Interaction of low density lipoproteins with human aortic elastin.

Interaction between lipoproteins and elastin in the arterial wall may play an important role in atherosclerotic lipid deposition, but binding affinities and other characteristics of the interaction have not been determined previously. Elastin was isolated by hot alkali treatment of human aortic tissue. At 4 degrees C, radioiodinated human low density lipoprotein (LDL) bound to more than one class of binding sites on elastin. Sites of highest affinity had an apparent dissociation constant of 3.6 x 10(-8) M. Total binding at an LDL concentration of 50 micrograms/ml ranged from 4 to 50 ng LDL protein/mg elastin. The binding was relatively specific, since binding was competitively inhibited by LDL and apo E-containing high density lipoprotein (HDL) but only modestly by HDL3. Atherosclerotic elastin exhibited a twofold to fourfold higher capacity for binding LDL, but a reduced affinity. At 37 degrees C, normal elastin exhibited an initial rapid binding of LDL, with a slower linear phase of binding over a 15-hour period, indicating an additional complex process at this temperature. Consideration of the expected LDL concentrations in the arterial intima, in comparison with binding affinities, suggests that LDL binding to elastin probably occurs in the intima and may foster atherosclerotic lipid deposition.

Effects of cyclosporine therapy on plasma lipoprotein levels.

Accelerated atherosclerosis is a leading cause of death in long-term survivors of heart and renal transplantation and may be exacerbated by the frequent occurrence of posttransplant hyperlipidemia. Attempts to define the mechanism for hyperlipidemia in transplant recipients are confounded by dramatic changes in metabolism and nutritional status after transplantation, as well as by treatment with multiple immunosuppressive and antihypertensive drugs. To avoid these pitfalls and to determine if cyclosporine alone adversely affects lipid levels, we measured lipoprotein levels in a prospective, double-blind, randomized, placebo-controlled trial of cyclosporine in 36 men with amyotrophic lateral sclerosis. Plasma total cholesterol, triglyceride, high-density lipoprotein cholesterol, and apolipoprotein B levels were measured at baseline, 2 weeks, 1 month, and 2 months. Significant increases of 21% in total cholesterol, 31% in low-density lipoprotein cholesterol, and 12% in apolipoprotein B levels occurred only in the cyclosporine group. Cyclosporine therapy alone adversely affects plasma lipoprotein levels by increasing total cholesterol levels, primarily due to an increase in low-density lipoprotein cholesterol level.

The pharmacokinetics of subcutaneous regular insulin in type I diabetic patients: assessment using a glucose clamp technique.

We recently reported that the peak effect and duration of action of regular insulin injected sc were prolonged in diabetic patients and were not related to the presence of insulin antibodies. The results suggested that the ambient level of plasma glucose might be an important factor in determining the pharmacokinetics of regular insulin. In the present study we used a glucose clamp technique, which minimizes interference by counterregulatory phenomena, to study the pharmacokinetics of regular insulin injected sc at 2 different blood glucose concentrations [276 +/- 7 (+/- SEM) and 130 +/- 5 mg/dl] in 10 insulin-dependent diabetic patients. The patient's blood glucose concentration was maintained constant by means of a variable rate iv infusion of 20% dextrose in water after sc injection of regular insulin (0.2 U/kg) in the deltoid region of the arm. The onset of insulin action occurred at similar times at both glucose concentrations (0.6 +/- 0.1 h at 276 mg/dl vs. 0.5 +/- 0.1 h at 130 mg/dl; P greater than 0.05). Peak insulin action (determined from the time of the maximal glucose infusion rate) was delayed in the studies done at 276 mg/dl (4.7 +/- 0.2 h) compared to that in studies done at mean glucose concentrations of 130 mg/dl (4.3 +/- 0.2 h; P less than 0.05). The duration of insulin action was also significantly prolonged in the studies done at the higher glucose concentrations (9.1 +/- 0.3 h at 276 mg/dl vs. 7.7 +/- 0.2 h at 130 mg/dl; P less than 0.01). These results confirm previous reports of prolonged insulin action in diabetic patients, especially in the presence of hyperglycemia.

Prolonged action of regular insulin in diabetic patients: lack of relationship to circulating insulin antibodies.

We previously reported that in insulin-treated diabetic subjects the time course of action of regular insulin injected sc is different from that reported in standard textbooks. The present studies evaluated the role of insulin antibodies (Abs) in the altered pharmacokinetics of regular insulin by comparing the time course of insulin action in 10 patients receiving chronic insulin therapy and having insulin Abs with that in 15 previously untreated patients without detectable Abs. After an overnight fast, the patients were given an infusion of 5% dextrose in water at 100 ml/h. Regular insulin (15 U) was then injected sc in the deltoid region of the arm. The onset of action of sc insulin, as indicated by a 10% fall in serum glucose, was similar in both patient groups [1.9 +/- 0.1 (+/- SEM) hour in Ab-negative and 1.8 +/- 0.1 h in Ab-positive patients]. The peak effect of insulin action, as determined by the nadir of serum glucose, was 4.6 +/- 0.2 h in the previously untreated patients, not significantly different from the value in the diabetic patients with insulin Abs (5.2 +/- 0.4 h). The duration of action of insulin was also similar in both groups (14.7 +/- 0.7 vs. 14.4 +/- 1.0 h). No significant correlations were found between insulin Ab levels and any of these 3 parameters of insulin action. However, the peak effect and total duration of insulin action were significantly correlated with the baseline serum glucose levels. A possible role of insulin Abs was evaluated in these patients by repeating the studies over a 2-year period. During this time, the previously untreated patients were treated with highly purified pork insulin, to which they developed low titers of insulin Abs. The diabetic patients who had been chronically treated with insulin were changed from less purified insulin to highly purified pork insulin, and all had a significant reduction in their Ab titers. No changes in insulin pharmacokinetics were found in either group. These studies demonstrate that the prolonged action of sc injected regular insulin in diabetic patients is not related to the effect of circulating insulin Abs.