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To study the role of nutritional factors in the genesis of diabetes, estimations of blood sugar concentration, food intake, and adiposity (as body mass index; BMI) were carried out on three normal population samples--namely, 961 employees of Beecham Ltd, 1005 employees of the Greater London Council, and 1488 middle-aged male civil servants (Whitehall study). Blood sugar concentrations and indices of glucose tolerance correlated positively with the degree of adiposity but tended to be negatively correlated with total food energy intake and its component nutrients (total carbohydrate, sucrose, and fat). This inverse trend was largely accounted for by highly significant inverse correlations between food energy intake and adiposity, a relation found in both sexes and in all three population samples and which extended across the whole range of nutrient intake and BMI. These findings suggest that greater degrees of adiposity are associated with lower than average food energy intakes and hence lower total energy expenditures. The association of increased adiposity with low food energy consumption may indicate an underlying "low energy throughput" state, and it may be the mechanisms of this, as well as the obesity, that are responsible for disease.

Intravenous glucose tolerance tests (25 g) were performed in the morning and afternoon on 13 apparently normal persons. The individual K values (rate of decline of blood sugar) were all higher in the morning tests, and the mean values were significantly higher in the morning. Fasting blood sugar levels were slightly lower in the afternoon. There was no difference between the fasting morning and afternoon plasma insulin levels, but the levels after glucose were lower in the afternoon. Growth hormone levels were low at all times in non-apprehensive subjects and unaffected by glucose. The results suggest that the impaired afternoon intravenous glucose tolerance, like oral glucose tolerance, is associated with impaired insulin release and insulin resistance.

To study the possible role of an "increased thrombotic tendency" in the vascular complications of diabetes several tests of haemostatic function were carried out on 91 men and 63 women with diabetes aged 35-54 years and the results compared with findings in 686 men and 393 women of the same age in the Northwick Park Heart Study. Mean values for factors VII and X, fibrinogen, and platelet adhesiveness were higher in the diabetics, but mean fibrinolytic activity and whole blood platelet counts were lower. Antithrombin III values were also higher in the diabetics, which may have constituted a protective response to other changes favouring the onset of vascular disease. Diabetics with retinopathy had higher factor VII and antithrombin III values, and those with proteinuria had higher values for factor VII, fibrinogen, and platelet adhesiveness than those without these complications. These findings suggest a potentially important association between a thrombogenic tendency and vascular disease in diabetes. Nevertheless, prospective data are needed to clarify whether the haemostatic abnormalities precede the onset of clinically manifest vascular complications or are a consequence of them.

A five-year therapeutic trial of carbohydrate restriction with or without phenformin (50 mg/day) was performed in men with borderline diabetes. The aim of treatment was to diminish the enhanced risk of cardiovascular disease and deterioration of glucose tolerance. Cardiovascular morbidity and mortality were not significantly affected by any form of treatment, alone or in combination. The predominant risk factor for cardiovascular morbidity and mortality and for overall mortality was the initial blood pressure level. The baseline plasma cholesterol concentration significantly predicted the onset of intermittent claudication. One implication of the results is that hypotensive treatment, supplemented when necessary with hypolipidaemic treatment, may be more effective in preventing the progression of arterial disease in people with mild to moderate glucose intolerance than conventional antidiabetic therapy.

A study was performed to examine the feasibility of achieving long periods of near-normoglycaemia in patients with diabetes mellitus by giving a continuous subcutaneous infusion of insulin solution from a miniature, battery-driven, syringe pump. Twelve insulin-dependent diabetics had their insulin pumped through a subcutaneously implanted, fine nylon cannula; the basal infusion rate was electronically stepped up eightfold before meals. The blood glucose profile of these patients was closely monitored during the 24 hours of the subcutaneous infusion and compared with the profile on a control day, when the patients were managed with their usual subcutaneous insulin. Diet and exercise were standardised on both days. In five out of 14 studies the subcutaneous insulin infusion significantly lowered the mean blood glucose concentration without producing hypoglycaemic symptoms; in another six patients the mean blood glucose concentration was maintained. As assessed by the M value the level of control was statistically improved in six out of 14 studies by the infusion method and maintained in six other patients. To assess the effects of blood glucose control on diabetic microvascular disease it will be necessary to achieve long-term normoglycaemia in selected diabetics. The results of this preliminary study suggest that a continuous subcutaneous insulin infusion may be a means of maining physiological glucose concentrations in diabetics. Though several problems remain--for example, in determining the rate of infusion--longer-term studies with the miniature infusion pumps are now needed.

Twenty-four subjects received three oral glucose tolerance tests, in the morning, afternoon, and evening of separate days. The mean blood sugar levels in the afternoon and evening tests were similar, and they were both significantly higher than those in the morning test. Plasma immunoreactive insulin levels, however, were highest in the morning test. The pattern of insulin levels during the afternoon and evening tests resembled that described as typical of maturity-onset diabetes.

Possible diurnal variation in the blood sugar response to oral glucose was studied by comparing, in the same individuals, the results of oral glucose tolerance tests performed in the morning and the afternoon. In a group of normal individuals the blood sugar levels were significantly higher in the afternoon. In hyperglycaemic individuals the diurnal variation decreased as the blood sugar levels reached during the morning test increased, so that in a group of grossly hyperglycaemic men the mean morning and afternoon tests were almost identical. The causes of this diurnal variation are not known.

Diurnal variation in oral glucose tolerance was studied in 122 male volunteers aged 40 yearsand over who participated in a screening health examination. In those with screening blood sugar levels exceeding 110 mg./100 ml. the degree of diurnal variation was least in those with the highest morning glycaemia; the latter also tended to have lower afternoon fasting bloodsugar levels.In a group of 40 control subjects, afternoon glucose tolerance tests yielded significantly higher post-glucose blood sugar levels. The degree of diurnal variation was significantly and inversely related to the degree of obesity.

The data available from the previous paper have been analysed to determine the interaction between the blood sugar and plasma insulin responses to oral glucose and a number of other biological variables. The total sugar and insulin responses were derived by calculating the total area and the incremental area under the curves.The blood sugar area was significantly correlated with age in both men and women, particularly the former. A striking degree of correlation was found in men between the level of fasting glycerides and the blood sugar area. There was a significant correlation also in women, but this was entirely due to the presence of the older, postmenopausal individuals. A lower degree of correlation was found in both sexes between fasting glycerides and the insulin area.Obesity, as defined by three interrelated factors-ponderal index, triceps fat-fold thickness, and arm girth -was significantly correlated with the insulin area (the association being stronger in the men) and with the blood sugar area only in men.The fasting cholesterol level was correlated with obesity in both sexes but with the blood sugar area and the insulin area only in men.

Oral glucose tolerance tests were performed on 220 people, a representative sample of the employees of a large pharmaceutical company. Blood sugar and plasma immunoreactive insulin levels were measured on each sample of venous blood obtained before and at half-hourly intervals for two hours after 50 g. of glucose by mouth; plasma cholesterol and glycerides were measured on the fasting sample only.Women had higher mean insulin levels throughout the test, though their mean blood sugar levels were higher only at 90 and 120 minutes. In both sexes there were positive correlations between age and the levels of blood sugar, plasma cholesterol, and plasma glycerides. Though the levels of glucose rose with age, those of insulin did not.