Danazol induces resistance to both insulin and glucagon in young women.

1. Danazol elevates plasma insulin, plasma glucagon and serum low-density lipoprotein concentrations and reduces the serum high-density lipoprotein concentration. 2. Associations between these disturbances were studied in 17 women receiving danazol therapy for endometriosis. Eleven women underwent intravenous glucose tolerance tests with measurement of plasma glucose, insulin, C-peptide and glucagon concentrations and modelling analysis of intravenous glucose tolerance test concentration profiles. Six women underwent glucagon sensitivity tests. Serum concentrations of lipids and lipoproteins were measured in all cases. 3. Danazol reduced the fasting plasma glucose and insulin concentrations, but markedly raised the fasting plasma glucagon concentration. The insulin and C-peptide responses to the intravenous glucose tolerance test were increased twofold and the net decrement in glucagon concentration was increased tenfold. The glucose response to the intravenous glucose tolerance test was unaffected. Insulin sensitivity was reduced by 55%. Both first-phase plasma insulin responsiveness and net first-phase pancreatic insulin secretion were increased; insulin half-life was prolonged. The glucose response to the glucagon sensitivity test was reduced on treatment. The calculated low-density lipoprotein cholesterol level rose by 20%, whereas high-density lipoprotein cholesterol level fell by 47%. None of these changes in serum lipoprotein levels correlated with changes in insulin metabolism. In general, metabolic changes normalized after 3 months. 4. Danazol increases the sensitivity of pancreatic insulin and glucagon secretion to glucose. Danazol-induced insulin and glucagon resistance could be due to receptor down-regulation resulting from hypersecretion of insulin and glucagon.     

Effects of jejuno-ileal bypass on serum lipoproteins and glucose tolerance in severely obese patients

Plasma insulin and blood glucose during oral glucose tolerance tests (OGTT) and serial determinations of serum lipoprotein fractions before and after jejuno-ileostomy in twenty severely obese (mean weight 137 kg) patients with a mean age of 29 years revealed statistically significant postoperative decreases in all parameters concomitant with a mean weight loss of 42 kg. Before the operation the patients were hyperinsulinaemic and had elevated blood glucose levels during OGTT though no patient had overt diabetes. Serum triglyceride and total cholesterol levels were normal but HDL cholesterol was significantly lower than in controls. During follow-up at least until body weight had levelled off a mean 19 months post-operative, there were statistically significant reductions in blood glucose and plasma insulin as well as serum total cholesterol and lipoprotein fractions. There was no change in serum triglycerides. The low preoperative HDL levels decreased. In a subgroup of these patients we have earlier shown postoperative increases in arterial tissue cholesterol coincident with the present significant decreases in HDL as well as in LDL cholesterol. Correlations between total cholesterol and lipoprotein cholesterol values in serum and blood glucose and plasma insulin at fast and during OGTT and changes in these parameters demonstrate interrelationships between lipid and carbohydrate metabolism. The bypass procedure most likely reduces the intestinal synthesis of HDL which in turn may increase hepatic cholesterol synthesis. Evidently there is a multifactorial aetiology for the low HDL levels in the severely obese both before and after jejuno-ileostomy.     

Insulin resistance--a risk factor for coronary heart disease?

Fasting insulin secretion was assessed by measuring fasting serum C-peptide levels in 529 women and 399 men aged 18-90 years, to study the relationship between insulin secretion, insulin resistance and risk factors for coronary heart disease. Subjects with low serum high density lipoprotein (HDL) cholesterol levels showed higher mean serum insulin and C-peptide levels than subjects with normal HDL cholesterol levels. In male subjects these differences were significant for both serum insulin and serum C-peptide results (P less than 0.005). In female subjects serum insulin results differed significantly (P less than 0.0005) but for the difference in mean serum C-peptide levels P was equal to 0.012. Fasting serum C-peptide correlated negatively with serum HDL cholesterol. However, serum C-peptide also correlated with serum triglyceride and serum triglyceride correlated negatively with serum HDL cholesterol. Each correlation was statistically significant (P less than 0.001). Multiple regression analysis suggested that the apparent association of C-peptide with HDL cholesterol was a consequence of the interrelated association between C-peptide, triglyceride and HDL cholesterol. The analysis was consistent with the hypothesis that obesity and increased insulin resistance were associated with increased insulin secretion and in turn with high serum triglyceride levels and consequentially low levels of serum HDL cholesterol. The data were compatible with the suggestion that insulin resistance rather than fasting insulin concentration per se could be a risk factor for coronary heart disease.     

Anti-inflammatory and anti-peroxidative roles of diacerein are possibly mediated through an alteration in thyroid functions in animal model of inflammation

This study was designed to reveal the possible involvement of thyroid hormones, if any, in diacerein induced alterations in glucose metabolism and tissue lipid peroxidation (LPO) in the animal model of carrageenan-induced inflammation. We studied the influence of diacerein administration on the changes in carrageenan-induced thyroid dysfunction; hepatic, renal and cardiac LPO as well as serum glucose, thyroid hormones and insulin concentrations in Wistar rats. Alterations in paw volume, serum levels of total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol and triglycerides as well as hepatic, renal and cardiac reduced glutathione (GSH) contents were also studied as supporting parameters. While a decrease in the level of serum thyroid hormones and HDL-C and in tissue GSH content was observed in carrageenan-treated animals, it increased paw volume, the concentration of other serum lipids, glucose and insulin as well as tissue LPO. However, following diacerein administration for 21 days to carrageenan-treated animals, level of thyroid hormones and all other thyroid dependent parameters were reversed suggesting that the drug might be acting through stimulation in the thyroid functions.     

Lipoprotein metabolism following gastroplasty in obese women.

In order to elucidate the long-term alterations in cholesterol transport and esterification as a part of the changes in the carbohydrate and lipoprotein metabolism subsequent to calorific restriction, 15 obese women were investigated before and after treatment with vertical banded gastroplasty. Insulin resistance and production, lipid levels in plasma, lipoproteins and the lecithin: cholesterol acyl transferase (LCAT) rate were assessed. There was a 60% decrease in mean calorific intake six months after surgery. A slight hyperglycaemia was almost normalized concomitant with a reduction of serum insulin and C-peptide after 1 year. The very low density lipoprotein (VLDL) level was unchanged. The high density lipoprotein (HDL) levels tended to rise after 1 year, when there was a significant increase of the HDL-2 subfraction. The lipid levels in the lipoprotein fractions showed a rise in mean HDL-2 cholesterol. Both the molar and fractional rates of LCAT were decreased. These results suggest that long-term calorific restriction reduces insulin resistance and production, and lowers VLDL levels and VLDL and cholesterol synthesis. However, the low density lipoprotein cholesterol levels are unchanged, probably because of a decrease in the previously elevated fractional cholesterol removal.     

High-density lipoprotein cholesterol, hepatic lipase and lipoprotein lipase activities in thyroid dysfunction--effects of treatment

We have investigated the effects of hyper- and hypothyroidism (clinical and subclinical) on lipid metabolism, with special emphasis on serum high-density lipoprotein cholesterol, post-heparin plasma hepatic lipase and lipoprotein lipase activities. In 16 patients with hyperthyroidism, increased post-heparin plasma hepatic lipase activity, decreased serum total cholesterol and serum high-density lipoprotein cholesterol were found while lipoprotein lipase activity and serum triglyceride were normal. In six patients with overt hypothyroidism serum total cholesterol and triglyceride were increased, post-heparin plasma hepatic lipase and lipoprotein lipase were decreased while serum high-density lipoprotein cholesterol was normal. In six patients with subclinical hypothyroidism, serum total cholesterol was increased, serum high-density lipoprotein cholesterol was decreased, while serum triglyceride, post-heparin plasma hepatic lipase and lipoprotein lipase were normal. When the three groups of patients became euthyroid, serum total cholesterol, serum triglyceride, post-heparin plasma hepatic lipase, lipoprotein lipase, and serum high-density lipoprotein cholesterol reverted to normal except for serum high-density lipoprotein cholesterol in the hyperthyroid group which showed no significant change with treatment. A positive correlation was found between serum T3 and post-heparin plasma hepatic lipase while negative correlations were found between serum total cholesterol and serum T3, post-heparin plasma hepatic lipase and serum total cholesterol, lipoprotein lipase and serum triglyceride respectively. Thus in these patients with thyroid dysfunction, significant reversible alterations in serum total cholesterol, triglyceride and high-density lipoprotein cholesterol were found and could be correlated with the observed changes in the activities of hepatic lipase and lipoprotein lipase.     

Does residual insulin secretion (assessed by C-peptide concentration) affect lipid and lipoprotein levels in insulin-dependent diabetes mellitus?

1. Residual endogenous insulin secretion can be assessed by the circulating C-peptide concentration and is present in up to 15% of subjects with established insulin-dependent diabetes mellitus (IDDM). Its role in lipid metabolism in IDDM is not clearly defined. We examined the relationships between serum lipid and lipoprotein concentrations and the response of circulating C-peptide to a test meal in 205 subjects with IDDM. 2. Lipid and lipoprotein levels and glycaemic control did not differ significantly between patients with undetectable, low or high C-peptide responses. 3. High density lipoprotein (HDL) cholesterol and its subfractions were inversely related to concentrations of serum triacylglycerols (P less than 0.01-0.001), but not to C-peptide or glycated haemoglobin (HbA1) levels. Levels of HbA1 and triacylglycerols were correlated with one another (P less than 0.01). Analysis of variance revealed that differences in gender and triacylglycerol concentrations were the most important determinants of HDL and HDL2 cholesterol levels. C-peptide only exerted a weak effect on HDL2 cholesterol levels and no significant predictors of HDL3 cholesterol were found. 4. It is concluded that endogenous insulin secretion (assessed by C-peptide concentration) is relatively unimportant in modifying HDL metabolism in IDDM and that associated clinical features, in particular ambient hypertriglyceridaemia, are of greater importance.     

Effects of pindolol on serum lipoproteins and postheparin lipolytic activities in hypertensive patients

Thirty-four hyperlipoproteinemic, hypertensive patients received 5 mg of pindolol twice daily for 12 weeks. During pindolol administration, there were significant decreases in serum triglyceride levels and increases in high-density lipoprotein cholesterol (HDL-C) levels, while total cholesterol levels did not change. Serum levels of very-low-density lipoprotein (VLDL) triglyceride and VLDL cholesterol decreased over time as HDL-C increased. There was a significant increase in low-density lipoprotein cholesterol at week 12. Apolipoprotein (apo) A-I, A-II, and B levels did not change during pindolol administration, but apo C-II, C-III, and E levels decreased significantly. Lipoprotein lipase activity in heparin-treated plasma was significantly higher after pindolol administration. The results suggest that the reduction in triglyceride levels and increase in HDL-C after pindolol are partly a response to an increase in the hydrolysis of VLDL resulting from an increase in lipoprotein lipase activity.     

Serum cholesterol in Wisconsin epidemiologic study of diabetic retinopathy.

OBJECTIVE--To describe serum total and high-density lipoprotein (HDL) cholesterol in a sample of people with diabetes. RESEARCH DESIGN AND METHODS--Subjects were those who participated in the 1984-1986 Wisconsin Epidemiologic Study of Diabetic Retinopathy. Data were from three groups of subjects: 304 younger-onset and 185 older-onset people taking insulin and 162 older-onset individuals not taking insulin. Serum lipids, duration of diabetes, glycosylated hemoglobin, diastolic blood pressure, sex, age, serum creatinine, units of insulin per kilogram per day, smoking status, serum C-peptide level, and alcohol use were analyzed statistically. RESULTS--In subjects taking insulin, glycosylated hemoglobin was correlated most strongly with total cholesterol. In those not taking insulin, C-peptide was correlated most strongly. In subjects taking insulin, the units used per day (fewer) and sex (female) were significantly associated with higher HDL cholesterol, and in both older-onset groups, serum C-peptide was significantly associated with lower HDL cholesterol. Mean total cholesterol levels were generally higher and mean HDL cholesterol levels were generally lower than those found in a nondiabetic comparison group. CONCLUSION--By the National Cholesterol Education Program guidelines, 17% of younger-onset and 30% of older-onset insulin users and 32% of older-onset subjects not taking insulin were in the high-risk range for total cholesterol. Lower levels of glycosylated hemoglobin might result in lower cholesterol levels.     

罗格列酮治疗2型糖尿病45例临床观察

目的观察马来酸罗格列酮治疗2型糖尿病（T2DM）前后血清高敏C反应蛋白（hsCRP）的变化,探讨其可能的药物作用。方法86例双胍类和磺脲类药物治疗3个月以上的T2DM病人随机分为罗格列酮组与对照组,进行为期16周的临床观察。结果罗格列酮组治疗前后比较空腹血糖（FPG）、餐后2h血糖（PPG）及糖化血红蛋白（HbA1c）均明显下降（P〈0．01）,胰岛素抵抗指数（IRI）明显下降（P〈0．05）,高密度脂蛋白胆固醇（HDL-C）明显升高（P〈0．01）,低密度脂蛋白胆固醇（LDL-C）明显下降（P〈0．01）,胆固醇（CH）和甘油三酯（TG）无明显变化,收缩压（SBP）平均下降9．6mmHg（P〈0．01）,舒张压（DBP）平均下降6．1mmHg（P〈0．01）,体重指数（BMI）无明显变化,hsCRP明显下降（P〈0．01）。而对照组各观察指标无明显变化。结论T2DM患者慢性高血糖状态与炎症关系密切。罗格列酮治疗在改善胰岛素敏感性的同时,还具有抗炎、调脂、降压等作用,长期使用可预防T2DM心血管疾病的发生。     

Lipoproteins and apolipoproteins in young nonobese Arab women with NIDDM treated with insulin

The effects of insulin on the lipid values of nonobese non-insulin-dependent diabetic (NIDDM) Arab women requiring insulin was investigated to find whether these patients have the same coronary artery risk factor related to lipid levels. In this study, 55 NIDDM women on insulin therapy (mean age 28 +/- 8.1 yr and duration of disease 5 +/- 1.2 yr) and 70 control subjects (matched for sex, age, and body mass index) were studied for their plasma levels of lipids, lipoproteins, and apolipoproteins. Concentrations of total cholesterol, very-low-density lipoprotein cholesterol, low-density lipoprotein (LDL) cholesterol, triglyceride (TG), LDL TG, high-density lipoprotein triglyceride (HDL TG), phospholipid, glucose, glycosylated hemoglobin (HbAtc), apolipoprotein B (apoB), LDL-apoB, and apoB/apoAl were significantly elevated in diabetic women compared with control subjects. There was no significant change in the levels of apoAll in plasma and lipoprotein fractions. Concentrations of HDL cholesterol (chol), HDL2-chol, HDL3-chol, plasma apoAl, HDL2-apoAl, HDL3-apoAl, and HDL-apoAl were significantly lower in diabetic women than in control subjects. There was no significant correlation between glucose or HbAtc and most of the lipids, lipoprotein lipids, and apolipoproteins measured. Despite normal body weight and insulin therapy, abnormalities in lipids, lipoprotein lipids, and apoB persisted in NIDDM patients compared with control subjects. Our data may favor an enhanced affinity toward atherosclerosis in these patients.     

Lowering of plasma glucose concentrations with bezafibrate in patients with moderately controlled NIDDM

The goal of this study was to investigate whether treatment with bezafibrate improves glucose tolerance in non-insulin-dependent diabetes mellitus (NIDDM). The study included 37 NIDDM patients with HbA1 concentrations greater than 8.5% and normal kidney and liver function who were being treated with diet alone or diet together with a sulfonylurea drug. One patient withdrew because of constipation. At randomization and after 3 mo of treatment, patients were given a standard mixed-test-meal tolerance test (MTT; 500 cal) after an overnight fast, and plasma glucose, insulin, C-peptide, metabolite, nonesterified fatty acid (NEFA), and triglyceride concentrations were measured at 15- to 30-min intervals. Serum lipid, HbA1, and fructosamine concentrations were measured at monthly intervals. Glucose, NEFA, and triglyceride concentrations were significantly lower throughout the second MTT in bezafibrate patients (P less than 0.01-0.001) but not in the placebo group. Fasting serum insulin and C-peptide levels, but not postprandial concentrations, were reduced only in bezafibrate patients (P less than 0.05). After 3 mo, mean fasting serum triglyceride concentrations fell from 2.2 to 1.4 mM (P less than 0.001), total serum cholesterol concentrations from 6.3 to 5.5 mM (P less than 0.001), and low-density lipoprotein cholesterol concentrations from 4.2 to 3.5 mM (P less than 0.001) in bezafibrate patients. There were no changes in serum lipid concentrations in the placebo group. Treatment of patients with moderately controlled NIDDM with bezafibrate improves glucose tolerance and the serum lipid profile. Bezafibrate treatment may be a useful adjunct to hypoglycemic therapy in patients with NIDDM.     

Insulin resistance and enhanced protein glycation in men with prehypertension.

BACKGROUND: Insulin resistance and hyperinsulinemia have been reported among patients with hypertension. However, little is known about insulin sensitivity in subjects with prehypertension. The aim of this study was to assess whether the metabolic characteristics of insulin resistance syndrome are present in prehypertensive subjects. METHODS: Plasma fasting glucose, lipid profile, glycated hemoglobin, fructosamine and insulin concentrations were evaluated in 35 prehypertensive subjects and in 30 healthy controls. RESULTS: Prehypertensive subjects had significantly higher levels of plasma insulin and triglycerides compared with normotensive subjects. The level of high-density lipoprotein cholesterol was significantly lower in prehypertensive subjects compared with controls. There was no significant difference in total cholesterol and low-density lipoprotein cholesterol levels. The levels of glycated hemoglobin and fructosamine were also significantly higher in prehypertensive subjects compared with controls. Plasma insulin levels were positively correlated with systolic and diastolic blood pressure in prehypertensive subjects. Similarly, plasma insulin was significantly positively correlated with triglyceride and negatively correlated with high-density lipoprotein cholesterol. CONCLUSIONS: The present study indicates that prehypertensive non-diabetic subjects have higher insulin resistance and protein glycation compared to normotensive subjects, which may contribute to the pathogenesis of prehypertension.     

Effect of simvastatin on plasma lipid and lipoprotein concentrations and low-density lipoprotein metabolism in the nephrotic syndrome.

1. The effect of inhibiting the rate-limiting enzyme (3-hydroxy-3-methylglutaryl-CoA reductase, EC 1.1.1.88) in cholesterol synthesis on plasma lipid and lipoprotein concentrations was investigated in 16 patients with primary glomerular disease, heavy proteinuria, well-preserved renal function and hypercholesterolaemia. 2. Detailed studies of low-density lipoprotein metabolism were performed on eight patients before and after 12 weeks of simvastatin therapy. Radioiodinated tracers were used to quantify the fractional catabolic rate of low-density lipoprotein by apolipoprotein B/E receptors and alternative pathways. 3. Simvastatin produced consistent reductions in total plasma cholesterol concentration (median 36.9%), plasma low-density lipoprotein-cholesterol concentration (43.6%) and apolipoprotein B pool size (29.9%). 4. In contrast, the changes in kinetic parameters of low-density lipoprotein metabolism showed no clear pattern. Although an increase in the receptor-mediated catabolism of low-density lipoprotein was demonstrated in five patients, no change or a slight decrease was seen in three patients. Production rates were not significantly altered, although there was a slight decrease in the median value (from 12.4 to 9.7 mg day-1 kg-1). Plasma lathosterol concentration was reduced in all eight patients (range 34-71%), indirectly confirming significant inhibition of cholesterol synthesis. 5. These results suggest that, as in patients with primary moderate hyperlipidaemia, the significant cholesterol-lowering effect of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors in the nephrotic syndrome is accompanied by variable changes in lipoprotein metabolism. The reasons for this heterogeneous response are unclear. This reflects our limited understanding of the metabolic basis of nephrotic hyperlipidaemia and the relationship between hepatic sterol synthesis and plasma lipoprotein kinetics.     

High-Density Lipoprotein Cholesterol, Hepatic Lipase and Lipoprotein Lipase Activities in Thyroid Dysfunction -- Effects of Treatment

We have Investigated the effects of hyper-and hypothyroidism(clinical and subclinical) on lipid metabolism, with specialemphasis on serum high-density lipoprotein cholesterol, post-heparinplasma hepatic lipase and lipoprotein lipase activities. In16 patients with hyperthyroidism, increased post-heparin plasmahepatic lipase activity, decreased serum total cholesterol andserum high-density lipoprotein cholesterol were found whilelipoprotein lipase activity and serum triglyceride were normal.In six patients with overt hypothyroidism serum total cholesteroland triglyceride were increased, post-heparin plasma hepaticlipase and lipoprotein lipase were decreased while serum high-densitylipoprotein cholesterol was normal. In six patients with subclinicalhypothyroidism, serum total cholesterol was increased, serumhigh- density lipoprotein cholesterol was decreased, while serumtriglyceride, post-heparin plasma hepatic lipase and lipoproteinlipase were normal. When the three groups of patients becameeuthyrold, serum total cholesterol, serum triglycyeride, post-heparinplasma hepatic lipase, lipoprotein lipase, and serum high-densitylipoprotein cholesterol reverted to normal except for serumhigh-density lipoprotein cholesterol in the hyperthyroid groupwhich showed no significant change with treatment. A positivecorrelation was found between serum T3 and post heparin plasmahepatic lipase while negative correlations were found beweenserum total cholesterol and serum T3, post-heparin plasma hepaticlipase and serum total cholesterol, lipoprotein lipase and serumtriglyceride respectively. Thus in these patients with thyroiddysfunction, significant reversible alterations In serum totalcholesterol, triglyceride and high- density lipoprotein cholesterolwere found and could be correlated with the observed changesin the activities of hepatic lipase and lipoprotein lipase.     

Treatment of hypertension with dyslipidemia

Lifestyle modifications are the first approach to the treatment of dyslipidemia and hypertension, that is, control of overweight; reduced intake of saturated fat, cholesterol, sodium chloride, and alcohol; and increased physical activity. In high doses, thiazide diuretics and loop diuretics can induce at least short-term increases in levels of total plasma cholesterol, triglycerides, and low-density lipoprotein cholesterol. Low-dose thiazide diuretics do not produce these effects. beta-blockers may increase levels of plasma triglycerides transiently and reduce levels of high-density lipoprotein cholesterol. alpha-blockers may decrease serum cholesterol concentration to a modest degree and increase high-density lipoprotein cholesterol. Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium antagonists, and central adrenergic agonists have clinically neutral effects on levels of serum lipids and lipoproteins.     

Metabolic and antihypertensive effects of nebivolol and atenolol in normometabolic patients with mild-to-moderate hypertension.

This was a double-blind, randomized, two-center, active-controlled, prospective, parallel study designed to evaluate the effects of nebivolol at daily doses of 5 mg on lipid and carbohydrate metabolism and on blood pressure in comparison with atenolol at daily doses of 50 mg. Normometabolic subjects with mild-to-moderate essential hypertension were recruited for this study, which included a 4-week, single-blind placebo washout phase and a 12-week double-blind treatment phase. After 12 weeks of treatment, both drugs demonstrated a significant decrease from baseline in high-density lipoprotein (HDL) apolipoprotein A-I (HDL-apoA-I) (nebivolol, P <.02; atenolol, P <.05). A significant reduction in HDL cholesterol (HDL-C) from baseline was also observed with nebivolol (P <.05). There were no significant differences between the drugs for these parameters, and the ratio low-density lipoprotein cholesterol (LDL-C)-to-HDL-C did not change significantly after 12 weeks of active treatment with nebivolol or atenolol. There were no significant changes in total cholesterol, HDL (2) -C, HDL (3) -C, LDL-C, very-low-density lipoprotein cholesterol (VLDL-C), total triglycerides, HDL-triglycerides (TG), LDL-TG, VLDL-TG, total apoB, LDL-B, VLDL-B (including the ratio LDL-C-to-LDL-apoB), or Lp(a) during treatment with both drugs. No significant differences in plasma apoA-I and apoC-III as well as in apoA-I-, C-III-containing lipoprotein particles (including the apoC-III ratio) were observed between the drugs, neither before nor after each active treatment. There were no significant differences between the drugs or within each treatment group in plasma glucose, insulin, or C-peptide concentrations after a 2-hour oral glucose tolerance test. Mean clinic trough sitting systolic blood pressure (SBP)/diastolic blood pressure (DBP) significantly decreased from 150/98 mm Hg at baseline to 141/90 mm Hg at termination for nebivolol and from 160/99 mm Hg at baseline to 145/88 mm Hg at termination for atenolol. No significant between-treatment differences were observed for the mean clinic trough sitting SBP/DBP. Both drugs significantly increased the atrial natriuretic factor (ANF) N-terminal plasma levels, whereas no changes were observed in ANF C-terminal plasma concentrations. A significant decrease (P <. 05) in the plasma adrenocorticotropic hormone levels was observed after administration of both drugs. A significant decrease (P <.05) in plasma cortisol levels was observed only after atenolol treatment. The incidence of adverse events reported during nebivolol treatment was comparable to that observed during atenolol treatment. Heart rate was significantly reduced by both drugs. There were no significant changes in hematology, biochemistry, or urinalysis studies. Neither nebivolol nor atenolol adversely affected lipid or carbohydrate metabolism in normometabolic hypertensive patients. Both treatments demonstrated adequate and similar antihypertensive effects and were well tolerated.     

Absorption and metabolism of cholesterol in familial hypercholesterolaemia

1. The present study investigated the role of intestinal cholesterol absorption in the regulation of cholesterol metabolism and serum lipoprotein levels in 22 patients with heterozygous familial hypercholesterolaemia on low to normal cholesterol intake. 2. The results showed that the higher the dietary cholesterol absorption, the lower was the overall synthesis of cholesterol. Efficient cholesterol absorption actually reduced the elimination of cholesterol as faecal neutral sterols but not consistently as bile acids. 3. In multifactorial analysis, body mass index and dietary plant sterols were negatively associated with cholesterol absorption, but were unrelated to cholesterol synthesis. 4. Fractional cholesterol absorption was related only to the serum very-low-density triacylglycerol level. It was not associated with the total or low-density lipoprotein cholesterol levels. On the other hand, cholesterol synthesis was significantly associated with the serum concentrations of very-low-density lipoprotein and intermediate-density lipoprotein cholesterol and triacylglycerols, and with those of low-density lipoprotein triacylglycerols. 5. In conclusion, dietary cholesterol absorption is an essential regulator of cholesterol homoeostasis in familial hypercholesterolaemia, even in patients on low cholesterol intake.     

Pharmacokinetics, Distribution in Serum Lipoproteins and Tissues, and Renal Toxicities of Amphotericin B and Amphotericin B Lipid Complex in a Hypercholesterolemic Rabbit Model: Single-Dose Studies

The purpose of this study was to determine if a relationship exists among total serum and lipoprotein cholesterol concentration, the severity of amphotericin B (AmpB)-induced renal toxicity, and the serum pharmacokinetics of AmpB in hypercholesterolemic rabbits administered AmpB and AmpB lipid complex (ABLC). After 10 days of cholesterol-enriched diet (0.50% [wt/vol]) or regular rabbit diet (control), each rabbit was administered a single intravenous bolus of AmpB or ABLC (1.0 mg/kg of body weight). Blood samples were obtained before administration and serially thereafter for the assessment of serum pharmacokinetics, kidney toxicity, and serum lipoprotein distribution. Rabbits were humanely sacrificed after all blood samples were obtained, and tissues were harvested for drug analysis. Before drug treatment, cholesterol-fed rabbits demonstrated marked increases in total serum cholesterol and low-density lipoprotein (LDL) cholesterol levels compared with levels in rabbits on a regular diet. No significant differences in triglyceride levels were observed. A significant increase in serum creatinine levels was observed in cholesterol-fed and regular diet-fed rabbits administered AmpB. However, the magnitude of this increase was 2.5-fold greater in cholesterol-fed rabbits than in regular diet-fed rabbits. No significant differences in triglyceride levels were observed. A significant increase in serum creatinine levels was observed in cholesterol-fed and regular diet-fed rabbits administered ABLC. Whereas AmpB pharmacokinetics were significantly altered in cholesterol-fed rabbits administered free AmpB, similar AmpB pharmacokinetics were observed in both rabbit groups administered ABLC. Renal AmpB levels were significantly increased in cholesterol-fed rabbits administered AmpB compared with those in all other groups. Hepatic and lung AmpB levels were elevated in cholesterol-fed rabbits administered free AmpB compared to controls. In addition, hepatic, lung, and spleen AmpB levels were significantly decreased in cholesterol-fed rabbits administered ABLC compared to controls. An increased percentage of AmpB was recovered in LDL–very-low-density lipoprotein fraction when free AmpB was administered to cholesterol-fed rabbits compared with those in all other groups. These findings suggest that increases in cholesterol, specifically, LDL cholesterol levels, modify the disposition and renal toxicity of free AmpB. However, the pharmacokinetics and renal toxicity of ABLC were independent of elevations in total and LDL cholesterol levels.     

Effect of cyclosporine on HMG-CoA reductase, cholesterol 7alpha-hydroxylase, LDL receptor, HDL receptor, VLDL receptor, and lipoprotein lipase expressions

Long-term administration of cyclosporine (CsA) has been shown to cause hypercholesteremia, hypertriglyceridemia, and elevations of plasma low-density and very low-density lipoprotein (LDL and VLDL) levels in humans. This study was undertaken to explore the effects of CsA on expressions of the key lipid regulatory enzymes and receptors. Thus, hepatic expressions of cholesterol 7alpha-hydroxylase (the rate-limiting step in cholesterol conversion to bile acids), LDL receptor, and high-density lipoprotein (HDL) receptor proteins, as well as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity were determined in rats treated with CsA (18 mg/kg/day) or placebo for 3 weeks. In addition, skeletal muscle and adipose tissue expressions of lipoprotein lipase and VLDL receptor were measured. Western blot analysis was used for all protein measurements using appropriate antibodies against the respective proteins. CsA-treated animals showed mild but significant elevations of plasma cholesterol and triglyceride concentrations. This was associated with a marked down-regulation of cholesterol 7alpha-hydroxylase in the liver and a severe reduction of lipoprotein lipase abundance in skeletal muscle and adipose tissue. However, hepatic LDL receptor and HDL receptor expressions and HMG-CoA reductase activity were not altered by CsA therapy. Likewise, skeletal muscle and adipose tissue VLDL receptor protein expressions were unaffected by CsA administration under the given condition. In conclusion, CsA administration for 3 weeks resulted in a significant reduction of hepatic cholesterol 7alpha-hydroxylase and marked down-regulation of skeletal muscle and adipose tissue lipoprotein lipase abundance in rats. The former abnormality can contribute to hypercholesterolemia by limiting cholesterol catabolism, whereas the latter may contribute to hypertriglyceridemia and VLDL accumulation by limiting triglyceride-rich lipoprotein clearance in CsA-treated animals.