Effects of continuous insulin infusion therapy on lipoprotein surface and core lipid composition in insulin-dependent diabetes mellitus

To determine whether intensive insulin therapy has the same beneficial effects on lipoprotein composition that it has been shown to have in insulin-dependent diabetes mellitus (IDDM) on the routinely measured plasma lipids, we studied 10 patients after 6 months of conventional therapy (CIT) and again after 6 months of therapy with continuous subcutaneous insulin infusion (CSII). While the mean of home blood glucose levels (8.1 +/- 0.5 v 7.9 +/- 0.5 mmol/L) decreased no further, plasma triglycerides (TG) (CIT, 102.7 +/- 25.0; CSII, 89.6 +/- 27.1 mg/dL; P less than .001) decreased after CSII, and high-density lipoprotein cholesterol (HDL-C) increased significantly, primarily as a consequence of an increase in HDL2 (CIT, 12.2 +/- 6.0; CSII, 18.1 +/- 6.3 mg/dL; P less than .02). Low-density lipoprotein cholesterol (LDL-C) was unchanged (CIT, 82.2 +/- 32; CSII, 84.0 +/- 27.8 mg/dL). After CIT, two indices of lipoprotein surface composition were altered: (1) the free cholesterol (FC) to lecithin ratio, which is a new cardiovascular risk factor, was abnormally increased in plasma, very-low-density lipoprotein (VLDL) + LDL, and HDL, and (2) the sphingomyelin to lecithin ratio, an index of the surface rigidity of lipoproteins, was increased in the HDL subfractions. While CSII treatment resulted in favorable changes in whole plasma lipids, it failed to correct these disturbances in composition. Since the participation of lipoproteins in certain steps in reverse cholesterol transport appears to be impaired when their surface constituents are altered, persistence of these disturbances may sustain the increased cardiovascular risk of IDDM patients, even when their clinical control is very good and their plasma lipids are normal.     

Insulin-treated Zucker diabetic fatty rats retain the hypertriglyceridemia associated with obesity

Lipoprotein and apolipoprotein changes were evaluated in 10-week-old Zucker diabetic fatty (ZDF) male rats following 12 weeks of insulin treatment, which normalized blood glucose and maintained weight gaining characteristic of nondiabetic Zucker fatty rats. Compared with untreated ZDF rats (saline-injected), insulin treatment resulted in increased very-low-density lipoprotein (VLDL; d < 1.006 g/mL) and decreased alpha lipoprotein on agarose gel electrophoresis. These findings were consistent with an observed increase in VLDL triglyceride and cholesterol, and decreased high-density lipoprotein (HDL) cholesterol with insulin treatment in isolated lipoproteins. B100 levels were unchanged by insulin treatment, but B48 levels were significantly increased in the VLDL fraction. Insulin treatment depressed apolipoprotein (apo) A-I levels in HDL, but had little effect on total apo E, apo A-IV, or apo C, although apo C was redistributed to the VLDL fraction. These results suggest that insulin treatment of ZDF rats normalizes hyperglycemia and prevents age-related changes in lipoprotein parameters associated with development of insulinopenic diabetes. Insulin therapy in ZDF rats thereby sustains the hyperlipidemic lipoprotein pattern associated with hyperinsulinemia and obesity.     

Effect of gemfibrozil on lipids, apoproteins, and postheparin lipolytic activities in normolipidemic subjects

The lipid lowering agent Gemfibrozil was tested in 8 normolipidemic subjects during a three-month intake. Plasma triglycerides decreased by 41% and Very Low Density Lipoprotein (VLDL) triglycerides decreased by 54%. The reduction of plasma cholesterol, less marked (by 10%), was due to a decrease of Low Density Lipoprotein by 20% while High Density Lipoprotein (HDL) increased up to 30%. The separation of HDL demonstrated that only HDL3 were increased. The determination of the apoproteins in plasma and lipoprotein fractions showed similar results with a decrease of apo B (by 20%) and an increase of apo A-I and apo A-II, mainly in the HDL3 fraction. Plasma postheparin lipolytic activities (PHLA) were not influenced by the therapy and no correlation was found between these activities and any of the plasma or lipoprotein lipids. The apo C-III/apo C-II ratio in VLDL decreased by 30%; however, no correlation was found between this ratio in plasma as well as VLDL and triglycerides. In addition, the Intra Venous Fat Tolerance Test did not demonstrate any improvement of the clearance of exogenous fat. The lipid lowering efficacy of Gemfibrozil, its collateral effects, and the possible mechanisms of action are discussed.     

Effects of insulin on hypercholesterolemia in the streptozotocin-induced diabetic rats fed a high cholesterol diet

The effect of dietary cholesterol (Ch) on plasma lipoprotein and apolipoproteins (apo) in diabetic rats was investigated. Ch-fed diabetic rats were severely hypercholesterolemic and hypertriglyceridemic. They had higher concentrations of very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL). Concentration of high density lipoprotein (HDL) was decreased. beta-VLDL increased predominantly in Ch-fed diabetic rats, whereas IDL increased in the Ch and propylthiouracil-fed control rats. According to sodium dodecyl sulfate polyacrylamide gel electrophoresis, VLDL and IDL from Ch-fed diabetic rats were unusual in that they contained more apo E, A-I and A-IV. Concentrations of plasma apo A-I and apo E were measured by radioimmunoassay. The diabetic rats fed a labo chow showed a significantly lower concentration of plasma apo E than control rats. Plasma apo E was extremely higher in the diabetic rats fed a cholesterol diet. Plasma apo A-I was significantly increased in the diabetic rats fed a labo chow and those fed a cholesterol. Insulin treatment significantly decreased the concentrations of VLDL, IDL and LDL and plasma concentration and distribution of apolipoproteins in lipoprotein subfractions changed toward normal. However, decreased HDL in the Ch-fed diabetic rats was not recovered by insulin treatment.     

Lipoproteins and apolipoproteins in young male survivors of myocardial infarction

Plasma and lipoprotein cholesterol, triglycerides, apolipoproteins (apo) A-I, A-II, B and phospholipid concentrations were measured at 10 days and 4 months after myocardial infarction (MI) in 60 young Kuwaiti male MI survivors below the age of 40 years. Controls were matched for age, relative weights, smoking, dietary habits and physical activities. The young MI survivors had significantly higher levels of total and LDL-cholesterol, and ratios of LDL/HDL- and LDL/HDL2-cholesterol. Total VLDL and LDL triglycerides, and phospholipids were also elevated in MI survivors compared to controls. Similarly, plasma and LDL-apo B as well as the ratios of apo B/apo A-I were higher in the MI group. There was no significant change in the levels of VLDL and HDL3-cholesterol and of apo A-II in these patients compared to their controls. Concentrations of HDL- and HDL2-cholesterol and of plasma and HDL apo A-I were significantly lower in the young MI survivors compared to the control subjects. The better discriminating lipoproteins and apolipoproteins in MI patients in descending order were HDL2-cholesterol greater than apo B greater than apo A-I greater than VLDL-triglyceride greater than HDL-cholesterol greater than LDL/HDL2-cholesterol greater than triglycerides. The data indicate that measurement of HDL2-cholesterol, apo B and apo A-I may be useful indicators in assessing coronary artery disease risk than triglycerides (TG), total cholesterol (TC), LDL-cholesterol and HDL-cholesterol.     

Predictive value of plasma apolipoprotein B in myocardial infarction in young subjects. Correlations with coronarographic data

In recent epidemiological studies, apolipoprotein-B (apo B), the main low density lipoprotein (LDL), was found to be significantly elevated in patients with early atherosclerosis. The aim of this study was to compare plasma apo B in a population of men who had suffered myocardial infarction before 45 years of age (N = 31) with a control population (N = 22). In the coronary group, there were 27 angiographies between the end of the first and third month. The plasma lipoproteins were separated by ultracentrifugation, cholesterol and triglycerides measured by enzymatic methods and apo B by Laurell's technique of immunoelectrophoresis. Our results showed significantly higher apo B in the coronary group (p less than 0.05). Serum cholesterol, triglycerides, very low density lipoprotein (VLDL) and LDL cholesterol were also significantly higher whilst high density lipoprotein (HDL) cholesterol was significantly lower. In addition, apo B levels correlated with the severity of the coronary lesions on angiography. Therefore, the plasma apo B level is a good predictive indicator of the presence of early coronary atherosclerosis and its severity.     

Continuous intraperitoneal insulin infusion partly restores the glucagon response to hypoglycaemia in type 1 diabetic patients

The glycaemic and hormonal responses to a hypoglycaemic event induced by an i.v. bolus of insulin was studied in seven type 1 diabetic patients treated first with continuous subcutaneous insulin infusion (CSII) and subsequently with continuous intraperitoneal insulin infusion (CIPII). Arterialised blood glucose and venous hormonal responses were analyzed. HbA1c was improved by CIPII. Although a regimen of a higher basal insulin infusion rate was applied during CIPII the basal peripheral venous insulin levels were lower. The i.v. bolus of insulin resulted in hypoglycaemia in both tests but was more pronounced during the CSII test expressed as a smaller area under the curve (AUC) for the first hour (13.0 +/- 2.3 vs. 13.7 +/- 1.2 mmol l(-1) h(-1), p=0.016, CSII vs. CIPII). The hypoglycaemia resulted in a significant and similar increase in the plasma levels of adrenaline, cortisol and growth hormone in both experiments. A significant increase in the glucagon level was only observed during CIPII. The incremental glucagon response was also significantly more pronounced in the CIPII test expressed as maximal responses (7.5 +/- 3.0 vs. 17.0 +/- 3.1 pg ml(-1), p =0.048, CSII vs. CIPII) as well as incremental AUC (5.1 +/- 12.0 vs. 44.4 +/- 13.2 pg ml(-1) h(-1), p =0.027, CSII vs. CIPII). It seems that CIPII in type 1 diabetic patients could improve the glucagon release to hypoglycaemia. This observation may contribute in explaining why CIPII is associated with a lower incidence of hypoglycaemia in spite of an improvement in metabolic control.     

Lipoprotein profile in men with peripheral vascular disease. Role of intermediate density lipoproteins and apoprotein E phenotypes.

BACKGROUND. The role of lipoprotein disturbances in the development of peripheral vascular disease (PVD) has not been sufficiently clarified. METHODS AND RESULTS. The relations among concentrations of intermediate density lipoproteins (IDL), apoprotein (apo) B, apo E, and other lipoproteins were studied in 102 men with PVD and 100 healthy men who formed the control group. Patients with PVD had significantly higher levels of serum triglycerides, very low density lipoprotein (VLDL) cholesterol, VLDL triglycerides, VLDL proteins, IDL cholesterol, and IDL triglycerides and lower levels of high density lipoproteins (HDL) than controls. Serum cholesterol and triglycerides were normal in 30 patients (cholesterol, less than 5.2 mmol/l; triglycerides, less than 2.3 mmol/l), who had significant increases in IDL triglycerides and significant decreases in HDL cholesterol compared with the 47 controls, who had normal cholesterol and triglyceride levels. Patients with more severe distal involvement showed higher cholesterol and triglycerides carried by IDL and a greater reduction in HDL cholesterol. Smoking patients with PVD showed increased VLDL cholesterol and VLDL triglycerides and lower HDL concentrations. Apo E polymorphism in our study population does not differ from that reported for other European populations. Alleles epsilon 2 and epsilon 4 had a major impact on serum triglycerides and VLDL lipids in our patients with PVD. CONCLUSIONS. Lipoprotein disturbances are a major risk factor for PVD. IDL abnormalities play an important role in the development and severity of PVD and should also be considered a vascular risk factor in normocholesterolemic and normotriglyceridemic patients.     

Apolipoprotein E polymorphism in men and women from a Spanish population: allele frequencies and influence on plasma lipids and apolipoproteins.

The apolipoprotein (apo) E phenotype and its influence on plasma lipid and apolipoprotein levels were determined in men and women from a working population of Madrid, Spain. The relative frequencies of alleles epsilon(2), epsilon(3) and epsilon(4) for the study population (n=614) were 0.080, 0.842 and 0.078, respectively. In men, apo E polymorphism was associated with variations in plasma triglyceride and very low-density lipoprotein (VLDL) lipid levels. It was associated with the proportion of apo C-II in VLDL, and explained 5.5% of the variability in the latter parameter. In women apo E polymorphism was associated with the concentrations of plasma cholesterol and low-density lipoprotein (LDL) and high-density lipoprotein (HDL) related variables. The allelic effects were examined taking allele epsilon(3) homozygosity as reference. In men, allele epsilon(2) significantly increased VLDL triglyceride and VLDL cholesterol concentrations, and this was accompanied by an increase of the apo C-II content in these particles. Allele epsilon(4) did not show any significant influence on men's lipoproteins. In women, allele epsilon(2) lowered LDL cholesterol and apo B levels, while allele epsilon(4) increased LDL cholesterol and decreased the concentrations of HDL cholesterol, HDL phospholipid and apo A-I. These effects were essentially maintained after excluding postmenopausal women and oral contraceptive users from the analysis. In conclusion: (1) the population of Madrid, similar to other Mediterranean populations, exhibits an underexpression of apo E4 compared to the average prevalence in Caucasians, (2) gender interacts with the effects of apo E polymorphism: in women, it influenced LDL and HDL levels, whereas in men it preferentially affected VLDL, and (3) allele epsilon(2) decreased LDL levels in women, while it increased both VLDL lipid levels and apo C-II content in men, but, in contrast to allele epsilon(4), it did not show an impact on HDL in either sex.     

Gemfibrozil therapy in primary type II hyperlipoproteinemia: effects on lipids, lipoproteins and apolipoproteins

Gemfibrozil lowers triglycerides, low density lipoprotein (LDL) and very low density lipoprotein (VLDL) cholesterol. It also promotes a significant increase of high density lipoprotein (HDL) cholesterol. It has been established that normalization of apolipoproteins is an important protective factor against atherosclerosis. The present report examines the effectiveness of 12 months of gemfibrozil treatment on plasma lipids and apolipoproteins in types IIa (VLDL 18 +/- 2 mg cholesterol/dL) and IIb (VLDL 58 +/- 7 mg cholesterol/dL) hypercholesterolemic patients. Gemfibrozil lowered plasma triglycerides, VLDL cholesterol and apolipoprotein B (apoB), increased HDL cholesterol and apoAI levels in both groups, and induced a very substantial reduction in LDL cholesterol in type IIa patients only. Even though HDL particles were enriched in cholesterol, indicating improvement in the reverse cholesterol transport and lower risk of atherosclerosis in both groups, it is important to note that production of cholesterol-poor LDL particles and reduction in LDL cholesterol and the LDL/HDL cholesterol ratio were observed only in the normotriglyceride group (type IIa). Due to the initially elevated concentration of plasma triglycerides and VLDL in type IIb patients and the increased catabolism of VLDL to LDL during gemfibrozil therapy, this drug has a more efficient regulating effect on LDL particles in type IIa compared with type IIb hyperlipidemia.     

Hyperthyroidism influences the distribution and apolipoprotein A composition of the high density lipoproteins in man

Hyperthyroidism has a different influence on the major high density lipoprotein (HDL) components cholesterol, apoprotein (apo) A-I, and apo A-II. To characterize in greater detail the alterations induced by hyperthyroidism within the HDL subclasses, we investigated HDL distribution and composition in 11 hyperthyroid women before and during treatment. The plasma concentrations of total cholesterol, HDL cholesterol, phospholipids, apo A-I, and apo B were decreased when the patients were hyperthyroid compared with the values during treatment. Apo A-II and apo C-III levels were only slightly lower in the hyperthyroid state. Triglyceride and apo E concentrations did not change significantly during therapy. Analysis of lipoprotein subclasses separated by isopycnic ultracentrifugation revealed 1) marked decreases in low density lipoprotein (LDL) cholesterol, phospholipids, and apo B; 2) less pronounced reductions in the very low density lipoprotein (VLDL) lipid and apo B concentrations; and 3) a consistent decrease in the HDL2b (density, 1.063-1.100 g/ml) fraction in the hyperthyroid patients. The reduction in HDL2b mass was associated with lower concentrations of HDL2b cholesterol, phospholipids, and apo A-I. The HDL2b apo A-II levels remained constant during treatment. Hyperthyroidism, therefore, modified the apo A composition of the HDL2b particles and resulted in a decreased molar apo A-I to apo A-II ratio within HDL2b. Further analysis of HDL particles differing in their apo A composition; i.e. HDL particles containing apo A-I only [(A-I)HDL] or containing both apo A-I and A-II [(A-I + A-II)HDL], by immunological procedures suggested that hyperthyroidism influenced the apo A content of HDL2b mainly by changing the proportions of (A-I)HDL and (A-I + A-II)HDL and the amount of apo A-I associated with (A-I)HDL. Treatment reversed the preferential decrease in (A-I)HDL within the HDL2b subclass. The particle sizes within HDL subfractions, measured by polyacrylamide gradient gel electrophoresis, were similar in the untreated and treated patients. Consequently, the decreased mass of apo A-I and lipids within HDL2b in the hyperthyroid patients could be attributed to a reduced number of identically sized particles within this fraction. These data demonstrate that the thyroid hormones are important regulators of HDL metabolism through their influence on the concentration and distribution of apo A-I.     

Lipoprotein distribution and composition in the human nephrotic syndrome

Plasma lipoprotein profiles were quantitated in 9 patients with the nephrotic syndrome. Six subjects were studied both during an active proteinuric phase and during a remission phase without proteinuria. During the proteinuric phase, the plasma triglyceride, cholesterol and apo B levels were markedly increased, whereas the HDL cholesterol, apo A-I, and apo A-II concentrations were normal. Analysis of the distribution and composition of the lipoprotein subclasses, separated by isopycnic ultracentrifugation, showed typical patterns characterized by: (1) elevated apo B-rich VLDL and LDL fractions, (2) the presence of a denser LDL subfraction, floating at d 1.053 g/ml, which contained about 35% of LDL cholesterol and apo B and (3) a redistribution among HDL subclasses. The HDL2b (d 1.063-1.100 g/ml) fraction was markedly decreased, while the HDL2a + 3a (d 1.100-1.150 g/ml) and HDL3b + 3c (d 1.150-1.210 g/ml) subclasses were moderately elevated. The decreased cholesterol and apo A-I contents of HDL2b therefore counterbalanced their increase in HDL2a + 3a and HDL3b + 3c, resulting in normal plasma HDL cholesterol and apo A-I concentrations. When reinvestigated during a remission phase without proteinuria, the nephrotic patient's overall lipoprotein distribution and composition were similar to those in healthy controls. The combination of several factors such as the presence of elevated apo B-rich VLDL, IDL and LDL, together with decreased HDL2 cholesterol and HDL2 apo A-I suggests that nephrotic patients are at increased risk for atherosclerosis.     

Lipoprotein abnormalities and extracoronary atherosclerosis in patients with premature ischemic heart disease

A study of serum lipoprotein (VLDL, LDL, HDL) concentration has been performed on 36 males who had undergone an aorto-coronary bypass operation before age 50. They have been compared to 33 healthy men in the same age range. The presence and severity of coronary, carotid and peripheral atherosclerosis in these patients has been evaluated on the basis of coronary angiograms, continuous wave Doppler and Duplex scanning by echo-Doppler. Lipoprotein abnormalities have been related to the occurrence of extracoronary arterial lesions in association with myocardial ischemia. Total serum cholesterol and triglycerides, LDL cholesterol and triglycerides were higher in IHD patients (p less than 0.05), while HDL cholesterol was lower (p less than 0.01). No statistically significant difference was detected in VLDL lipids or apo B and in LDL apo B. Signs of extracoronary atherosclerosis were more frequent among IHD patients than in controls. Ankle/arm pressure ratio was abnormally low in 12 patients as compared to only one control (p less than 0.01). Echo-Doppler examinations of iliac arteries demonstrated a higher prevalence of lesions among IHD patients as compared to controls (20 versus 2; p less than 0.01). All patients (4 out of 36) with audible carotid bruits had stenoses in the internal carotid artery. In order to evaluate the relationships between lipoprotein concentration and occurrence of extracoronary atherosclerosis, analysis of variance and multiple comparisons were performed on values for lipoprotein concentration in three groups: controls, IHD patients without evidence of extracoronary atherosclerosis, IHD patients with detectable extracoronary lesions. Significant differences among the three groups were demonstrated as regard to LDL cholesterol or triglycerides and HDL cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)     

Alterations in the HDL system after rapid plasma cholesterol reduction by LDL-apheresis

Changes in high density lipoprotein (HDL) subfraction structure and composition were analyzed during and after extracorporeal removal of apo B containing lipoproteins in seven familial hypercholesterolemic (FH) patients. After the apheretic procedure, carried out with dextran-sulfate-cellulose columns, the plasma levels of very low density lipoproteins (VLDL), low density lipoproteins (LDL), and HDL decreased by 72%, 50%, and 19%, respectively. The free cholesterol to esterified cholesterol ratio in plasma increased, with a 26% drop in the lecithin:cholesterol acyl transferase (LCAT) activity. In the ensuing 24 hours, VLDL, HDL, and LCAT activity approached the pretreatment levels. During this phase, possibly as a consequence of increased cholesterol esterification and exchange of cholesteryl esters for triglycerides between HDL and VLDL, HDL2a particles were detected in plasma. However, these metabolic changes did not result in clearcut modifications in the HDL2-HDL3 subfraction distribution. These findings clearly demonstrate that rapid changes in the plasma VLDL-LDL levels affect several processes involved in the HDL metabolism, but confirm that the HDL system, in spite of a considerable plasticity, displays a marked stability of the HDL2-HDL3 subfraction distribution.     

Effects of estrogen replacement on plasma lipoproteins and apolipoproteins in postmenopausal, dyslipidemic women.

The effects of oral estrogen replacement (ethinyl estradiol 0.02 mg/d) on plasma triglyceride, total cholesterol, very-low-density lipoprotein (VLDL) cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and apolipoprotein (apo) A-I and B levels and LDL particle size were assessed in 20 postmenopausal women with a previous hysterectomy and various forms of dyslipidemia (LDL cholesterol > or = 4.14 mmol/L [160 mg/dL] and/or HDL cholesterol < or = 1.03 mmol/L [40 mg/dL]). All subjects were studied while on a standard cholesterol-lowering diet, and were sampled in the fasting state before beginning estrogen therapy and after a mean of 13 weeks of estrogen therapy. Lipids were measured by standardized enzymatic techniques, apos were measured by enzyme-linked immunoassays, and LDL particle size was measured by gradient gel electrophoresis. Mean values for plasma lipid parameters (mmol/L) at baseline and during estrogen replacement were as follows: triglyceride, 2.11 and 2.75 (30% increase); total cholesterol, 7.45 and 6.52 (13% decrease); VLDL cholesterol, 1.09 and 1.22 (12% increase); LDL cholesterol, 5.09 and 3.70 (27% decrease); and HDL cholesterol, 1.27 and 1.58 (24% increase). Mean values for apo A-I were 163 and 254 mg/dL (56% increase), and for apo B they were 170 and 148 mg/dL (13% decrease). The LDL particle score was 4.09 and 4.52 (11% smaller). Changes in all parameters were statistically significant (P = .05) except for VLDL cholesterol. These data indicate that estrogen replacement is effective in decreasing LDL cholesterol and apo B concentrations and increasing HDL cholesterol and apo A-I concentrations in dyslipidemic postmenopausal women, but it should not be used in patients with baseline fasting triglyceride levels higher than 2.82 mmol/L (250 mg/dL) unless it is accompanied by a progestin. Our data indicate that this form of estrogen replacement could lower the risk of coronary artery disease (CAD) by more than 50% in these women, based on favorable alterations in plasma lipoproteins.     

High density lipoprotein subfractions during continuous insulin infusion therapy

This study compared the effects of continuous subcutaneous insulin infusion (CSII) and conventional insulin therapy (CIT) on serum lipid and lipoprotein levels in type I diabetic patients during 1 year cross-over study (6 months on CSII and 6 months on CIT). The study group consisted of 28 normolipidemic and nonobese diabetic patients (14 males and 14 females) aged 31 +/- 2 yr. The glycemic control was moderate (HbA1 10.2 +/- 0.3%) before starting the study. During the first 6 months, the HbA1 level fell significantly in the CSII group (from 10.4 +/- 0.5% to 9.8 +/- 0.4%, P less than 0.05), but remained unchanged in patients on CIT. During the second 6 months after cross-over no significant alterations in HbA1 levels were observed in either group. HDL-cholesterol (HDL-chol) rose by 38% during the first 6 months in the patients using CSII (P less than 0.001) and by 18% in the CIT group (P less than 0.005). The rise in HDL-chol was accounted for by an increase in both HDL2-chol and HDL3-chol subfractions. Following the shift from CIT to CSII, HDL2-chol rose further (P less than 0.05), whereas HDL3-chol remained unchanged. When CSII was changed to CIT, the HDL3-chol level decreased (P less than 0.02), but HDL2-chol remained constant. There was no correlation between HDL-cholesterol and HbA1 levels or between the changes in either variable. HDL2-chol was 35% higher in females when compared to males at entry, and it rose in both sexes during CSII. HDL3-chol elevated during CSII only in females. CSII or CIT treatments did not cause significant changes in cholesterol or triglyceride levels of VLDL or LDL lipids during the study. Thus, even a mild improvement in glycemic control during CSII is associated with a rise in HDL-chol, particularly the HDL2 subfraction.     

Changes in the composition of plasma lipoproteins in the chronic uremic rat

The effect of chronic renal failure on the lipid and apolipoprotein concentrations of plasma, very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), low density lipoproteins (LDL) and high density lipoproteins (HDL) was studied in an experimental uremic rat model. Control rats were sham-operated and were divided into adlibitum-fed and pair-fed groups. The rats were studied (after an overnight fast) 32 days after the onset of uremia. The uremic rats had a 4-fold increase in plasma urea nitrogen and creatinine. The pair-fed and ad-lib-fed controls had similar levels of plasma urea nitrogen and lipid profiles. In the uremic rats, plasma triglyceride (TG) levels were increased 3.8-fold due to increased TG in the VLDL, IDL and HDL fractions. Their 2-3-fold increase in plasma free cholesterol (FC), esterified cholesterol (EC) and phospholipids (PL) were due to FC, EC and PL increases in VLDL, IDL, LDL and HDL. Their increase in plasma apo B (x 2.4) and apo E (x 1.5) were due to increases in VLDL, IDL and LDL. Their plasma apo A-I increased 2.4 fold due to increases in the LDL and HDL fractions. Uremic rats also had increases in the FC/PL molar ratio in VLDL, IDL and LDL. In their LDL, the apo B/total cholesterol (TC), apo B/PL and apo B/apo E molar ratios were decreased. In their HDL, the apo E/TC and apo E/PL molar ratios were decreased and the apo A-I/apo E molar ratio was increased. In conclusion, chronic uremia causes both quantitative changes in the levels and qualitative changes in the composition of the plasma lipoprotein particles. These results are compatible with the decreased hepatic lipase activities and impairment of remnant clearance observed in human chronic renal failure.     

Insulin and the metabolism of lipoproteins

In normal individuals, insulin regulates lipoprotein metabolism. It increases hepatic triglycerides (TG) secretion and makes VLDL and chylomicrons post prandial removal easy by stimulating adipose tissue lipoprotein lipase (LPL). Insulin activity and cholesterol rich lipoprotein is more complicated: by its action on VLDL and chylomicrons turn-over, it influences LDL and HDL formation. It regulates cellular cholesterol pool at different levels: stimulation of LDL receptor, but also of HMG CoA reductase. Controlling LCAT, in participates in cholesterol removal by HDL. In insulin dependent diabetes, lack of adipose tissue LPL stimulation augments triglycerid-rich lipoproteins, by slowing their catabolism, resulting in a weak increase of LDL and a lowering of HDL. In non insulin dependent diabetes with hyperinsulinism, VLDL are elevated because of insulin stimulation of triglycerid hepatic production. LDL are increasing. HDL status remains discussed: HDL cholesterol is low but HDL triglycerid is high, there is no known disturbance of apo A level. In the two types of diabetes, although mechanism is different, perturbation of lipoprotein metabolism may account for the atherogenicity of this disorders.     

Cholesterol Rich apo B Containing Lipoproteins and Smoking are Independently Associated with Macrovascular Disease in Normotensive NIDDM Patients

A cross-sectional study of macrovascular disease (MVD) and associated metabolic and other risk factors was conducted in 87 normotensive NIDDM patients. MVD was assessed by Rose questionnaire, 12 lead resting ECG, duplex scanning of carotid and peripheral vessels, and ankle:brachial systolic blood pressure ratio. Fasting serum total cholesterol, total triglycerides, LDL cholesterol, HDL cholesterol, apolipoproteins AI and B, lipoprotein (a), HbA₁, plasma glucose, insulin, and C-peptide responses to a carbohydrate rich meal, body mass index (BMI), waist-hip ratio, urinary albumin excretion rate, blood pressure, smoking and family history were assessed as possible ‘risk factors’. Apolipoprotein:lipid ratios were calculated to estimate lipoprotein composition. Thirty-six patients had demonstrable MVD. The presence of MVD was associated with higher total triglycerides (p < 0.05), BMI (p < 0.05), systolic blood pressure (p < 0.01), a lower apo B:non HDL cholesterol ratio (p < 0.001), and smoking (p < 0.005) but no other measures. Multiple regression analysis revealed smoking and a low apo B:non HDL cholesterol to be independently associated with MVD. The low apo B:non HDL cholesterol suggests a high cholesterol content of apo B containing lipoproteins. This lipoprotein abnormality is not a feature of NIDDM, but when present in these patients may be particularly atherogenic.     

Growth hormone regulation of serum lipoproteins in the rat: different growth hormone regulatory principles for apolipoprotein (apo) B and the sexually dimorphic apo E concentrations

Growth hormone (GH) regulation of serum lipoproteins and apolipoproteins was studied using hypophysectomized (Hx) male and female Sprague-Dawley rats. Hypophysectomies were performed at 45 or 50 days of age. Hx rats were given replacement therapy with L-thyroxine (10 micrograms/kg/d) and hydrocortisone (400 micrograms/kg/d) unless otherwise specified. Bovine GH (bGH) was given either as two daily subcutaneous (SC) injections at 12-hour intervals or as a continuous SC infusion. Serum cholesterol and apolipoprotein (apo) E concentrations decreased after Hx of female rats. In contrast, Hx of male rats resulted in increased serum cholesterol concentrations and had no effect on serum apo E concentrations. There were no effects of Hx on high-density lipoprotein (HDL) apo E levels in male rats in contrast to female rats. bGH given twice daily to Hx male rats had no effect on HDL apo E levels, but a continuous infusion of bGH resulted in a marked increase in HDL apo E concentration, to levels above those of intact male rats. As previously observed in female rats, serum and HDL apo A-I concentrations decreased and serum and low-density lipoprotein (LDL) concentrations of apo B increased after Hx of male rats. Treatment with L-thyroxine and hydrocortisone reduced the serum concentrations of apo B. bGH given alone resulted in even lower concentrations of apo B. Serum concentrations of cholesterol and apo E were unaffected by replacement therapy with L-thyroxine and hydrocortisone. Treatment with bGH alone had similar effects on serum cholesterol, apo E, and apo B concentrations as treatment with L-thyroxine, hydrocortisone, and bGH in combination.(ABSTRACT TRUNCATED AT 250 WORDS)