Decreased cAMP responsiveness to glucagon in livers from ethynyl estradiol treated rats.

The effects of glucagon on the concentration and output of cAMP were studied in liver slices and in perfused livers from female rats and from animals treated with ethynyl estradiol (15 μg/kg daily for 14 days). The basal content of cAMP in liver slices, or of cAMP released into the perfusion medium in the absence of glucagon, was unaffected by prior treatment of the animal with estrogen. When glucagon was added to the medium, the concentration of cAMP in liver slices was 2.29 ± 0.32 and 1.10 ± 0.11 pmol cAMP/mg wet weight from control and ethynyl estradiol treated rats, respectively. When glucagon was added, the output of cAMP by perfused livers was maximal at 20 minutes with livers from either control or ethynyl estradiol treated rats. Output of cAMP by the perfused liver, when glucagon was added to the medium, was 8.76 ± 0.69 and 1.84 ± 0.08 nmol/g by livers from control and ethynyl estradiol treated rats, respectively. This effect was the same whether animals had been fasted for 12 hours previously, or were allowed free access to food until sacrifice. Clearly, as measured by cAMP accumulation, prior treatment of the rat with ethynyl estradiol reduced the sensitivity of the hepatic cAMP response to glucagon.     

The Male Obese Wistar Diabetic Fatty Rat Is a New Model of Extreme Insulin Resistance

The male obese Wistar Diabetic Fatty (WDF) rat is a genetic model of obesity and non-insulin dependent diabetes (NIDDM). The obese Zucker rat shares the same gene for obesity on a different genetic background but is not diabetic. This study evaluated the degree of insulin resistance in both obese strains by examining the binding and post binding effects of muscle insulin receptors in obese, rats exhibiting hyperinsulinemia and/or hyperglycemia. Insulin receptor binding and affinity and tyrosine kinase activity were measured in skeletal muscle from male WDF fa/fa (obese) and Fa/? (lean) and Zucker fa/fa (obese) and Fa/Fa (homozygous lean) rats. Rats were fed a high sucrose (68% of total Kcal) or Purina stock diet for 14 weeks. At 27 weeks of age, adipose depots were removed for adipose cellularity analysis and the biceps femoris muscle was removed for measurement of insulin binding and insulin-stimulated receptor kinase activity. Plasma glucose (13.9 vs. 8.4 mM) and insulin levels (14,754 vs. 7440 pmoI/L) were significantly higher in WDF obese than in Zucker obese rats. Insulin receptor number and affinity and TK activity were unaffected by diet. Insulin receptor number was significantly reduced in obese WDF rats (2.778 ± 0.617 pmol/mg protein), compared to obese Zucker rats (4.441 ± 0.913 pmol/mg potein). Both obese strains exhibited down regulation of the insulin receptor compared to their lean controls. Maximal tyrosine kinase (TK) activity was significantly reduced in obese WDF rats (505 ± 82 fmol/min/mg protein) compared to obese Zucker rats (1907 ± 610 fmol/min/mg protein). Only obese WDF rats displayed a decrease in TK activity per receptor. These observations establish the obese WDF rat as an excellent model for exploring mechanisms of extreme insulin resistance, particularly post-receptor tyrosine kinase-associated defects, in non-insulin dependent diabetes.     

Hyperglucagonemia and altered responsiveness of hepatic adenylate cyclase-adenosine 3′,3′-monophosphate system to hormonal stimulation during chronic ingestion of dl-ethionine

Basal activity and hormonal responsiveness of the adenylate cyclase-adenosine 3′,5′-monophosphate system were examined in premalignant liver from rat chronically fed the hepatic carcinogen DL-ethionine, and these data were correlated with endogenous levels of plasma glucagon. By 2 weeks basal hepatic cyclic AMP levels, determined in tissue quick-frozen in situ, were 2-fold higher in rats ingesting ethionine than in the pair-fed control. Enhanced tissue cyclic AMP content was associated with an increase in the adenylate cyclase activity of whole homogenates of fresh liver from rats fed ethionine (68 ± 5 pmol cyclic AMP/10 min per mg protein) compared to control (48 ± 4). Cyclic AMP-dependent protein kinase activity ratios were also significantly higher (control, 0.38 ± 0.04; ethionine 0.55 ± 0.05) and the percent glycogen synthetase activity in the glucose 6-phosphate-independent form was markedly reduced (control, 52 ± 7%; ethionine, 15 ± 1.5 %) in the livers of ethionine-fed rats compared to the controls, suggesting that the high total hepatic cyclic AMP which accompanied ethione ingestion was biologically effective. These changes persisted throughout the 38 weeks of drug ingestion. Immunoreactive glucagon levels, determined in portal venous plasma, were 8-fold higher than control after 2 weeks of the ethionine diet (contro, 185 ± 24 pg/ml; ethionine, 1532 ± 195). Analogous to the changes in hepatic parameters, plasma glucagon levels remained elevated during the entire period of drug ingestion until the development of hepatomas. The hepatic cyclic AMP response to a maximal stimulatory dose of injected glucagon was blunted in vivo in ethionine-fed rats (control, 14-fold increase over basal, to 8.63 ± 1.1 pmol/mg wet weight; ethionine, 4.6-fold rise over basal, to 5.42 ± 0.9). Reduced cyclic AMP responses to both maximal and submaximal glucagon stimulation were also evident in vitro in hepatic slices prepared from rats fed the drug, and the reduction was specific to glucagon. Absolute or relative hepatic cyclic AMP responses to maximally effective concentrations of prostaglandin E₁ or isoproterenol in hepatic slices from ethionine-fed rats were greater than or equal to those observed in control slices. Parallel alterations in hormonal responsiveness were observed in adenylate cyclase activity of whole homogenates of these livers, implying that the changes in cyclic AMP accumulation following hormone stimulation were related to an alteration in cyclic AMP generation in the premalignant tissue.In view of the recognized hepatic actions of glucagon and the desensitization of adenylate cyclase which can occur during sustained stimulation of the liver with this hormone, the endogenous hyperglucagonemia that accompanies ethionine ingestion could play a role in the pathogenesis of both the basal alterations in hepatic cyclic AMP metabolism and the reduced responsiveness to glucagon observed in liver from rats fed this carcinogen.     

Effects of oxidative stress on the pharmacokinetics and hepatic metabolism of atazanavir in rats

Abstract

We studied the effects of oxidative stress (OS) on the pharmacokinetics of atazanavir (ATV), particularly the distribution of ATV in the plasma and its metabolism in hepatic microsomes, using a rat model of ferric-nitrilotriacetate-induced OS (OS rats). The areas under the plasma concentration–time curves for intravenous bolus, oral, and intraportal administration of ATV in the OS rats were significantly greater than those in the control rats, whereas blood clearance of ATV after intravenous bolus injection in the OS rats (0.94 ± 0.04 L/h/kg) was approximately half of that in the control rats (2.08 ± 0.20 L/h/kg). Moreover, the intrinsic clearance (CLint), which is determined by in vitro metabolic studies using hepatic microsomal fractions of rats, was approximately 43% lower in the OS rats (0.489 ± 0.017 mL/min/mg protein) than in the control rats (0.851 ± 0.004 mL/min/mg protein). ATV concentrations in both the plasma-bound fraction and erythrocytes of the OS rats were significantly greater than those in the control rats. These results suggest that the hepatic metabolism of ATV may be reduced in patients under OS.     

Peer review: the process

Abstract

Objectives

This study was focused on the monitoring how the anti-inflammatory substance, N¹-methylnicotinamide (MNA), could influence oxidation and glycooxidation stress markers in rats under conditions of streptozotocin (STZ)-induced diabetes mellitus.

Methods

Diabetes mellitus was induced in 60 male Wistar rats by intraperitoneal injection of STZ and after 7 days diabetic animals were allocated to five groups according to the dose of MNA administered for 7 weeks. The degree of DNA damage in lymphocytes, as well as advanced glycation endproducts (AGEs), protein carbonyls, lipid peroxides, and total antioxidant capacity (TEAC) in plasma were measured.

Results

Glycation damage to proteins (represented by AGEs level) was significantly increased in all diabetic groups compared to untreated non-diabetic animals. MNA did not affect TEAC of plasma in any group of diabetic rats. Supplementation of diabetic rats with MNA at the dose of 200 mg/kg resulted in decreased protein carbonyls (from 0.0818 ± 0.0091 to 0.0558 ± 0.0044 nmol/mg proteins; P < 0.05, n = 15) and DNA oxidation, reflected by the levels of 8-oxoG (0.6302 ± 0.085 vs. 0.9213 ± 0.108 8-oxoG/10⁶ G; P < 0.05, n = 15), compared to untreated diabetic animals.

Discussion

Our results demonstrated that MNA at suitable concentrations could influence oxidative modifications of proteins and DNA.     

Identification, Development, and Regional Distribution of Ribonucleotide Reductase in Adult Rat Brain

The development and regional distribution of ribonucleotide reductase (EC 1.17.4.1) were determined in rat brain. Ribonucleotide reductase was partially purified by ammonium sulfate fractionation (20-40% saturation). Enzyme activity was measured by a specific radiochemical assay. This method involved the reduction of [¹⁴C]cytidine diphosphate (CDP) to [¹⁴C]deoxy-cytidine diphosphate with subsequent hydrolysis and separation of the product ([¹⁴C]deoxycytidine) from substrate ([¹⁴C]cytidine) by Dowex-1-borate ion-exchange chro-matography. The specific activity of ribonucleotide reductase in whole brain of newborn rats was 3.78 ± 0.55 units (pmol/h)/mg protein (SEM; n = 6) and declined to 0.17 ± 0.01 units/mg protein (n = 7) at 10-12 weeks of age, with a further decline to 0.11 ± 0.01 units/mg protein (n = 3) at 1 year. Ribonucleotide reductase activity in rat liver decreased from 4.58 ± 0.62 units/mg protein (n = 3) in newborn animals to 0.06 ± 0.01 units/mg protein (n = 7) at 10-12 weeks and was present at trace levels at 6 months of age. The decline in specific activity with age was not due to a change in the K_m for CDP. The K_m for CDP in brain of newborn and adult rats was 80-90 μM. In 10- to 12-week-old rats, the specific activity of ribonucleotide reductase was similar in the various regions of the brain tested except for the brainstem, which had 50% lower specific activity than the whole brain. These results indicate that ribonucleotide reductase activity is present and widely distributed in adult rat brain.     

Nicotinamide and heat preconditioning – Effects on hepatic HSP70, carbohydrate and oxidative disturbances in STZ-induced diabetic rats

ObjectiveNicotinamide (NA) is known to have antioxidant potential and partially to protect insulin-secreting cells against diabetogenic agent STZ (streptozotocin). In a combination to heat stress (HS), NA is also known to induce heat-shock proteins (HSPs) production. Heat preconditioning (HP) and HSPs have cytoprotective effects against development of cellular injury caused by application of subsequent stressor. We aimed to determine if pretreatment with NA and HP (as HSP70 –inducers) can affect STZ-induced diabetic disturbances in rats.MethodsNA-pretreatment (250 mg/kg b.w., 7 days) and heat preconditioning (41 ± 1 °C, 45 min) of diabetic rats was performed. The changes in hepatic carbohydrate- and antioxidative-related enzymes and substrates were investigated.ResultsNA-pretreatment, alone or in combination with HS, resulted in significant increase of HSP70 concentration in the liver of control and diabetic rats. Compared to diabetic controls, pretreatment with NA, in combination with HP, resulted in decrease of blood and liver glucose, increase of glycogen and glucose-6-phosphate level, increase of glycogenolytic/glycolytic enzymes, decrease of gluconeogenic enzymes, as well as an increase of glutathione content and glutathione peroxidase, decrease of glutathione reductase and catalase activities.ConclusionsNA is a potent HSP70 coinducer, alone or in a combination with HS in the liver of both control and diabetic rats. Pretreatment with NA, accompanied by HP, has a pronounced corrective effect on STZ-induced diabetes disturbances in the key hepatic carbohydrate- and antioxidative-related parameters. It seems that this corrective effect is based on the increased production of hepatic HSP70.     

Malonyl-CoA in skeletal muscle and liver of streptozotocin-diabetic rats.

Malonyl-CoA, the inhibitor of carnitine palmitoyl transferase I, has been examined in this study in the muscle and liver of diabetic rats. Male Sprague-Dawley rats were rendered diabetic with streptozotocin (6 mg/100 g body wt). The gastrocnemius/plantaris muscles and liver samples were frozen at liquid nitrogen temperature. Muscle malonyl-CoA was 1.8 +/- 0.2 pmol/mg in control rats and 1.5 +/- 0.2 pmol/mg in the diabetic rats. This difference was not statistically significant. Liver malonyl-CoA of control rats was 8.6 +/- 0.8 pmol/mg, in comparison to 4.3 +/- 0.6 pmol/mg in diabetic rats. In the liver, high concentrations of malonyl-CoA inhibit fatty acid oxidation and ketogenesis. Failure of malonyl-CoA to decline in muscle in the diabetic may be responsible in part for the diversion of fatty acids to the liver, thereby enhancing hepatic fatty acid oxidation and ketogenesis.     

Short-term parenteral application of α-tocopherol leads to increased concentration in plasma and tissues of the rat

Numerous studies suggest that supplemental vitamin E prior to or during vast surgeries might diminish or even prevent ischemia/reperfusion-induced injuries. In the present placebo-controlled study male Sprague-Dawley rats were supplemented parenterally or orally with α-tocopherol for three consecutive days. The applied amount of α-tocopherol was 2.3 μmol per day for oral and 1.2 μmol per day for parenteral supplementation. The enrichment of vitamin E concentrations in plasma and tissue samples (aortic endothelium, liver, and lung) was determined by HPLC. The vitamin E level was elevated following intravenous supplementation in plasma (21.4±1.9 μmol/L vs. 10.2±1.7 μmol/L in parenteral control group), in aortic endothelium (1.1±0.2 pmol/mm² vs. 0.5±0.1 pmol/mm²) and in liver and lung (41.3±7.5 pmol/mg vs. 22.9±6.5 pmol/mg and 75.6±13.6 pmol/mg vs. 51.7±5.9 pmol/mg, respectively). Oral supplementation for three days also led to an increased level in liver (38.2±7.7 pmol/mg vs. 22.9±6.6 pmol/mg in oral control group) and in lung (67.8±5.7 pmol/mg vs. 51.7±9.3 pmol/mg) but not in aortic endothelium or plasma (0.8±0.3 pmol/mm² vs. 0.6±0.3 pmol/mm² and 12.0±2.2 μmol/L vs. 10.7±2.6 μol/L.)     

Direct effect of the luteinizing hormone releasing hormone analog D-Trp6-Pro9-Net-LHRH on rat testicular steroidogenesis

The luteinizing hormone releasing hormone analog D-Trp⁶-Pro⁹-Net-LHRH (LHRH_a) inhibits rat testicular testosterone secretion. To determine whether LHRH_a decreases serum testosterone concentrations solely by inhibiting gonadotropin secretion or, in addition, by influencing directly testicular testosterone biosynthesis, we examined the effects of LHRH_a on the activities of 5 key testicular steroidogenic enzymes. Thirty hypophysectomized, hCG treated rats were given either LHRH_a (1 μg sc/day) or saline during 7 days. The LHRH_a treated animals exhibited a significant decrease of serum testosterone when compared to the control group (498 ± 37 ng/dl vs 2044 ± 105 ng/dl, mean ± SEM, P 〈0.001). 17-Hydroxyprogesterone serum levels were also decreased in the LHRH_a treated rats (61 ± 6 ng/dl vs 93 ± 7 ng/dl, P 〈0.005), while serum progesterone levels were similar in both groups of animals. These changes in steroid concentrations were associated with decreases in the musomal enzyme activities of 17-hydroxylase (37 ± 9 vs 654 ± 41 pmol/mg protein/min, P 〈0.001), 17, 20-desmolase (103 ± 9 vs 522 ± 47 pmol/mg protein/min, P 〈0.001), 3β-hydroxysteroid dehydrogenase (1.7 ± 0.02 vs 4.1 ± 0.1 nmol/mg protein/min, P 〈0.001), aromatase (95 ± 7 vs 228 ± 6 pmol/mg protein/ min, P 〈0.001) and 17-ketosteroid reductase (167 ± 9 vs 290 ± 18 pmol/mg protein/min, P 〈0.01) in the LHRH_a treated animals. These findings indicate that LHRH_a can inhibit directly rat testicular testosterone biosynthesis.     

Dietary Modulation of Plasma Bilirubin and of Hepatic Microsomal Lipid Peroxidation in the Gunn Rat

An in vitro assay for the simultaneous measurement of lipid peroxidation (LPO) and bilirubin degradation BRD) activities in rat liver microsomes has been developed; a good correlation between the 2 activities was observed (r = 0.78). In the Gunn rat a lipid free diet caused an increase in plasma bilirubin (62.4 ± 25.8%, n = 6) and a concomitant decrease in both hepatic microsomal LPO and BRD to zero. In contrast, on a 25% lipid diet there was a decrease in plasma bilirubin (46.1 ± 3.6%; n = 8) associated with an increase in LPO (1.26 ± 0.11 nmol/min/mg protein, and BRD (0.21 ± 0.6 nmol/min/mg protein). Therefore, in the absence of bilirubin glucuronidation, dietary modulation of plasma bilirubin and lipid peroxidation appear to be closely associated.     

Hepatic protein kinase C is not activated despite high intracellular 1,2-sn-diacylglycerol in obese Zucker rats

High intracellular 1,2,-sn-diacylglycerol (DAG) usually activates protein kinase C (PKC). In choline-deficient Fischer 344 rats, we previously showed that fatty liver was associated with elevated hepatic DAG and sustained activation of PKC. Steatosis is a sequelae of many liver toxins, and we wanted to determine whether fatty liver is always associated with accumulation of DAG with activation of PKC. Obese Zucker rats had 11-fold more triacylglycerol in their livers and 2-fold more DAG in their hepatic plasma membrane than did lean control Zucker rats. However, this increased diacylglycerol was not associated with translocation or activation of PKC in hepatic plasma membrane (activity in obese rats was 897 pmol/mg protein×min⁻¹ vs. 780 pmol/mg protein×min⁻¹ in lean rats). No differences in PKC isoform expression were detected between obese and lean rats. In additional studies, we found that choline deficiency in the Zucker rat did not result in activation of PKC in liver, unlike our earlier observations in the choline deficient Fischer rat. This dissociation between fatty liver, DAG accumulation and PKC activation in Zucker rats supports previous reports of abnormalities in PKC signaling in this strain of rats.     

Hepatoprotective potential of flavonoid-rich extracts from Gongronema latifolium benth leaf in type 2 diabetic rats via fetuin-A and tumor necrosis factor-alpha

Background

This study assessed the hepatoprotective potential of flavonoid-rich extracts from Gongronema latifolium Benth on diabetes-induced type 2 rats via Fetuin-A and tumor necrosis factor-alpha (TnF-α).

Methods

In a standard procedure, the flavonoid-rich extract was prepared. For experimental rats, streptozotocin was injected intraperitoneally (45 mg/kg body weight) to induce diabetes mellitus. Following this, rats were given 5% of glucose water for 24 h. Hence, the animals were randomly divided into five groups of ten rats each, consisting of non-diabetic rats, diabetic controls, diabetic rats treated with low and high doses of flavonoid rich-extracts from Gongronema latifolium leaf (FREGL) (13 and 26 mg/kg, respectively), and diabetic rats treated with 200 mg/kg of metformin glibenclamide orally for 3 weeks. Afterwards, the animals were sacrificed, blood and liver were harvested to evaluate different biochemical parameters, hepatic gene expressions and histological examinations.

Results

The results revealed that FREGL (especially at the low dose) significantly (p?<?0.05) reduced alanine transaminase (ALT), aspartate aminotransferase (AST) and alkaline phosphate (ALP) activities, lipid peroxidation level, as well as relative gene expressions of fetuin-A and TNF-α in diabetic rats. Furthermore, diabetic rats given various doses of FREGL showed an increase in antioxidant enzymes and hexokinase activity, as well as glucose transporters (GLUT 2 and GLUT 4), and glycogen levels. In addition, histoarchitecture of the liver of diabetic rats administered FREGL (especially at the low dose) was also ameliorated.

Conclusion

Hence, FREGL (particularly at a low dose) may play a substantial role in mitigating the hepatopathy complication associated with diabetes mellitus.

     

Low [3H]Cytochalasin B Binding in the Cerebral Cortex of Newborn Rat

The concentrations of glucose transporter in the cerebral cortex and brainstem of neonatal (4–7 days old) and adult rats were measured using [³H]cytochalasin B binding. There was significantly lower binding in neonatal cortex (1.9 ± 0.7 pmol/mg protein) compared to adult (8.9 ± 2.5 pmol/mg protein). Scatchard analysis indicates this difference is due to a lower B_max (neonate, 9.7 pmol/mg protein; adult, 18.6 ± 1.3 pmol/mg protein). Measurement of [³H]cytochalasin B binding in microvessels prepared from cortex of adult (28.1 ± 3.5 pmol/mg protein) and neonate (12.8 ± 1.9 pmol/mg protein) indicates a lower binding in the microvasculature of neonates, whereas no such difference was seen in the binding in microvessels prepared from adult and neonatal brainstem (adult, 11.8 ± 2.3 pmol/mg protein; neonate, 9.4 ± 2.7 pmol/mg protein). In both adult and neonate brain, there is an enrichment of glucose transporters in the microvasculature.     

非酒精性脂肪性肝病大鼠肠粘膜紧密连接蛋白ZO-1及肌球蛋白轻链激酶的变化

目的:研究不同阶段非酒精性脂肪性肝病(NAFLD)大鼠肠粘膜紧密连接蛋白ZO-1及肌球蛋白轻链激酶(MLCK)的变化。方法:将60只雄性清洁级SD大鼠随机分为两组:正常饮食组(NDG)和高脂饮食组(FDG)。于4周、8周、12周时观察各组大鼠肝脏病理学改变;应用ELISA方法测定各阶段大鼠血清谷丙转氨酶(ALT)、谷草转氨酶(AST)、甘油三酯(TG)、胆固醇(CHOL)的变化;应用鲎实验测定各阶段大鼠门静脉血中内毒素(ET)水平;应用免疫组化方法检测肠道粘膜肌球蛋白轻链激酶(MLCK)及紧密连接蛋白(ZO-1)的表达及分布情况。结果:随着高脂饮食时间增长,高脂饮食组大鼠肝脏脂肪变性程度逐渐加重;血清ALT、AST、TG、CHOL水平逐渐升高(4周时,P0.05,8周和12周时P0.05);大鼠血浆内毒素的水平逐渐上升(0.11±0.01比0.11±0.01,P0.05;0.36±0.01比0.11±0.01,P0.05;0.44±0.15比0.18±0.03,P0.05);高质饮食组较正常饮食组大鼠紧密连接蛋白ZO-1表达逐渐下降(3.6±0.7比3.9±0.32,P0.05;2.8±0.63比3.8±0.42,P0.05;1.8±0.79比3.7±0.48,P0.05),MLCK表达逐渐增多(0.5±0.53比0.3±0.48,P0.05;1.3±0.48比0.4±0.52,P0.05;1.9±0.74比0.5±0.53,P0.05)。结论:肠粘膜紧密连接蛋白ZO-1及MLCK可通过影响肠粘膜屏障功能,改变肠粘膜的通透性,促进非酒精性脂肪肝病发生发展。     

Increase of Lipid Hydroperoxides in the Rat Liver and Kidney after Administering Ferric Nitrilotriacetate

Two hours after an intraperitoneal injection of ferric nitrilotriacetate to rats at a dose of 15 mg of Fe/kg of body weight, the level of lipid hydroperoxides, which was determined by a specific method involving chemical conversion into 1-naphthyldiphenylphosphine oxide and HPLC, had increased significantly in the liver (from 190.1±58.8 of the control to 467.1±175.8 pmol/mg of protein) and kidney (from 181.8±52.3 of the control to 405.9±22.7 pmol/mg of protein). These results demonstrate that oxidative stress was transiently increased by an iron overload in these tissues.     

Increased sensitivity to dietary cholesterol in diabetic and hypothyroid rats associated with low levels of hepatic HMG-CoA reductase expression

We recently postulated that hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase functions as a cholesterol buffer to protect against the serum and tissue cholesterol raising action of dietary cholesterol. This postulate predicts that diminished basal expression of hepatic HMG-CoA reductase results in increased sensitivity to dietary cholesterol. Because diabetic and hypothyroid animals are known to have markedly reduced hepatic HMG-CoA reductase, these animals were selected as models to test our postulate. When rats were rendered diabetic with streptozotocin, their hepatic HMG-CoA reductase activity decreased from 314 to 22 pmol. min(-1). mg(-1), and their serum cholesterol levels increased slightly. When the diabetic animals were challenged with a diet containing 1% cholesterol, their serum cholesterol levels doubled, and their hepatic reductase activity decreased further to 0.9 pmol. min(-1). mg(-1). Hepatic low-density lipoprotein (LDL) receptor immunoreactive protein levels were unaffected in the diabetic rats whether fed cholesterol-supplemented diets or not. In rats rendered hypothyroid by thyroparathyroidectomy, serum cholesterol levels rose from 100 to 386 mg/dl in response to the 1% cholesterol challenge, whereas HMG-CoA reductase activity dropped from 33.8 to 3.4 pmol. min(-1). mg(-1). Hepatic LDL receptor immunoreactive protein levels decreased only slightly in the hypothyroid rats fed cholesterol-supplemented diets. Taken together, these results show that rats deficient in either insulin or thyroid hormone are extremely sensitive to dietary cholesterol largely due to low basal expression of hepatic HMG-CoA reductase.     

Intermittent hypoxia maintains glycemia in streptozotocin-induced diabetic rats

Increasing studies have shown protective effects of intermittent hypoxia on brain injury and heart ischemia. However, the effect of intermittent hypoxia on blood glucose metabolism, especially in diabetic conditions, is rarely observed. The aim of this study was to investigate whether intermittent hypoxia influences blood glucose metabolism in type 1 diabetic rats. Streptozotocin-induced diabetic adult rats and age-matched control rats were treated with intermittent hypoxia (at an altitude of 3 km, 4 h per day for 3 weeks) or normoxia as control. Fasting blood glucose, body weight, plasma fructosamine, plasma insulin, homeostasis model assessment of insulin resistance (HOMA-IR), pancreas β-cell mass, and hepatic and soleus glycogen were measured. Compared with diabetic rats before treatment, the level of fasting blood glucose in diabetic rats after normoxic treatment was increased (19.88?±?5.69 mmol/L vs. 14.79?±?5.84 mmol/L, p?<?0.05), while it was not different in diabetic rats after hypoxic treatment (13.14?±?5.77 mmol/L vs. 14.79?±?5.84 mmol/L, p?>?0.05). Meanwhile, fasting blood glucose in diabetic rats after hypoxic treatment was also lower than that in diabetic rats after normoxic treatment (13.14 ± 5.77 mmol/L vs. 19.88 ± 5.69 mmol/L, p<0.05). Plasma fructosamine in diabetic rats receiving intermittent hypoxia was significantly lower than that in diabetic rats receiving normoxia (1.28?±?0.11 vs. 1.39?±?0.11, p?<?0.05), while there were no significant changes in body weight, plasma insulin and β-cell mass. HOMA-IR in diabetic rats after hypoxic treatment was also lower compared with diabetic rats after normoxic treatment (3.48?±?0.48 vs. 3.86?±?0.42, p?<?0.05). Moreover, intermittent hypoxia showed effect on the increase of soleus glycogen but not hepatic glycogen. We conclude that intermittent hypoxia maintains glycemia in streptozotocin-induced diabetic rats and its regulation on muscular glycogenesis may play a role in the underlying mechanism.