A randomized double-blind study was performed to examine the effect of clofibrate on glucose tolerance in subjects with non-insulin-dependent diabetes mellitus (NIDDM). Clofibrate (1.5 g/day) or placebo was administered to 70 patients and an oral glucose tolerance test (OGTT) was performed before and 12 wk after treatment. Blood glucose levels were significantly improved in clofibrate-treated groups at all time points during OGTT, whereas there was no change in insulin levels. Improvement of fasting glucose levels required 8 wk of clofibrate treatment. Insulin binding to erythrocytes demonstrated no significant change in the clofibrate-treated subjects. These results suggest that clofibrate improves glucose tolerance in NIDDM subjects without a change in insulin receptors and that clofibrate increases insulin sensitivity through an unknown postreceptor mechanism.

No abstract

No abstract

Abstract. We analyzed the heterogeneity of apo E in very low density lipoprotein from 58 hyperlipidemic subjects with or without atherosclerosis, 69 patients with ischemic heart disease, and 100 apparently healthy individuals. Apo E gene frequencies in the group of healthy individuals were comparable with those in German and American populations. The distribution of six common apo E phenotypes in the groups of hyperlipidemia and ischemic heart disease was similar to that in the healthy group.In addition to the three major isoforms of apolipoprotein E (apo E-4, E-3, and E-2) and the new one (apo E-5) which was recently found in this laboratory, we have discovered an additional series of components, which showed themselves as at least three bands on an isoelectric focusing gel in the region of E-VII through E-V, in four patients with hyperlipidemia and atherosclerosis. The new series of apo E components, named apo E-Suita, was identical with the ordinary apo E in its interaction with heparin-Sepharose gel and with antiapo E antibody. The most basic component of apo ESuita (E-VII) was the unsialylated form and other components (E-VI and E-V), the sialylated forms. Family studies revealed that apo E-Suita was determined by inheritance of a new apo E allele located at the same locus as the hitherto known apo E components.Apo E-5 and apo E-Suita isoproteins had isoelectric points more basic than apo E-3, the parent type, by two and four units of charge, respectively. While the apo ESuita isoprotein had the same molecular weight as ordinary major apo E isoproteins, the molecular weight of the apo E-5 isoprotein was -1,500-2,000 lower than the other apo E isoproteins by sodium dodecyl sulfatepolyacrylamide gel electrophoresis. The incidence of abnormal apo E components, including apo E-5 and apo E-Suita, was high among patients with hyperlipidemia and ischemic heart disease (7:127), while we could not find such components among 100 healthy individuals. Moreover, five of seven patients with the abnormal apo E had overt atherosclerotic disease. The findings suggest that these kinds of apolipoprotein mutation are closely related to the development of atherosclerosis.

SUMMARY The lesions of the aortic root, which are supravalvular aortic stenosis and coronary ostial stenosis, in familial hypercholesterolemia were studied using two-dimensional echocardiography. The subjects were 25 heterozygotes, six homozygotes and 30 control subjects.The internal diameters of the aortic ring, the sinus of Valsalva and the supravalvular aortic ring were measured. Measurement variation due to body size was avoided by normalizing the latter two values by the diameter of the aortic ring. Four heterozygotes and all homozygotes were judged to have stenosis of the supravalvular aortic ring; none of heterozygotes and four homozygotes had stenosis of the sinus of Valsalva. In three of the four patients with stenosis of both the supravalvular aortic ring and the sinus of Valsalva, a pressure gradient was demonstrated. The degree of supravalvular aortic stenosis correlated with the serum cholesterol level but not with patient age. All homozygotes, even very young ones, had a severe aortic root lesion. In the short-axis view of the aortic root, a lump (raised mass) on the aortic wall indicating atheromatous plaquing was demonstrated in five heterozygotes and all homozygotes. Coronary ostial stenosis was shown in three of the four patients whose plaquing echoes were adjacent to the coronary orifice.We conclude that two-dimensional echocardiography is useful in diagnosing lesions of the aortic root in patients with hypercholesterolemia.

No abstract

SummaryWe examined the physical constitution, serum lipids, fasting serum insulin (IRI), food intake, and physical activity in 1,330 children in three age groups (6-7, 9-10, and 12-13) in Nagao village for the period 1994-1996. Serum total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) levels were positively correlated, and HDL-C and TG were negatively correlated in all age groups. IRI was significantly higher among the elder children, and it was also higher in girls than in boys. IRI was positively correlated with the body mass index (BMI) and triceps skinfold thickness in ages 9-10 and 12-13, but no significant correlation was noted with waist hip ratio (W/H ratio). In ages 12-13 , IRI was positively correlated with TC and TG and negatively correlated with HDL-C. In high-IRI children (above 11.4RU/mL) ages 12-13 , the high-fat diet (fat-energy ratio above 30%) and low physical activity children (physical activity score below 10 points) were more frequent, and the mean levels of triceps skinfold were higher. The positive correlation between TC and HDL-C was not significant among high-IRI children . We concluded that a high-fat diet, low physical activity, and body fat accumulation influence the IRI level, which is closely related to serum lipid levels.

Glucose-lowering mechanism by clofibrate was studied in non-insulin dependent diabetics managed with dietary therapy alone. Clofibrate 1500 mg was administered for 1 month to 15 patients, and 75 g oral glucose tolerance test and insulin tolerance test were carried out before and after 1 month of the treatment. Fasting plasma glucose values were decreased from 9.34 + 0.53 mmol/l to 7.58 ± 0.33 mmol/l (P < 0.01), and fasting insulin levels were decreased from 13.8 ± 1.7 ,uu/ml to 10.1 + 1.5 5,u/ml (P < 0.05). However, insulinogenic index and 2IRI/Eglucose ratio during 75 g oral glucose tolerance test were not changed. Enhanced glucose fall in insulin tolerance test was also observed. As these results suggested the enhanced tissue sensitivity to insulin, we examined the insulin binding to erythrocytes before and at 3 months' treatment of clofibrate in 10 non-insulin dependent diabetics. Insulin bindings were increased from 3.41 ± 0.17% to 4.11 + 0.20% in the presence of 1 ng/ml of native insulin (P < 0.01). This increased binding was due to an increased affinity without a change in the number of insulin receptors. These results suggest that improved glucose tolerance by clofibrate might be derived from the enhanced tissue sensitivity to insulin, probably through an enhanced affinity of insulin receptors.