Possible dietary factors in the induction of diabetes and its inheritance in man, with studies in mice.
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Biomedical subjects
Publications and source records attributed to J M Stowers.
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In a study of 10 diabetic patients, each of whom was in a severely decompensated state, notable alteration of blood flow properties was observed in those six patients who were hyperosmolar. In this form of diabetic decompensation, whole blood filtration was distinctly impaired. The additional impairment was shown to be due to an accumulation of solute within the erythrocytes occurring as a consequence of hyperosmolarity. The alterations in erythrocytes were revealed by Coulter blood count abnormalities and confirmed by osmotic fragility studies. When biochemical improvement was achieved in these patients, rapid resolution of the erythrocyte abnormalities occurred. Microvascular ischaemia due to such erythrocyte alterations may be a possible explanation for the characteristic cerebral disturbances of the hyperosmolar diabetic state. Altered blood flow properties would also promote vascular thrombosis, a common terminal event in the hyperosmolar non-ketotic syndrome with associated 50 per cent mortality. An improved design of the insulin and fluid replacement therapy for patients in hyperosmolar diabetic coma might be based on the findings of these and further studies.
One hundred twelve women with impaired glucose tolerance (IGT) diagnosed by intravenous glucose tolerance test (IVGTT) after pregnancy were followed up for a period of up to 22 yr (mean 12.9 yr). About one-third have been treated with chlorpropamide and the others by diet only. At the final assessment, approximately 35% had abnormal intravenous glucose tolerance and less than 7% overt diabetes. Chlorpropamide did not prove significantly more effective than diet only. Factors associated with deterioration in glucose tolerance were age at diagnosis and follow-up and the initial fasting plasma glucose (FPG) level (greater than or equal to 5.8 mM), but obesity was less important, although it was associated with an increased rate of vascular complications. Tests for islet cell antibodies (ICA) were weakly positive in 12.5% of 72 subjects and in only 0.5% of an unselected population; they did not correlate with the final state of glucose tolerance. Only three patients developed insulin-dependent diabetes (IDDM) and did so before the ICA study was started. A comparison is made between the results reported by O'Sullivan in patients diagnosed as having gestational diabetes, only 2% of whom still had abnormal oral glucose tolerance postpartum, and the results of our patients, all of whom had IGT after pregnancy. In spite of differences of technique and in the populations studied, the prevalence of IGT and overt diabetes at follow-up was significantly less in the Aberdeen series, who were initially a higher risk group. It seems probable that this is mainly attributable to dietary treatment in the follow-up period as O'Sullivan's cases were treated only during pregnancy.
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Antibodies to insulin were found in 92% of the 138 insulin-treated pregnant diabetic patients studied. No effect of pregnancy was shown on insulin antibody levels. Higher insulin antibody levels were significantly associated with the previous use of conventional insulins. Change from conventional to highly purified porcine insulin during pregnancy produced a significant reduction in insulin antibody levels. The combination of protamine zinc and soluble insulin used before pregnancy was found to be the most immunogenic. Insulin antibodies were freely transferred to the fetus but not detectable after the first 8 months of life. No insulin antibodies were found in the cord blood or during the next few weeks in the infants of mothers who had no antibodies to their injected insulin. There was a tendency for higher insulin antibody levels to be associated with indices of neonatal morbidity but not with percentile birth weights and C-peptide levels in cord sera.
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There is circumstantial evidence of a causal connection between type 1 diabetes in young Icelandic males and consumption of smoked cured mutton, containing N-nitroso compounds, by their parents at about the time of conception. This hypothesis has been examined in CD1 mice, and such processed mutton, consumed by the parents before mating and during pregnancy and by the offspring from day 19 until study 1-5 weeks later, produced diabetes in just over 16% of male progeny and 4.2% of female progeny. Light and electron-microscopic changes in the beta-cells were those of stages of cell death. The parent mice showed no features of diabetes. When both parents were fed the Icelandic cured mutton only up to the time of fertilisation, there was first a fall and then a significant rise in the plasma glucose of the male progeny after the 3rd week of age. The female progeny showed a significant fall in plasma glucose at 5-6 weeks of age. These findings suggest that an environmental factor in the aetiology of human diabetes mellitus had been identified. The mechanism seems to involve parental as well as maternal influences of germ cells.
In 9 patients with juvenile-onset chemical diabetes treated with oral chlorpropamide, oral or intravenous assessments of carbohydrate tolerance were made regularly three weeks after withdrawal of therapy. 6 patients with sequential intravenous tests achieved statistically significant reversal of their carbohydrate intolerance and have remained normal for an average of 5.6 years (range 1-11 years). 2 patients who subsequently required insulin therapy were maintained in remission for 3.5 years and 5 years, respectively. There appears to be a group of young patients with chemical diabetes who achieve significant remission with sulphonylurea therapy.
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A new and specific method is used for the measurement of plasma free fatty acids (FFA) in pregnancy. Fasting plasma FFA and glucose concentrations were measured serially in twenty normal and twelve overweight women in pregnancy and related to infant birth weight. Large variation between individuals was noted for FFA and no change was found with advancing gestation. Studies of the day-to-day variation in the same women at 20 and 36 weeks gestation showed wide variations in concentrations. No significant change in glucose concentration was noted with advancing gestation, but postnatal values were significantly higher. Small variability of glucose concentrations was noted in both the serial and day-to-day studies. In normal-weight women a positive correlation between the observed birth weight of their infants and the fasting plasma glucose levels was found at 20 and 40 weeks and also with the mean of 5 levels measured in pregnancy. No similar correlation was found for the group of overweight women.
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Glibornuride is an addition to the second-generation sulphonylureas, that has been shown in clinical trials to be effective and non-toxic. Twenty-three diabetics who were poorly controlled on other oral hypoglycaemic agents and seven newly diagnosed diabetics were treated with glibornuride. The efficacy and lack of toxicity of this drug was confirmed, but there was no evidence to suggest that it is significantly more potent than other sulphonylureas. It does not seem to represent a significant therapeutic advance.
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