regulation and medication (group e; N = 59) had developed diabetes. Of those on diet regulation, but without active medication (group b plus group c, N = 98), 13% had diabetes. No individual maintaining tolbutamide and diet regulation (N = 23) had progressed to diabetes. In this group, 80% of those later examined (N = 11) had serum tolbutamide concentrations in the therapeutic range. No individual with initially normal OGTT developed diabetes or impaired OGTT. The findings suggest that normal oral glucose tolerance signifies little risk of progress to impaired glucose tolerance and manifest diabetes, whereas impaired glucose tolerance is associated with a high risk of progression to diabetes. In addition, it seems possible that treatment with diet regulation, in combination with tolbutamide, may prevent or postpone progression from impaired glucose tolerance to manifest diabetes.

Interindividual variation in the responses of cultured human lymphocytes to exposure from DNA damaging chemical agents: Interindividual variation to carcinogen exposure

Human population variability to standardized doses of N-acetoxy-2-acetylaminofluorene (NA-AAF) and 7, 12-dimethylbenz(a) anthracene (DMBA) was determined in cultured lymphocytes by measuring (a) differential stimulation of unscheduled DNA synthesis after 1 h induction of DNA damage by 10 micrometer NA-AAF, (b) the level of NA-AAF induced chromosome aberrations remaining after 8 h of DNA-repair synthesis, and (c) the level of [3H]DMBA bound to DNA after 18 h incubation of resting lymphocytes in 5 micrometer DMBA. All 3 parameters indicated individual variation to carcinogen exposure and were correlated to the population differences in age, sex, blood pressure and mortality rates. Males always had a greater potential to accumulate DNA-damage than did females regardless of the sampled population. DNA-damage potentials increased with increasing age, blood pressure or mortality rates. There was always proportionally greater DNA-damage potentials in the males than in females. The in vitro response of mature granulocytes to a 10 micrometer NA-AAF dose, as estimated by [3H] thymidine incorporation from unscheduled DNA synthesis, was much lower than lymphocyte response. Nevertheless, individual variations in granulocyte NA-AAF induced unscheduled DNA synthesis paralleled the inter-individual fluctuations observed in the lymphocyte responses to NA-AAF.

The periodate-Schiff reaction: specificity, kinetics, and reaction products with pure substrates.

A quantitative test-tube method has been used to study the periodate-Schiff reaction of a number of pure substances. The rate of reaction, the amount of color produced, and in some cases the amount of periodate consumed, have been measured. The dye produced by different carbohydrates has been analyzed by spectrophotometry and paper chromatography. Glycogen, starch and dextran reacted slowly and produced much less color than the corresponding amount of free monosaccharides. Oligosaccharides and heteropolysaccharides were either periodate-Schiff-negative or very weakly positive. Proteins and nucleic acids were negative. There was no simple relation between the intensity of the periodate-Schiff reaction and the amount of periodate consumed or the amount of aldehyde groups formed on the oxidation by periodate. The dyes formed with different carbohydrates had essentially the same absorption curve, but differed in their chromatographic mobility.

Purification of the mitosis-stimulating factor from Phaseolus vulgaris

Abstract The mitosis-stimulating factor from the phytohaemagglutinin of red kidney beans ( Phaseolus vulgaris ) has been purified by: (1) extraction of the beans with phosphate buffer; (2) removal of inert proteins by heat coagulation at 80° for 10 min; (3) ethanol fractionation at 2° at pH 6.8; (4) column chromatography on calcium phosphate. The material finally obtained was of protein or polypeptide nature and contained 6% carbohydrate. Maximal number of mitosis was induced in cultures of growing lymphocytes with only 0.2 μg/ml culture medium. The haemagglutinating property was still present but could be removed by adsorption with red blood cells without any detectable loss of the mitosis-stimulating activity.

A genetic component of the variance of N-acetoxy-2-acetylaminofluorene-induced DNA damage in mononuclear leukocytes determined by a twin study.

SummaryThe level of N-acetoxy-2-acetylaminofluorene (NA-AAF)-induced unscheduled DNA synthesis and the level of covalent binding of NA-AAF to DNA were determined in the mononuclear leukocytes of monozygotic and diazygotic twin pairs (n=16 for each type). A statistically significant high degree of heritability was calculated for both parameters which, in turn, indicate genetic control of individual levels of induced DNA damage by NA-AAF.

Changes in the deoxyadenylate regions in 5 cases of chronic lymphocytic leukemic DNA

Abstract The (dA) levels in the DNAs from normal human tissues and from the lymphocytes of five CLL patients were estimated by formation of ribonuclease A-resistant poly (U)-DNA complexes. Alterations in the (dA) levels of all five CLL DNAs were observed when comparison was made to the normal (dA) pattern. The type of (dA) alterations varied among the different CLL patients, but the variation correlated to the WBC levels of the patients at the time of study. A specificity of neoplastic-associated (dA) alterations for slow repeated + unique DNA sequences and for main band DNA was demonstrated with two of the CLL DNAs.

The effect of an individual's blood pressure on the percentage of total 7,12-dimethylbenz[a]anthracene metabolites that bind covalently to DNA in cultured resting lymphocytes

A method for the quantitative analysis of the percent metabolism that results in covalent binding of 7,12-dimethylbenz[a]anthracene (DMBA) to DNA in viable resting human lymphocytes is described. The inter- and intra-experimental reproducibility as judged by the coefficient of variation and examined in the same individual over a 3-month period was 31.4% and 13.9%, respectively. When the lymphocytes from 30 hypertensive individuals were exposed to 1 microM DMBA for 18 h, the percent of total DMBA metabolites that bind DNA covalently was correlated to the blood pressures of the patients at the time of sampling (r = 0.53, P less than 0.005). No influences on the data from the type or duration of hypertensive drug treatment could be statistically determined for this sample of hypertensive patients. It was concluded that high blood pressure is a strong determinant in predisposing lymphocytes to increased genetic risk from induced DNA damage and that this relationship is not statistically affected by hypertensive drug therapy.

Studies in subjects with positive postprandial Clinistix test. II. Serum insulin-like activity (SILA) in non-diabetic glucosurics.

. In a diabetes detection survey based on postprandial Clinistixr testing, 2477 out of 228,833 participants (1.08%) reacted positively. In 2180 a 3-hour oral glucose tolerance test was performed. Diagnostic criteria for diabetes were established in a random sample from the same population matched in age and sex. The controls were healthy and had no known heredity for diabetes. The requirement for a diagnosis of diabetes was that all 10 capillary blood sugar values during the tolerance test should exceed the corresponding mean plus 3 S.D. for the control group. Likewise a normal tolerance was only considered present when none of the 10 values reached the mean plus 2 S.D. for the control group. A diagnosis of diabetes was made in 538 subjects, i.e. 0.2% of the population under study. Fasting SILA values in 16 normal men less than 50 years of age showed a mean of 94 μU per ml. and in 12 men more than 50 a mean value of 83 μU per ml was found. Fasting SILA values in eight normal women less than 50 showed a mean of 34 μU per ml, and in nine women more than 50 a mean of 75 μU per ml was found. The low value in women less than 50 was significantly different (p <0.001) from the male group and also from values found in women more than 50 years of age (p<0.01). Fasting SILA in 16 men and 14 women with newly discovered diabetes and age more than 50 showed all values in the normal range. Three diabetic women less than 50 had 50, 61, and 146 μU per ml. SILA during the glucose tolerance test in six patients with diabetes showed a subnormal response in all of them. SILA during the glucose tolerance test in five subjects considered diabetics by conventional criteria, but not according to our criteria, showed a normal response. Fasting serum corticosteroids in six diabetic subjects were significantly higher than in five controls. Serum corticosteroids during the glucose tolerance test dropped to the same base level both in the diabetic and in the normal group.

A Reference Population: For the Evaluation of Natural Occurring Interindividual Variation in the Response to Genotoxic Agents

A reference population is theoretically a “normal population” with which any other population suspected to be exposed to genotoxic or other unwarranted environmental factors can be compared for the evaluation of health hazards.