Effect of oral carnitine supplementation on disturbances of lipid metabolism in the uremic rat

Carnitine deficiency has recently been incriminated in the pathogenesis of the disturbed lipid metabolism observed in hemodialysis patients. The present study was performed to investigate the effects of L-carnitine administration on the lipid metabolism of rats with experimental chronic renal failure as compared to normal rats. Three groups of rats were studied: the first had induced chronic uremia, the second was sham-operated and pair-fed with the first, and the third was sham-operated and fed ad libitum. Serum triglycerides were significantly higher in uremic rats than in control animals of both groups. In addition to triglycerides, serum total cholesterol and phospholipids were also increased in uremic rats. The fractional clearance rate of Intralipid [K2(%)] was decreased in uremic as compared to control animals. The in vivo oxidation of radiolabeled palmitate was lower in uremic than in ad libitum-fed control animals but not lower than in pair-fed control rats. The daily oral administration of L-carnitine to uremic rats was associated with stable serum triglycerides. On the contrary, serum triglycerides increased significantly in the untreated uremic rats over the same period of time. Serum total cholesterol and phospholipids remained similar in the presence and the absence of L-carnitine treatment. The intravenous fat tolerance test of carnitine-supplemented uremic rats improved slightly, although not significantly, when compared to that of untreated uremic rats. In conclusion, oral L-carnitine supplementation in chronically uremic rats had only modest or no effects on several plasma lipid parameters.(ABSTRACT TRUNCATED AT 250 WORDS)     

Factors of increase in serum triglyceride-rich lipoproteins in uremic rats

The possible mechanisms of the increase in serum triglycerides (TG) and TG-rich lipoproteins were studied in chronically uremic (U) rats by comparison with either ad-lib fed control (C) rats or diet-restricted (DR), sham-operated pair-fed control rats. A first series of animals was studied in the fed state and a second series after a 16-hr fast. In U animals the concentration of serum TG and TG-rich particles was lower than that of C rats in the fed state but significantly higher than that of C and DR rats after a 16-hr fast. Serum glucose and lactate concentrations in the fed or fasted state were unchanged by uremia. Serum insulin concentration was significantly decreased in U rats as compared to C and DR rats in both series. The fast did not increase the concentration of serum nonesterified fatty acids (NEFA) in U or DR animals to the same extent as in C rats, whereas the serum concentration of beta-hydroxybutyrate (BOB), which was higher than that of C rats in the fed state, was significantly lower after a 16-hr fast. In U animals, as compared to control rats of either series, a significant decrease of epididymal lipoprotein lipase (LPL) activity was observed during both nutritional states when expressing the enzymic activity per number of cells. In conclusion, our data provide evidence against hepatic over-production of TG-rich lipoproteins in rats with chronic renal failure and strongly point to an LPL-mediated defect of their peripheral catabolism, probably related to the insulin deficiency state.     

Effect of magnesium deficiency on lipid metabolism in uremic rats

The effects of acute magnesium deficiency on lipid metabolism were examined in five-sixths nephrectomized uremic rats and sham-operated rats. Three weeks after the surgery, both groups were divided into two subgroups. Half of the uremic and sham-operated rats received a magnesium-deficient diet. The rest of the experimental animals received a control diet. After 2 weeks on this regimen, all animals were sacrificed. In uremic rats, magnesium deficiency increased serum triglyceride levels and decreased high-density lipoprotein cholesterol levels as in sham-operated rats. Total serum cholesterol levels were higher in uremic rats than in sham-operated rats with or without magnesium deficiency. Serum free fatty acid levels were increased only in uremic rats with magnesium deficiency. These results suggest that magnesium deficiency worsens several parameters of lipid in uremic rats.     

Thyroid gland volume and serum concentrations of thyroid hormones in chronic renal failure

Thyroid gland volume, ultrasonically determined, and thyroid function were investigated in 40 patients with chronic renal failure (33 of these on hemodialysis) and 40 sex-, age- and weight-matched healthy controls. None had thyroid autoantibodies or a clinically detectable goiter. The median thyroid gland volume was significantly elevated in the uremic patients: 24 ml (range 8-43 ml) compared with the healthy controls 17 ml (range 10-22 ml) (p less than 0.005). The serum concentrations of thyroxine (T4), triiodothyronine (T3), free thyroxine index (FT4I) and free triiodothyronine index (FT3I) were significantly decreased in uremic subjects compared with the controls. The serum concentration of thyrotropin did not differ significantly between patients and controls. None of the thyroid function variables correlated with thyroid gland volume. In conclusion, thyroid gland volume was increased in patients with chronic renal failure. The alterations in thyroid hormone concentrations could, however, not explain this finding.     

Triglyceride-lowering effect of dietary vitamin E in streptozocin-induced diabetic rats. Increased lipoprotein lipase activity in livers of diabetic rats fed high dietary vitamin E

High vitamin E supplementation in the diets of streptozocin-induced diabetic rats eliminates accumulation of lipid peroxides in the plasma and the liver, returns the plasma triglycerides toward normal levels, and increases the activity of lipoprotein lipase. Vitamin E has no effect on the levels of insulin or glucose. These findings suggest that vitamin E increases the total hepatic triglyceride lipase activity by increasing the lipoprotein lipase activity possibly by protecting the membrane-bound lipase against peroxidative damage.     

Effect of exercise and diet on triglyceride metabolism in rats with moderate insulin deficiency

The ability of exercise and diet to modify the effects of moderate streptozotocin-induced insulin deficiency on triglyceride metabolism has been studied in the rat. Insulin-deficient rats allowed to run spontaneously in exercise wheel cages had significantly lower (P less than 0.001) plasma glucose levels (187 +/- 19 mg/dl) than either sedentary (374 +/- 24 mg/dl) or sucrose-fed (450 +/- 13 mg/dl) diabetic rats, despite the fact that plasma insulin levels were comparable in all these groups. Plasma triglyceride (TG) levels in exercise-trained rats with diabetes (51 +/- 5 mg/dl) were actually lower than in control rats with normal glucose tolerance (90 +/- 14 mg/dl). In contrast, plasma TG levels were higher than control levels in diabetic sedentary rats (128 +/- 11 mg/dl), and severe hypertriglyceridemia developed in sucrose-fed diabetic rats (369 +/- 35 mg/dl). The ability of exercise training to attenuate diabetic hypertriglyceridemia, which was observed in both chow-fed and sucrose-fed rats, was secondary to a decrease in TG secretion, and appeared to be related to lower plasma FFA concentrations. In contrast, the accentuation of diabetic hypertriglyceridemia seen in sucrose-fed rats was related to a defect in TG catabolism. Adipose tissue lipoprotein lipase (LPL) activities were essentially identical in all diabetic rats, suggesting that the observed difference in TG kinetics could not be attributed to concomitant increases or decreases in adipose tissue LPL activity. These results emphasize the powerful impact of exercise and diet on TG metabolism in rats with moderate degrees of insulin deficiency.     

Insulin release from column-perifused isolated islets of uremic rats

In order to examine the insulin secretion in chronic renal failure, isolated pancreatic islets either from uremic rats or from control rats were mixed into a short column of Bio-Gel P-2 polyacrylamide beads and perifused. Uremic rats had higher concentrations of blood urea nitrogen, serum creatinine, and immunoreactive insulin and lower concentration of plasma 1,25-(OH)2D3 than control rats. Although the basal insulin release in the presence of 5.0 mM glucose showed no difference between uremic and control rats, the initial insulin release in the presence of 16.2 mM glucose was significantly lower (p less than 0.05) in uremic than in controls rats. The insulin content in islets was not different between both groups. These findings suggest that there might be impairment of the initial insulin secretion without changes of insulin content in pancreatic islets in uremia.     

Induction of insulin resistance in normal adipose tissue by uremic human serum

An incubation of uremic human serum with normal rat adipose tissue will make the subsequently isolated adipocytes less responsive to insulin. To examine the extent of insulin resistance, we obtained sera from nondiabetic, uremic patients, who had not undergone dialysis therapy. The sera were then dialyzed (3500 molecular-weight cutoff) for 18 hr against a defined culture medium to eliminate possible in vitro effects of altered levels of end-product metabolites, electrolytes, and metabolic substrates. After an incubation of epididymal fat tissue from normal rats, for 3 hr with the dialyzed sera (50% vol/vol), cells were isolated and washed. The insulin stimulation of 14C-glucose (0.2 mM) incorporation to 14CO2 and total lipids was significantly reduced in the adipocytes pretreated with sera from 19 of the 29 uremic patients. Although elevated in the uremic patients, the sera levels of insulin, and parathyroid and growth hormones were not correlated to insulin resistant activity. Furthermore, incubation of adipose tissue for 3 hr with insulin, glucagon, or PTH did not produce resistance. The uremic sera reduced glucose utilization equally at 0.2 and 50 mM glucose, suggesting that the insulin resistance was induced additionally at a site distal to the glucose transport system. However, the concentration of insulin (22 microunits/ml) required for half-maximal stimulation of glucose metabolism was not altered by pretreatment with uremic serum. Also, neither the isoproterenol-stimulated lipolysis nor the inhibition of this cellular event was influenced by pretreatment with uremic sera.(ABSTRACT TRUNCATED AT 250 WORDS)     

Selenium in Uremia

Abstract: The importance of selenium as an essential trace element for man has been increasingly recognized during the last several years. Selenium deficiency has been associated with cases of congestive cardiomyopa-thy, skeletal myopathy, anemia, enhanced cancer risk, elevated incidence of cardiovascular disease, immune system alterations, hair and nail changes, and abnormalities in thyroid hormone metabolism. These symptoms are frequently present in chronic uremic patients. Nevertheless, the prevalence and significance of selenium deficiency in the uremic syndrome is still not clearly defined. This article reviews the selenium status in chronic uremic patients, the supposed pathogenetic mechanisms of selenium disturbance in uremia, and the possible role of selenium deficiency on some uremic abnormalities.     

Effect of Acetate Administration on Rats with Chronic Uremia

To investigate the effect of long-term acetate administration on uremic and nonuremic rats, the blood lipid level, the incorporation of [14C]acetate into exhaled 14CO2 and into tissue lipids, and morphological changes were studied. Experimental chronic uremia was caused by partial nephrectomy, and sodium acetate of NaC1 was given intraperitoneally for approximately 12 weeks. Controls were sham-operated rats given acetate or NaC1. Hyperlipidemia was found in the uremic rats; it was more severe in the rats given acetate. Incorporation of [14C]acetate into 14CO2 was lower in uremic rats given acetate than in other groups, and incorporation into liver lipids was not different in different groups. Small fat droplets had accumulated diffusely in the hepatocytes of nonuremic and uremic rats, but accumulation was more severe in the former. Large fat droplets were found in rats given acetate, mostly in the periphery of liver lobules. Uremic rats given NaC1 did not have such changes. The results suggested that chronic acetate administration may contribute to hyperlipidemia in uremic rats and to lipid accumulation in hepatocytes in both uremic and nonuremic rats, causing fatty degeneration of the liver.     

Influence of Magnesium Deficiency on Concentration of Calcium in Soft Tissue of Uremic Rats

The influence of magnesium (Mg) deficiency on the concentration of calcium (Ca) in the aorta, heart, and kidney was evaluated in uremic rats. A total of 32 rats were randomly assigned to two groups: one group made uremic by the 5/6 nephrectomy method, and the other serving as sham-operated controls. Both groups were randomly assigned to two subgroups: one group given a Mg-deficient diet and the other fed a Mg-supplemented diet. After 12 weeks on the regimen, all animals were sacrificed. In Mg-supplemented uremic rats, the concentration of Ca in the aorta was higher than in Mg-supplemented control rats. The concentration of Ca in the aorta was further increased in Mg-deficient uremic rats. The concentrations of Ca in the heart and the kidney were also increased in Mg-deficient uremic rats, as compared with Mg-supplemented uremic rats. The concentration of Mg was decreased in the aorta and increased in the kidney of Mg-deficient rats. There was no significant influence of Mg deficiency on the concentration of phosphate in tissue. Results suggest that Mg deficiency in uremia may increase aortic calcification.     

Limited value of zinc protoporphyrin as a marker of iron status in chronic hemodialysis patients

BACKGROUND: In an attempt to find new parameters able to evaluate the actual iron availability by bone marrow cells, zinc protoporphyrin (ZnPP), a metabolic intermediate generated in the red blood cell by the incorporation of zinc instead of iron, has been proposed. ZnPP is a good marker of iron-deficiency anemia in non-uremic people, as red blood cell ZnPP concentration rises specifically (except for lead intoxication) in this condition. Existing data on ZnPP as a marker of iron deficiency in uremic patients comes mainly from cross sectional studies on chronic hemodialysis and has produced conflicting results. SUBJECTS AND METHODS: Therefore, we prospectively studied 42 HID patients, 28-88 years old, 13-346 months of dialysis age, beginning from a period of maximal iron deficiency, due to the lack of parenteral iron compounds (T0) up to the end of more than one year of follow-up with continuous parenteral iron supplementation (T4). ZnPP, hemoglobin, transferrin saturation and ferritin were serially determined before and after six weeks (T1), four months (T2), seven months (T3) and 14 months (T4) of parenteral iron supplementation at a maintenance dose of 0.5-1 mg/kg/week. RESULTS: In comparison with baseline values (95+/-37 micromol/mol heme) there were no significant changes in ZnPP levels at T1 and T2 despite a continuous increase in both transferrin saturation and ferritin values, while ZnPP significantly decreased at T4 (63+/-37 micromol/mol heme, p<0.001). There was no correlation between ZnPP and both transferrin saturation and ferritin at any time during the study, the same was true for ZnPP and zinc and lead serum concentration, fibrinogen and reactive C protein levels at T1 and T4, respectively. At T4, only 2/10 patients who still showed ZnPP levels >80 micromol/mol heme had absolute or functional iron deficiency, when the percentage of hypochromic red cells were measured. CONCLUSION: We conclude that ZnPP untimely parallels a change in iron balance in only a proportion of uremic people, in as much as confounding factors, such as chronic inflammation and uremia in itself may obscure its relationship with iron status. Therefore, ZnPP cannot be assumed to be a first-line diagnostic marker of iron balance in uremic patients.     

从糖肾宁对糖尿病肾病大鼠糖脂代谢的影响研究其肾脏保护作用

目的：探讨糖肾宁对糖尿病肾病大鼠糖脂代谢的影响及其肾脏保护作用的机制。方法：雄性SD大鼠40只,采用腹腔内注射福氏完全佐剂、链脲佐菌素及高脂饲料喂养的方法建立糖尿病肾病大鼠模型。按24h尿微量白蛋白（24hU-Alb）测定值随机分为模型组（M组）、糖肾宁组（T组）,格列喹酮组（G组）和正常组（N组）各8只,8周后,检测各组大鼠空腹血糖、空腹胰岛素（INS）、糖化血红蛋白（HbA1c）、三酰甘油（TG）,胆固醇（TC）、高密度脂蛋白（HDL）、低密度脂蛋白（LDL）、24hU-Alb及肾功能。结果：M组空腹血糖、TC、LDL显著升高,INS、HDL明显下降。治疗8周后T组INS明显上升,TC、LDL显著下降、HDL明显升高,24hU-Alb减少,肾功能显著改善,且明显优于G组。结论：格列喹酮和糖肾宁均可不同程度影响血糖水平,糖肾宁还可有效调节脂代谢。糖肾宁可能是通过调节肾组织糖代谢及血脂代谢,延缓了肾小球硬化及肾间质纤维化进程,发挥了独立于降糖作用之外的降蛋白及肾功能保护作用。     

Protein synthesis and degradation in skeletal muscle of chronically uremic rats

We used the perfused hemicorpus preparation to measure individual rates of protein synthesis and degradation. Using fed animals, perfused either with or without insulin, muscle protein synthesis and hemicorpus protein degradation rates were similar, but myofibrillar protein degradation was clearly increased in the uremic preparations. When the animals were fasted, differences in the rates of skeletal muscle protein turnover were apparent. Uremic rats lost more wt at both 24 and 48 hr of fasting when compared to either ad libitum fed or pair-fed controls who started fasting at body wts equivalent to our uremic rats. The accelerated wt loss was accompanied by lower rates of protein synthesis, higher degradation rates, and greater net protein catabolism in our uremic rats. Alterations in body lipid content were present in uremia and correlated with the rate of protein degradation in both control and uremic rats. These data demonstrated that even in the fed state, uremia is associated with subtle alterations in skeletal muscle protein turnover. When stressed, these alterations become more pronounced. Insufficient stores of body lipids, either due to inadequate nutrition or altered metabolism, may contribute to the alterations in muscle protein turnover seen in chronic renal insufficiency.     

Influence of an uremia-associated serum factor on CNS alpha 2-adrenoceptors

The action of blood serum from uremic rats and chronically hemodialyzed patients was investigated for effects on alpha 2-adrenoceptors labeled with 3H-clonidine. Compared to blood sera of rats and patients with normal kidney function, uremic serum significantly inhibited specific 3H-clonidine binding. In saturation experiments the density and affinity of alpha 2-adrenoceptors for 3H-clonidine was lowered by uremic serum. Heating, or trypsin or lipase treatment of the serum did not affect this phenomenon. The effect of the patient's serum could likewise be demonstrated after hemodialysis treatment. The presence of an allosteric regulating substance for clonidine binding to adrenoceptors could at least partially explain the altered and attenuated action of this drug in renal insufficiency.     

小肠代谢在十二指肠空肠旁路术对2型糖尿病的治疗作用及机制

目的:观察十二指肠空肠旁路术(DJB)对2型糖尿病(T2DM)大鼠的治疗效果及机制。方法:将高脂饲料联合小剂量链脲佐菌素诱导的T2DM模型大鼠随机分为DJB组和假手术组,每组15只。观察2组大鼠手术前后体质量、空腹血糖及血脂的变化;于术后8周取DJB组大鼠Roux肠袢以及假手术组大鼠相应的肠组织标本,称重并用RT-PCR和Western blot检测参与糖代谢和脂代谢关键酶m RNA和蛋白表达。结果:术前两组空腹血糖、血脂水平、体质量均无统计学差异(均P0.05)。术后DJB组与假手术组比较,空腹血糖水平与各血脂指标均明显降低(均P0.05),但体质量无统计学差异(P0.05);Roux肠袢质量明显增加(2.025 g vs.0.702 g),肠组织参与糖代谢和脂代谢关键酶的m RNA及蛋白水平均明显升高(均P0.05)。结论:DJB能有效降低T2DM大鼠的血糖、血脂水平,该作用可能与术后小肠自身代谢的改变有关。     

Effects of a low-phosphorus, low-nitrogen diet supplemented with essential amino acids and ketoanalogues on serum beta-endorphin in chronic renal failure

The effects of a vegetarian low-protein, low-phosphorus diet supplemented with essential amino acids and ketoanalogues, on the serum beta-endorphin, growth hormone, parathyroid hormone, thyroid hormones (T3 and T4), pituitary TSH and total cortisol were studied in 12 male chronic uremics. beta-Endorphin decreased, as well as growth hormone. Parathyroid hormone and T3 improved significantly, reaching almost normal values. It is hypothesized that the correction of the beta-endorphin excess may account in part for the improvement of some endocrinological and metabolic effects exerted by this dietary treatment. The possible pathophysiological mechanisms which could explain the antiendorphinic action of this treatment in uremic patients are discussed, as well as the possible beneficial endocrine and metabolic effects exerted by the fall in circulating beta-endorphin.     

Association of adiponectin with cardiovascular events in diabetic and non-diabetic hemodialysis patients

Adiponectin is a novel collagen-like protein synthesized by white adipose tissue. Its levels are decreased in obesity, type-2 diabetes and insulin-resistant states, and are increased in chronic renal failure. It has anti-inflammatory and anti-atherogenic properties. This study was planned to evaluate the levels of adiponectin in uremic patients with and without diabetes and to find any relationship between adiponectin levels and some cardiovascular risk factors, and to determine the possible predictive value of adiponectin for cardiovascular complications (CVC). The study included 100 subjects, 20 of them were healthy subjects and served as the control group (group I), 40 were uremic non-diabetic patients (group II) (half of them were without CVC, group IIA, and the other half were patients with CVC, group IIB) and, lastly, 40 uremic diabetic patients (group III) (half of them were without CVC, group IIIA, and the other half were patients with CVC, group IIIB). All subjects were subjected to complete clinical examination, including determination of mean arterial blood pressure (MABP), body mass index (BMI), waist to hip ratio, routine laboratory investigations, fasting plasma glucose, fasting plasma insulin, lipid profile (cholesterol, TG, LDL, HDL), determination of insulin resistance by homeostasis model assessment index (HOMA-IR) and estimation of serum levels of adiponectin. There was a significant increase in serum adiponectin levels in all the uremic patients (group II and group III) when compared with the control (group I) group, P <0.01; also, serum adiponectin levels were significantly decreased in uremic diabetic patients (group III) when compared with uremic non-diabetic patients (group II), P <0.01; but this was still higher than in the controls. The patients with CVC, whether uremic non-diabetic (group IIB) or uremic diabetic (group IIIB), had a significant decrease in serum adiponectin levels when compared with patients without CVC (group IIA and group IIIA), P <0.01. Serum adiponectin has a significant positive correlation with HDL and a significant negative correlation with MABP, BMI, plasma insulin, HOMA-IR, LDL, TG and cholesterol in all the patients. Therefore, it can be concluded that adiponectin levels in uremic patients, whether diabetic or non-diabetic, may be a good indicator of cardiovascular disease risk.     

金刚丸抗去卵巢大鼠骨质疏松症血清代谢组学研究

目的 利用代谢组学初步探讨金刚丸治疗绝经后骨质疏松症的作用机制。方法 采用去双侧卵巢手术法复制绝经后骨质疏松大鼠模型,将SD雌性大鼠随机分为空白组、假手术组、模型组、金刚丸组(3.6 g/kg)和戊酸雌二醇组(9 mg/kg),每组6只,每天灌胃1次。连续给药12周后取大鼠右侧股骨进行苏木精-伊红染色法(hematoxylin-eosin staining, H&E)及骨密度(bone mineral density, BMD)测定,取腹主动脉血采用酶联免疫吸附法(enzyme-linked immunosorbent assay, ELISE)检测骨代谢指标碱性磷酸酶(alkaline phosphatase, ALP)、骨钙素(osteocalcin, OCN)、血清抗酒石酸酸性磷酸酶5b(tartrate resistant acid phosphatase 5b, TRAP 5b)以及用生化法检测血脂(total cholesterol, TC)、甘油三酯(total triglycerides, TG)、低密度脂蛋白胆固醇(low-density lipoprotei...     

Chronic inhibitory effect of insulin on plasma lipid concentrations in rats with transplanted pancreas

BACKGROUND: Hyperinsulinemia, which is usually related to insulin resistance, is considered to be an important risk factor for coronary artery disease. Our study examines the influence of portal delivery of endogenous insulin after pancreas transplantation on plasma lipid metabolism, as compared with systemic delivery of insulin. METHOD: Pancreas was transplanted heterotopically in normal rats by anastomosis of the donor portal vein to the recipient portal vein (PPTx) or inferior vena cava (CPTx) as an in vivo model of endogenous hyperinsulinemia. RESULTS: The mean value of plasma insulin concentration of CPTx and PPTx rats was 149 and 165% that of control rats, whereas the plasma glucose concentration of CPTx and PPTx rats did not differ significantly from that of control rats. Plasma triglyceride (TG) concentrations were significantly lower in both PPTx and CPTx rats than control rats. During the intravenous glucose tolerance test, the area under the insulin concentration curves of CPTx and PPTx rats was 204 and 215% that of control rats, and they were correlated negatively with plasma TG concentrations. Plasma cholesterol and TG concentrations were significantly lower in PPTx rats than in control and CPTx rats. CONCLUSIONS: Chronic hyperinsulinemia has a dose-dependent inhibitory effect on the regulation of plasma TG concentrations in rats with a transplanted pancreas. Significant lower lipid levels in PPTx rats than in CPTx rats suggest that portal delivery of insulin from the transplanted pancreas is relatively preventive for the atherosclerotic process as compared with systemic delivery of insulin.