Jan L. Breslow

HYPERGLYCEMIA AND PLASMA LIPID LEVELS: A PROSPECTIVE STUDY OF YOUNG INSULIN-DEPENDENT DIABETIC PATIENTS

We explored the relation of plasma lipid levels to the degree of blood glucose control in young, insulin-dependent diabetic patients. Levels of total plasma cholesterol and triglyceride, of their lipoprotein subfractions, and of hemoglobin A, and fasting blood glucose were measured repeatedly over a one-year period in 105 patients. Lipid levels were also measured in 74 nondiabetic siblings. Increasingly poor control of diabetes, reflected by levels of hemoglobin A1 or of fasting blood glucose, was associated with statistically significant increases in total cholesterol (P less than or equal to 0.01), total triglyceride (P less than or equal to 0.007), and lipoprotein subfractions except for high-density lipoprotein cholesterol. Diabetic patients in best control had lipid levels similar to those in their nondiabetic siblings. These data on the relation of plasma lipid levels to diabetic control lend credence to the hypothesis that poor control of blood glucose is conducive to accelerated atherosclerosis in diabetes mellitus.

Plasma-exchange therapy of homozygous familial hypercholesterolemia.

FAMILIAL hypercholesterolemia is a common, dominantly inherited disease characterized by increases in plasma cholesterol and low-density lipoproteins (LDL), xanthomas, and premature atherosclerosis...

Genetic mutations affecting human lipoprotein metabolism.

Lipoproteins are macromolecular complexes of lipids and proteins that are synthesized mainly by the liver and intestine and catabolized by hepatic and extrahepatic tissues. Their main well-defined physiological function is to transport dietary and/or endogenously synthesized lipids (cholesterol, triglycerides, and phospholipids) from one organ to another,(1) although they may also be involved in the regulation of other important physiological processes. In normal plasma, there are traditionally considered to be four lipoprotein classes: (1) chylomicrons, (2) very low-density lipoproteins (VLDL), (3) low-density lipoproteins (LDL), and (4) high-density lipoproteins (HDL) (Table I). Several subfractions of VLDL, LDL, and HDL and a lipoprotein class of density intermediate between VLDL and LDL (IDL) have also been described. The plasma lipoproteins are spherical particles with cores of nonpolar neutral lipid consisting of cholesteryl ester and triglycerides and coats of relatively polar materials consisting of phospholipid, free cholesterol, and proteins(2,3) (Table I; for reviews see Refs. 4–6). The protein components of lipoproteins are called apoproteins and have been designated apo A-I, apo A-II, apo A-IV, apo B, apo CI, apo CII, apo CIII, apo D, and apo E.(7)

Dexamethasone-resistant cystic fibrosis fibroblasts show cross-resistance to sex steroids

Diploid skin fibroblasts derived from individuals with the autosomal recessive disease, cystic fibrosis (CF), were shown previously to be significantly more resistant to the cytotoxicity of dexamethasone, a glucocorticoid hormone, than were normal human fibroblasts. Here cystic fibrosis fibroblasts are also shown to be more resistant than normal human fibroblasts to the cytotoxic effects of the sex hormones, 17 beta-estradiol, dihydrotestosterone and progesterone. Since cells are believed to contain different receptors for each of the steroid hormones, it is not probable than the resistance of CF cells to these hormones results from a receptor deficiency. This was shown by the fact that CF cells were found to exhibit the same receptor activity as normal cells for 3-H-dexamethasone. Furthermore, neither normal human nor CF fibroblasts could be demonstrated to contain detectable receptor activity for 3H-17 beta-estradiol. In addition, the studies of fibroblast killing by hormones led to the further interesting observation that normal human diploid fibroblasts, regardless of the sex of the tissue donor, are sensitive to killing by each of the sex hormones. These findings suggest that the cytotoxic effects of the steroid hormones may be observed independently of the specific hormone receptors. The studies reported here thus suggest that the resistance of CF cells to the different steroid hormones is probably the result of a defect in a pathway in cellular steroid hormone metabolism other than that involving receptors.

Effect of lipoprotein on 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase activity in rat liver cell culture: Special suppressant effect of a lipoprotein isolated from hypercholesterolemic rat plasma

Abstract A significant advance in cell culture methodology has permitted an analysis of the regulation of liver cell cholesterol metabolism by lipoproteins. The effect of rat lipoproteins on the activity of the rate limiting enzyme in cholesterol biosynthesis, HMG CoA reductase, was studied in monolayer cultures of adult rat hepatic parenchymal cells. Lipoproteins isolated from normocholesterolemic rat plasma, including low density lipoprotein, did not suppress HMG CoA reductase activity. However, enzyme activity was profoundly suppressed by a cholesterol rich d

Decreased ouabain binding in cystic fibrosis fibroblasts in potassium-free medium.

We have previously demonstrated that cystic fibrosis (CF) cells show increased survival compared to normal cells when exposed to ouabain in medium lacking potassium. In this report, we show that the CF cells bind significantly less ouabain than the normal cells in potassium-deficient medium. Using age-matched normal and CF skin fibroblast strains, we show that (1) at ouabain concentrations <20 × 10−9 M binding for both normal and CF cells is linear with time for 1 h and reaches equilibrium after 4 h; (2) at ouabain concentrations between 2 and 20 × 10-9 M, the initial rate of binding for CF cells is approx. 70% of the normal cells; (3) under equilibrium-binding conditions, Scatchard analysis reveals that three different CF strains have 12, 16, and 44% fewer ouabain-binding sites than their matched normal controls. In addition, studies in potassium-free medium of the inhibition of 86Rb flux (a K+ analogue) into the cell by ouabain show no differences between CF and normal cells. We have also previously shown that in a low glucose, potassium-deficient medium the CF cells survived ouabain exposure no better than normal cells. In this report, equilibrium-binding studies with [3H]ouabain clearly show that CF cells bind less ouabain under these conditions than normal cells. These results indicate that ouabain resistance in CF cells is not solely a function of differences in ouabain binding. Furthermore, the differential ouabain killing may not be due to ion transport differences, but rather to as yet unknown mechanisms. CF cells thus appear to be unlike previously characterized ouabain-resistant mutants.

Human osteogenic sarcoma cells exhibit enhanced protein phosphorylation

Protein phosphorylation was compared in normal human cells and human osteogenic sarcoma cells. The phosphorylation of endogenous cellular protein substrates was measured by two independent methods, incubation of homogenized cells with [gamma-32P]ATP or labeling of intact cells with Na2H32PO4. Phosphorylated proteins were identified by SDS-polyacrylamide gel electrophoresis and autoradiography. The stained protein bands of all four osteosarcoma cell lines were nearly identical to those of the normal cells. However, each of the osteosarcoma cell lines showed autoradiographic evidence of enhanced phosphorylation in many different protein bands which was neither cyclic AMP-dependent nor a function of cellular growth rate or density. When normal and tumor cell homogenates were mixed prior to incubation with [gamma-32P]ATP, the resulting phosphoprotein patterns resembled those obtained with the tumor cells alone. In addition, a surgically derived osteogenic sarcoma was cultured and an established line obtained; another portion of the fresh tumor was immediately homogenized and used in a phosphorylation assay. The same enhanced phosphorylation pattern was obtained with the homogenized fresh tumor as with the cell line established from it. These results suggest that human osteogenic sarcoma cells are able to perform a significantly increased amount of phosphorylation of endogenous cellular protein substrates when compared to normal human cells.