Biomedical subjects
Publications and source records attributed to R J Jarrett.
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An epidemiological study was carried out to compare the prevalence of facial flushing in non-diabetics, patients with insulin dependent diabetes, and patients with non-insulin dependent diabetes in response to 40 ml sherry taken 12 hours after 250 mg chlorpropamide or placebo, administered double blind in randomised order. A flush after chlorpropamide but not placebo was reported by 6.2% of non-diabetics (17/273), 9.7% of insulin-dependent diabetics (14/145), and 10.5% of non-insulin dependent diabetics (25/239), excluding those receiving long term chlorpropamide treatment. The differences were not significant. This response was unrelated to age, sex, body mass index, and family history of diabetes in all three groups. Patients taking long term chlorpropamide, however, showed a significantly (p less than 0.01) higher prevalence of flushing after both chlorpropamide and placebo (56.3%; 9/16) compared with the rest of the non-insulin dependent diabetics (16.7%; 40/239), the insulin dependent diabetics (6.9%; 10/145), and the non-diabetics (5.9%; 16/273). Patients receiving long term chlorpropamide would be expected to flush with sherry after a placebo tablet because of therapeutic plasma concentrations of the drug. It is concluded that there is no evidence of an increased prevalence of chlorpropamide alcohol flushing in response to the single challenge test in non-insulin dependent diabetics compared with insulin dependent diabetics and non-diabetics except in selected patients taking chlorpropamide long term. This study does not support the hypothesis that the chlorpropamide alcohol flush is a specific marker for a subtype of non-insulin dependent diabetes.
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In the Whitehall study of 18 403 male civil servants aged 40-64 years the 10 year mortality rates from coronary heart disease and stroke showed a non-linear relation to two hour blood glucose values, with a significantly increased risk for glucose intolerant subjects with concentrations above the 95th centile point (5.4-11.0 mmol/l; 96-199 mg/100 ml) and for diabetics (blood glucose greater than or equal to 11.1 mmol/l; greater than or equal to 200 mg/100 ml). Multiple logistic analysis showed that between one half and three quarters of the relative risks for deaths from coronary heart disease and stroke were "unexplained" by between group differences in risk factors such as age, blood pressure, obesity, smoking, cholesterol concentration, and electrocardiographic abnormalities. Within the glucose intolerant and diabetic groups the risk factors most strongly related to subsequent death from coronary heart disease were age and blood pressure, with less consistent relations for smoking, cholesterol concentration, and obesity. This study confirms the importance of hypertension as a cardiovascular risk factor in groups with glucose intolerance and diabetes, and this may have important preventive implications.
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After the Bedford Survey observations were made upon retina and lens in borderline diabetics (persons with impaired glucose tolerance) and in age and sex matched controls with normal glucose tolerance. Seven years after the Survey, the prevalence of retinal abnormalities ("microaneurysms" and "exudates") was similar in each group. Of 145 initially borderline diabetics examined 10 years after the Survey, 25 had worsened to diabetes. Only two of the total group had "micro-aneurysms" present and the maximum recorded in any eye was three. Lens opacities were of similar frequency in both groups shortly after the Survey and at the seven year follow-up examination. By contrast, 24% of 79 diabetics newly diagnosed during the Survey had "microaneurysms" recorded five years later. These results further justify the diagnostic category of impaired glucose tolerance, which, at least when discovered by population screening, carries no risk of clinically apparent eye disease for at least ten years after ascertainment.
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Ten-year mortality rates in men aged 40-64 years in the Whitehall Study were analysed in relation to weight and height at the initial examination. At ages 40-49 "all-causes" mortality increased with increasing body mass index; but this simple relation disappeared at older ages, where there was an increased mortality in the lowest quintile of body mass index. The "all-ages" relation was "J"-shaped, and this could not be explained by the confounding effects of blood pressure, cholesterol values, and cigarette smoking. Some, but not all, of the J shape was due to a high short-term mortality in thin men from cancers (presumably already present at examination). At younger ages mortality from coronary heart disease was positively related to body mass index, but this depended on its association with other risk factors. Mortality from causes other than cancers or coronary heart disease was highest in the lowest quintile of body mass index.
The overnight urinary albumin excretion rate (AER) of 87 patients with insulin-dependent diabetes mellitus was measured in 1966-67, 14 years later information was obtained on 63 of the original cohort; those alive were restudied, and for those who had died relevant clinical information and case of death were recorded. The development of clinical diabetic nephropathy ('Albustix'positive proteinuria) was related to the 1966-67 AER values. Clinical proteinuria developed in only 2 of 55 patients with AER below 30 microgram/min but in 7 of 8 with AER between 30 and 140 microgram/min. The risk of clinical diabetic nephropathy in the latter group was twenty-four time higher than inthe former. 9.1% of patients with AER below 30 microgram/min had died, compared with 37.5% with higher AER. The two groups did not differ significantly in age, sex composition, and initial blood pressure. Mean duration of diabetes was longer, but not significantly so, in those with AER above 30 microgram/min. Thus, elevated levels of microalbuminuria strongly predict the development of clinical diabetic nephropathy. These levels of AER are potentially reversible, and their detection and treatment may prevent diabetic renal disease.
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In a 10-year prospective study of 241 people with 'borderline diabetes' (impaired glucose tolerance) identified by screening of the Bedford adult population, 36 (15%) worsened to diabetes and 128 (53%) substantially improved their glucose tolerance. The major predictor of worsening to diabetes was the level of blood glucose at baseline. This was statistically significant (p less than 0.05), independent of other factors, both for deterioration in the first and in the second five years of observation. Body mass index, a measure of adiposity, did not predict worsening to diabetes during the first five years, but was an independent and significant predictor of worsening during the second five years (p less than 0.05). The apparent effect of adiposity was complex, for it was also significantly related to improvement in glucose tolerance during the 10-year follow-up. Persons with impaired glucose tolerance are a heterogeneous group and with present knowledge the ability to predict metabolic deterioration is limited.
Mortality rates from coronary heart disease and from all causes have been ascertained over ten years in three groups of people participating in the Bedford Survey--newly-diagnosed diabetics, borderline diabetics and control subjects with normal glucose tolerance. Age corrected mortality rates, from all causes and coronary heart disease, were highest in the diabetics and intermediate in the borderline diabetics and in both groups were similar in men and women. When statistical allowance was made for baseline differences in age, blood pressure and obesity, female borderline diabetics still had a significantly increased risk over their controls of death from 'all causes'. Much of the difference appeared to be due to a relative excess of deaths due to coronary heart disease. It is concluded that borderline diabetes (or impaired glucose tolerance) is associated with a relatively greater increase in mortality risk in women than men. During the 10-year follow-up of the Bedford borderline diabetics, coronary heart disease morbidity and mortality rates were similar in men and women. Age at entry to the study was the major independent and significant predictor of mortality from all causes. The level of systolic blood pressure and current cigarette smoking at baseline were statistically significant predictors only of mortality due to coronary heart disease.
In a multinational study, fasting plasma glucose values in 3583 diabetic patients, aged 34-56 years, were related to the characteristics of these subjects and to the presence and severity of microangiopathy as ascertained by standardised methods. The patients were from nine different populations and ranged in number from 193 to 686 per population (London, Warsaw, Berlin (FRG), New Delhi, Tokyo, Havana, Oklahoma Indians, Arizona Pima Indians, and a national sample in Switzerland). In the total group, mean fasting plasma glucose was 8.1 mmol/l for those on diet alone, 9.7 mmol/l for those on oral agents, and 12.7 mmol/l for insulin-treated patients, of whom 25% had values exceeding 16.5 mmol/l. Since many variables were measured in each patient, it was possible to take into account many confounding factors in evaluating the relationship of plasma glucose levels to retinopathy and nephropathy.
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The urinary excretion of albumin and beta 2-microglobulin in response to two different types of oral water load was studied in 18 healthy subjects. Both acute water loading (1 litre of tap water given over 10 min) and chronic water loading (250 ml of water given every 20 min for the 4-h duration of the test) produced a short-lived but significant increase in the urinary excretion of albumin, but not in beta 2-microglobulin. Albumin excretion returned promptly to basal values in spite of high and sustained urine flow. The decrease in haematocrit, plasma osmolality, plasma sodium concentration and pulse rate and the increase in creatinine clearance suggest that the elevation in albumin excretion might be the result of a transient volume expansion associated with an increase in glomerular filtration rate and in filtration of albumin. However, a washout of proteins from the tubular lumen with preferential reabsorption of small molecular weight proteins (i.e. beta 2-microglobulin) during high tubular flow cannot be excluded. Studies investigating changes in urinary albumin excretion should be performed after baseline conditions of stable urinary excretion of albumin have been established.
Blood glucose and plasma insulin levels during a 50 g oral glucose tolerance test were measured in a population sample of 220 people (109 men; 111 women), who also earlier recorded their diet over a 2-d period. In the men, but not the women, there was a statistically significant inverse relationship between total daily energy intake and both fasting and post-load plasma insulin concentrations. This correlation, which was independent of the degree of adiposity, may be a confounding factor in epidemiological studies relating plasma insulin levels to subsequent coronary heart disease.
In this paper the general concepts of the relationship between body weight, food intake and susceptibility to vascular disease are re-examined in the light of recent evidence. Several studies suggest that the traditional view of the relationship between mortality and adiposity as direct and linear are mistaken and that the relationship is 'U' shaped with minimal mortality at 'average' rather than 'ideal' weight. Furthermore, the notion that higher levels of food energy intake may be responsible for the enhanced susceptibility to arterial disease are also challenged by those in the lower than the upper ranges of total caloric intake. This may account for some of the anomalous inverse relationships found within countries between food (including fat) intake and arterial disease deaths, findings which have stood for years in irreconcilable contrast with the direct relationship between fat intake and cardiovascular mortality between countries. These apparently paradoxical relationships may be explained by the further unexpected finding of low order but highly significant inverse correlations between food energy intake and adiposity. This has supported the notion of a spectrum of energy conservation/dissipation with the energy conserver storing fat even on low intakes and the dissipator expending a high intake yet remaining lean. Adaptive responses to excess intake and to food deprivation may also be involved in this constitutional variation in energy handling.