The effect of clinofibrate, a fibrate derivative, on lipoprotein metabolism was studied using male Wistar rats each weighing 160 g on initiation to the study. They were given access ad libitum to standard or clinofibrate-containing (0.1%) chow. On the 14th day of clinofibrate administration, plasma lipoprotein fraction was separated by ultracentrifugation and triglyceride secretion rates (TgSR) were measured using Triton WR1339.
Cholesterol and phospholipid in total plasma and VLDL-and HDL-cholesterol were suppressed significantly in rats receiving clinofibrate. Plasma triglyceride levels were also suppressed by 75%(11.0±2.4 vs 44.0±10.8 mg/dl, p<0.001). The TgSR in the clinofibrate group decreased (16%) but not significantly (0.44±0.06 vs 0.64±0.04 mg/min). A small but significant increase in cholesterol content of the newly-secreted VLDL particles during the 90 minutes after Triton injection in the clinofibrate group was also observed (p<0.001). Thus, the discrepancy between magnitude of suppression of TgSR and plasma triglyceride level in the clinofibrate group suggest that clinofibrate primarily suppresses plasma triglyceride level by accelerating its removal from the circulation, and that clinofibrate-induced reduction of triglyceride entry into the circulation may also play some limited role. Moreover, clinofibrate might make VLDL particles more readily catabolized by changing their lipid composition.

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To determine whether short-term caloric restriction evokes a favorable response in coronary risk factors in obese children, lipoprotein metabolism and lipid peroxide in serum were evaluated. Twenty-four obese children, 13 males and 11 females, were venipunctured just prior to and 2 weeks after they were fed a weight-reducing diet. Activities of lipoprotein lipase and hepatic triglyceride lipase were measured in the plasma obtained 5 minutes after 10 IU/kg of heparin was administered. Serum levels of total cholesterol, triglyceride, atherogenic index, insulin and lipid peroxide were significantly decreased after the dietary therapy. The cholesterol concentrations in high-density lipoprotein (HDL) subfractions were unaltered, whereas the ratio of HDL2-cholesterol/total cholesterol was increased after the diet. Thus, there was an improvement in most of the coronary risk factors studied here. Hepatic dysfunction, which was improved by the dietary therapy, appeared to contribute to the elevated serum total cholesterol level. The levels of serum apolipoprotein Al, A2 and B decreased during the therapy, while the activities of lipoprotein lipase and hepatic triglyceride lipase were unaltered. Serum insulin level cbrrelated with percent ideal body weight, and inversely correlated with cholesterol concentrations in HDL and HDL₂. The decrease in serum lipid peroxide level using dietary therapy is suggested not only to reduce atherogeneity but also to protect cells against free radical-mediated injury.

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To determine the influence of circulating insulin antibodies on the pharmacokinetics of insulin, we examined ¹²⁵I-monoiodoinsulin binding, total and free insulins and plasma glucose after rapid intravenous insulin injection (0.1 U/kg or 0.04 U/kg) in 12 diabetic patients. In the patients with insulin antibodies, ¹²⁵1-monoiodoinsulin binding decreased to the lowest level immediately after insulin injection and returned to baseline by 120 min. In contrast, total and bound insulins of those patients increased to the maximum levels immediately after injection. Compared with diabetic subjects without insulin antibodies, diabetic subjects with antibodies had reduced initial increases in free insulin and late hyperinsulinemia. The plasma total insulin half-lives (T 1/2), which were determined by least squares regression computer program, showed apparent prolongation (40.2±5.1 min: 0.1 U/kg, 65.5±13.3 min: 0.04 U/kg) in the patients with insulin antibodies.
We conclude that moderate insulin antibodies in insulin-treated diabetics can bind insulin entering the circulation very rapidly and subsequently release it more slowly, resulting in late hyperinsulinemia and possible hypoglycemia.

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Using a non-invasive ambulatory blood pressure monitoring system (ABPM-630), we measured 24-hour ambulatory blood pressure in 30 diabetic patients with essential hypertension and 36 essential hypertensive controls without diabetes mellitus, orthostatic hypotension and heart disease. The circadian pattern of blood pressure was examined using cosine method. Although the blood pressure in non-diabetic hypertensive controls increased during the daytime, blood pressure in some of diabetic patients was elevated in the night and early morning. Examination of diabetic complications revealed that diabetic neuropathy and retinopathy influenced abnormality of the circadian pattern of blood pressure. In particular diabetic autonomic disturbance, which is judged on heart rate variation, heart rate ratio and orthostatic hypotension, was suggested to have a strong effect on the circadian pattern of blood pressure. Measured plasma renin activities and aldosterone concentrations were all normal in these diabetic patients. This data suggests that an abnormal circadian rhythm of blood pressure in diabetic hypertensive patients is related to diabetic autonomic dysfunction.

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To evaluate the influence of glucose (one of the non-creatinine chromogens) on measurement of creatinine clearance (Ccr), Ccr measured by Owen's method, which eliminates the influence of glucose, was compared with values obtained by the standard Peters' method in 118 NIDDM patients. Serum and urine creatinine concentrations measured by Peters' method increased with increasing glucose concentration when compared with Owen's method. Serum creatinine measurment was even more markedly affected than urinary creatinine. Consequently, Ccr measured by Peters' method decreased with increasing plasma glucose concentration when compared with Owen's method, and was only 74 m//min on average in non-albuminuric (AER<15 μg/min) cases, in which Ccr measured by Owen's method was 101 ml/min. Ccr determined by Owen's method in microalbuminuric (15-150 μg/min) cases was significantly higher (p<0.05) than in non-albuminuric cases. With Owen's method, elevated Ccr was seen more frequently in cases with a duration of diabetes less than 10 years. In conclusion, Owen's method seems to be preferable to Peters' method for the detection of renal hyperfunction in early diabetic nephropathy in NIDDM patients.

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Blood pressure (BP) was examined using a noninvasive ambulatory BP monitor in 35 patients with non-insulin-dependent diabetes mellitus (NIDDM) and 11 healthy controls. BP recordings were made every 30 minutes for 24 hours. Various tests of autonomic nervous system function were also conducted.
In the controls, average BP during wakefulness was higher than during sleep. Of the 35 diabetic patients, 26 exhibited a diurnal BP variation pattern similar to that of the controls (group A), but in 9 patients, average BP during sleep was higher than during wakefulness (group B). Group B had a longer duration of disease and a higher incidence of somatic neuropathy and retinopathy than did group A.
In the diabetic groups, the magnitude of the difference between average BP during sleep and during wakefulness was significantly related to duration of disease and to the effects of standing and sustained handgrip on the BP. It was also related to the CV% of the R-R interval and to heart rate change in response to the Valsalva maneuver.
The results suggest that both sympathetic and parasympathetic nervous system dysfunction may be involved in changes in the diurnal BP pattern of patients with NIDDM.

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A 49-year-old woman with non-insulin-dependent diabetes mellitus (NIDDM) complained of a local skin rash after animal insulin therapy. She had poor glycemic control during 8 years of oral drug therapy, and commenced insulin therapy in 1981, initially with bovine Lente insulin. After 6 weeks of insulin therapy, the patient experienced a local skin rash, which was not improved by changing to purified porcine NPH insulin. Subsequently, she developed insulin lipoatrophy, and this complication was not affected by replacing the medication with various human insulin preparations. Only when insulin mixed with dex amethasone was injected into the lipoatrophic lesions, did the local skin reactions improve, but over 4 months the lipoatrophy was unchanged. Finally, the insulin used was changed to AR-HM [mixed with NPH/Actrapid human (P-NPH/A-HM), 7: 3, Novolin 30 R]. After one year of this therapy, all lesions have regressed. Judging from the results of a series of skin tests and determinations of insulin-specific antibodies (IgE/IgG ratio), it is indicated that the patient has gone through a process of spontaneous desensitization to insulin by AR-HM administration.

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This report describes a patient having insulin-dependent diabetes mllitus, with onset at the age of 7 years, who gave birth to three healthy babies without the related development of any diabetic complications as a result of planned parenthood and efforts to normalize her blood sugar. The patient was a 31-year-old American (Caucasian) housewife (of Japanese nationality). When she was 7 years old, she was diagnosed as having diabetes mellitus. Since then, she was treated with NPH insulin, at a dose of 20 U daily. She came to Japan at the age of 19, and married a Japanese man at 20 years of age. When she was 24 years old, she visited our department prior to planning a pregnancy. Because of unsatisfactory blood sugar control she was managed with twice daily (morning and evening) injections of mixed insulin. Blood sugar control became satisfactory, there was no problem of diabetic complication, and she conceived. The patient gave birth to a 2, 140 g baby by induced labor at 38 weeks of pregnancy at 26 years of age. The male baby showed no abnormalities except for low birth weight. She subsequently gave birth to a 3, 224 g male baby by induced labor at 38 weeks of pregnancy at 27 years of age, and to a 3, 305 g male baby by spontaneous delivery at 37 weeks of pregnancy at 31 years of age. The second and third babies showed no abnormalities except for neonatal hypoglycemia and hyperbilirubinemia. The mother showed no complications except for diabetic retinopathy (Scott Ia). This patient is a valuable example of juvenile onset diabetes achieving 3 successful pregnancies as a result of careful family planning. She is the youngest onset diabetic reported in Japan who has been able to achieve a successful pregnancy.

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We report a case of a pregnant woman diagnosed as having IDDM at 4 years of age, with the complication of proliferative retinopathy. She bore a normal healthy infant without progression of retinopathy through planned pregnancy after photocoagulation. From the time of diagnosis, the patient has had subcutaneous injections of insulin twice a day. She grew up without diabetic complications until she started work at 18 years of age when rapid progression of retinopathy occurred due to poor diabetic control.
In 1984, aged 20, she was referred to our hospital for prepregnancy management. When first examined, she was found to have proliferative retinopathy. We treated this with photocoagulation and tried to maintain good glycemic control. Retinal edema and new vessels disappeared, but proliferative membrane remained (Scott Va).
In 1987, at age 23, she conceived. During pregnancy, her HbAi was 10.0-12.3%, and her maximum insulin requirement was 60 units/day. The retinopathy did not change throughout pregnancy. At 37 weeks of gestation, The patient delivered a boy weighing 3, 718 g by Caesarian section. The newborn had no complications except for hypoglycemia, and has been growing up healthily now for 1 year and 2 months. The grade of the mother's diabetic retinopathy has remained consistently Scott Va.
We would like to emphasize that planned pregnancy with prepregnancy diabetic management can achieve our goal of preventing not only fetal anomaly. but also the progression of proliferative retinopathy.

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Considering the implication of vascular and metabolic disruption in the pathogenesis and progression of diabetic neuropathy (DN), we investigated the effects of a combination of prostaglandin (PG) E₁ analogue, OP 1206·α CD (OP), and aldose reductase inhibitor (ARI), ICI 128436 (ICI), on the polyneuropathy in long-term streptozocin (STZ)-induced diabetic (DM) rats. DM rats were treated daily with OP alone (10μg/kg/day), OP (10μg/kg/day) and ICI (35mg/kg/day), or saline by gastric gavage for 2months, heginning 5 months after induction of diabetes. Age-matched non-DM rats were treated with saline in the same manner, as controls.
Body weight reduction and hyperglycemia of DM rats were unchanged throughout the experiment irrespective of treatment. The reduction in sciatic motor nerve conduction velocity in DM rats (49.8±2.1m/s), p<0.01 vs control (57.6±1.4) was significantly improved at the end of the experiment with OP (53.2±1.7, p<0.05 vs untreated DM), and was normalized by treatment with the combination of OP and ICI (55.9±1.7, p<0.01 vs untreated DM). Sciatic sorbitol accumulation and myo-inositol depletion in DM rats were improved only by the combined regimen. Impaired sciatic Na+, K+-ATPase activity in DM rats, moreover, was restored to the control level with this regimen.
These results suggest that (1) a combination of PGEi and ARI may be more effectivefor neuropathy in long-term STZ-DM rats, (2) both vascular and metabolic disruptions may be implicated in the progression of DN, and (3) this combination therapy should be considered for the treatment of human DN.

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