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1.
Plasma profiles of glucose, insulin and lipids were examined in the male WBN/Kob-Lepr(fa) (fa/fa) rat, a new model of type 2 diabetes (T2D), in comparison with age-matched original male WBN/Kob (lean) rats. The fa/fa rats developed hypertriglycemia, obesity and hyperglycemia from 5, 7, and 9 weeks of age, respectively. Plasma insulin levels in fa/fa rats were significantly higher than those in lean rats at 5 weeks of age, but after 11 weeks of age gradually declined to the levels in lean rats. HOMA-IR, a measure of insulin resistance status, showed that fa/fa rats had insulin resistance. The fa/fa rat has the potential to become an important animal model of T2D with obesity.  相似文献   

2.
This study aimed to investigate the biotransformation of cat liver microsomes in comparison to dogs and humans using a high throughput method with fluorescent substrates and classical inhibitors specific for certain isozymes of the human cytochrome P450 (CYP) enzyme family. The metabolic activities associated with CYP1A, CYP2B, CYP2C, CYP2D, CYP2E and CYP3A were measured. Cat liver microsomes metabolized all substrates selected for the assessment of cytochrome P450 activity. The activities associated with CYP3A and CYP2B were higher than the activities of the other measured CYPs. Substrate selectivity could be demonstrated by inhibition studies with α-naphthoflavone (CYP1A), tranylcypromine/quercetine (CYP2C), quinidine (CYP2D), diethyldithiocarbamic acid (CYP2E) and ketoconazole (CYP3A) respectively. Other prototypical inhibitors used for characterization of human CYP activities such as furafylline (CYP1A), tranylcypromine (CYP2B) and sulfaphenazole (CYP2C) did not show significant effects in cat and dog liver microsomes. Moreover, IC50-values of cat CYPs differed from dog and human CYPs underlining the interspecies differences. Gender differences were observed in the oxidation of 7-ethoxy-4-trifluoromethylcoumarin (CYP2B) and 3-[2-(N, N-diethyl-N-methylamino)ethyl]-7-methoxy-4-methylcoumarin (CYP2D), which were significantly higher in male cats than in females. Conversely, oxidation of the substrates dibenzylfluorescein (CYP2C) and 7-methoxy-4-trifluoromethylcoumarin (CYP2E) showed significant higher activities in females than in male cats. Overall CYP-activities in cat liver microsomes were lower than in those from dogs or humans, except for CYP2B. The presented difference between feline and canine CYP-activities are useful to establish dose corrections for feline patients of intensively metabolized drugs licensed for dogs or humans.  相似文献   

3.
The objective of the current study was to examine cyclooxygenase (COX), cytochrome P450 1A (CYP1A) and 2C (CYP2C) activity in bovine endometrial cell cultures following exposure to oxytocin (OT), interferon‐τ (IFN), estradiol (E2) and/or progesterone (P4). Bovine endometrial epithelial cells were treated with OT, IFN, a combination of OT+IFN or control (CON) media for 24 h. For the second experiment, cells were treated with E2, P4, a combination of E2 + P4 or CON media for 24 h. Treatments were performed in triplicate, and the experiment was repeated four times (n = 12 per treatment). Treatment with OT alone increased (p < 0.01) activity of COX compared with CON; however, OT alone did not alter activity of CYP1A (p = 0.55) or CYP2C (p = 0.46) compared with CON. Activity of CYP1A and CYP2C was decreased in cells exposed to IFN (p < 0.01) or OT+IFN (p < 0.01) compared with CON. Treatment with E2 alone did not alter activity of CYP1A (p = 0.64) or CYP2C (p = 0.06) compared with CON. Activity of CYP1A and CYP2C was decreased (p < 0.01) in P4 vs CON. In summary, IFN exposure, irrespective of OT treatment, decreased the activity of CYP1A and CYP2C. Activity of CYP1A was decreased following P4 treatment alone, while that of CYP2C was decreased following both P4 and E2 + P4 treatment. The mixed function monooxygenase enzymes, CYP1A and CYP2C, have been implicated in synthesizing embryotoxic compounds; therefore, downregulation in the endometrium may be necessary during maternal recognition of pregnancy.  相似文献   

4.
Objective – To describe the clinical presentation, treatment, and outcome of a neonatal foal diagnosed with transient Type 1 diabetes mellitus. Case Summary – A 3‐day‐old Thoroughbred foal presented with a 24‐hour history of diarrhea and depression. Coronavirus particles were observed in the feces via electron microscopy. During hospitalization the foal developed hyperglycemia concomitantly with low insulin concentration and an adequate response to exogenous insulin therapy supported a diagnosis of Type 1 diabetes mellitus. The foal required SC insulin for 26 days, but developed complications associated with insulin therapy that resolved with appropriate care. On follow up assessment the foal was found to be a healthy euglycemic animal with normal insulin concentration at 11 months of age. New or Unique Information Provided – To our knowledge this is the first report of Type 1 diabetes in this age group and the first report of transient neonatal diabetes mellitus in horses. Type 1 diabetes mellitus should be considered a differential diagnosis for hyperglycemia in equine neonates and that it can be transient and managed successfully.  相似文献   

5.
采用胶原酶二步灌流法获取怀孕大鼠的原代肝细胞,以Aroclor1254诱导肝细胞损伤,用不同剂量的槲皮素分别处理损伤的肝细胞24～72h,RT—PCR及Western—blot法检测肝细胞中细胞色素酶P450（CYP450）的表达。结果显示,槲皮素处理损伤的肝细胞后,肝细胞CYPIAl、CYP281及CYP2E1的表达随槲皮素浓度的增加和处理时间的延长而呈先升高后降低的趋势。10mg／LAroclor1254是诱导体外培养的原代肝细胞损伤的最适质量浓度,10μmol／L槲皮素是对损伤的怀孕大鼠肝细胞的最佳保护浓度。结果表明,槲皮素对损伤的怀孕大鼠肝细胞具有保护作用。  相似文献   

6.
The effects of human chorionic gonadotropin (hCG) stimulation on fat skatole concentrations and hepatic activities of cytochromes P4502E1 (CYP2E1) and P4502A (CYP2A) were studied in Landrace and Duroc breeds of entire male pigs. Pigs were divided into four groups: two control groups of each breed, without hCG stimulation (n = 20 for each breed), and two experimental groups of each breed, with hCG stimulation (n = 18 for each breed). Pigs were slaughtered 3 days after hCG stimulation and activities of CYP2E1 and CYP2A were measured in liver homogenate. Activities of both CYP2E1 and CYP2A were lower in hCG‐stimulated pigs than control pigs for both Landrace (p = 0.005 for CYP2E1, p = 0.016 for CYP2A) and Duroc breeds (p = 0.003 for CYP2E1, p = 0.001 for CYP2A), and skatole concentrations in fat were higher in the hCG‐stimulated pigs of both breeds (p < 0.01). For both control and hCG‐stimulated groups, Duroc pigs had lower skatole concentrations than Landrace pigs (p = 0.001 for both groups). The activity of CYP2E1 did not differ significantly between breeds in either the control group or the experimental group (p = 0.233 for control pigs and p = 0.210 for experimental pigs). However, whereas CYP2A activity did not differ significantly between breeds in the control groups (p = 0.181 for CYP2A), in the hCG‐stimulated groups, CYP2A activity was lower in Duroc pigs than in Landrace (p = 0.011). Based on these findings, we conclude that hCG stimulation can suppress hepatic CYP2E1 and CYP2A activities, probably through an increase in the levels of testicular steroids. Between‐breed variations in skatole levels in fat were not related to the activities of CYP2E1 and CYP2A.  相似文献   

7.
An 18-year-old Spanish Mustang mare was referred for evaluation of progressive weight loss and persistent hyperglycemia. Clinicopathologic abnormalities included marked hyperglycemia and glycosuria. Serum cortisol concentration was appropriately decreased following administration of dexamethasone, indicating that the horse did not have pituitary pars intermedia dysfunction. Serum insulin and plasma C-peptide concentrations were low, suggesting that hyperglycemia was a result of decreased secretion of insulin by pancreatic beta cells. In addition, glucose concentration did not return to the baseline concentration until 5 hours after i.v. administration of a glucose bolus, suggesting that insulin secretion, insulin effect, or both were reduced. However, i.v. administration of insulin caused only a slight decrease in the plasma glucose concentration, giving the impression that the action of insulin was impaired. Within 5 hours after administration of a combination of glyburide and metformin, which is used to treat diabetes mellitus in humans, the glucose concentration was within reference limits. The horse was euthanized, and a postmortem examination was done. Immunohistochemical staining of sections of the pancreas revealed attenuation of the pancreatic islet beta-cell population, with beta cells that remained generally limited to the periphery of the islets. These findings indicate that, albeit rare, pancreatic beta-cell failure may contribute to the development of diabetes mellitus in horses.  相似文献   

8.
The purpose of this study was to investigate the effects of a medetomidine-midazolam combination on some neurohormonal and metabolic variables in healthy cats. Five cats were used repeatedly in each of 5 groups, which were injected intramuscularly with physiological saline solution (control), 0.5 mg/kg of midazolam, 40 microg/kg of medetomidine, 80 microg/kg of medetomidine, and 40 microg/kg of medetomidine plus 0.5 mg/kg of midazolam. Blood samples were taken 10 times over 24 h from a catheter introduced into the jugular vein. Plasma concentrations of glucose, insulin, glucagon, cortisol, nonesterified fatty acids (NEFAs), norepinephrine, and epinephrine were determined. In addition, the duration of lateral recumbency, rectal temperature, heart rate, and respiratory rate were examined. The combination of medetomidine and midazolam enhanced the duration of lateral recumbency and reduced the hyperglycemia induced by medetomidine alone. Recovery from hypoinsulinemia induced by the medetomidine-midazolam combination tended to be more rapid than when the same dose of medetomidine was used alone. The decrease in plasma norepinephrine levels induced by medetomidine alone was diminished by the addition of midazolam. Midazolam alone did not significantly change the plasma glucose, insulin, glucagon, cortisol, epinephrine, or NEFA concentration, but increased the norepinephrine concentration. This study revealed that the combination of medetomidine and midazolam produces minimal neurohormonal and metabolic changes when compared with medetomidine alone in cats.  相似文献   

9.
Mink nursing sickness is a metabolic disorder characterized by hyperglycemia that is similar to the metabolic syndrome associated with type 2, or non-insulin-dependent, diabetes mellitus. This research studied the effects of short-term administration of antidiabetic supplements on the blood glucose concentration in female mink during late lactation. Female mink that had blood glucose levels < 5.5 mmol/L (normoglycemic [NG]) or > or = 5.5 mmol/L (hyperglycemic [HG]) early in lactation were given daily supplements of various combinations of herring oil (HerO, 3% in diet), chromium picolinate (CrPic, 200 microg), and acetylsalicylic acid (ASA, 100 mg) for 1 wk starting at day 21 post partum. In the NG mink, most of the treatments did not significantly change the blood glucose concentration from day 28 to 42 post partum. However, treatment with ASA alone and treatment with the combination HerO-CrPic-ASA elevated the blood glucose levels when compared with those of the control group, which had received just the basal diet. In the HG mink, all treatment combinations except CrPic alone and ASA alone, reduced the blood glucose concentration. Thus, in lactating mink with hyperglycemia, the blood glucose concentration may be effectively lowered by dietary antidiabetic supplementation; however, because hyperglycemia also occurs before nursing, preventive measures are recommended throughout the year.  相似文献   

10.
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11.
Thirteen cats with diabetes mellitus were evaluated. Clinical signs included polydipsia, polyuria, polyphagia, lethargy, and weight loss. Results of physical examination included obesity, hepatomegaly, mild seborrhea sicca, muscle wasting, and dehydration. One cat walked plantigrade and was suspected of having a diabetic neuropathy. Persistent hyperglycemia, glucosuria, high liver enzyme activities, hypercholesterolemia, hyperproteinemia, and low electrolyte concentrations were the common laboratory findings. In 3 cats diabetes mellitus developed after megestrol acetate therapy; 2 of these cats required only temporary insulin treatment. In a 3rd cat, which had no history of receiving diabetogenic drug therapy, remission of diabetes mellitus also was observed. Serum insulin and plasma glucose concentrations were determined in 6 cats after administration of an intermediate-acting insulin (isophane insulin) and in 3 cats after administration of a long-acting insulin (protamine zinc insulin). The insulin concentration peaked 2 to 6 hours after the injection of intermediate-acting insulin and 6 to 12 hours after the injection of long-acting insulin. The lowest glucose concentration was recorded 4 to 8 hours after injection of intermediate-acting insulin, and 6 to 12 hours after injection of long-acting insulin. It was concluded that, although insulin therapy must be adjusted to the individual, the diabetic cat usually requires twice-daily administration of isophane insulin; however, the protamine zinc insulin can be given once daily for satisfactory control.  相似文献   

12.
The objective of this study was to evaluate the safety and efficacy of a purified porcine insulin zinc suspension for treating dogs with uncomplicated diabetes mellitus. Fifty-three dogs were treated for 60 days after an initial dose determination period. The means of the blood glucose concentrations during 12-hour glucose curves and the means of the blood glucose nadir concentrations during 12-hour glucose curves for all dogs were determined before beginning insulin therapy (time 0), at the end of the dose determination period (time 1), 30 days after time 1 (time 2), and 60 days after time 1 (time 3). Presence of polyuria, polydipsia, and ketonuria was determined at each time point. Adequacy of control of hyperglycemia was based on 12-hour blood glucose curves and improvement in clinical variables (results of physical examinations, historic information, polyuria, polydipsia, and ketonuria). Safety was evaluated by questionnaire, performance of physical examination, CBC, serum chemistry profile, and urinalysis. The means of the blood glucose concentrations during 12-hour glucose curves and the means of the blood glucose nadir concentrations during 12-hour glucose curves for all dogs at times 1, 2, and 3 were significantly lower compared with time 0 (P < .0001). There was a reduction in the proportion of dogs with polyuria, polydipsia, and ketonuria of 82, 86, and 80%, respectively. All of the dogs had adequate glycemic control at time 1, 66% at time 2, and 75% at time 3. At time 3, 66% of dogs required insulin injections q12h. Other than hypoglycemia, there were no important adverse effects of insulin administration. The insulin, was safe and efficacious for reducing blood glucose and clinical signs in dogs with diabetes mellitus.  相似文献   

13.
本研究旨在探讨锰对公鸡肝脏细胞色素P450酶系的影响。50日龄海兰褐公鸡400只,随机分为4组,分别在饲料中添加0、600、900、1 800 mg.kg-1MnCl2建立亚慢性锰中毒模型,于30、60、90 d采取肝脏检测肝微粒体细胞色素P450酶系活性以及CYP2H1基因转录水平的变化。结果显示,细胞色素P450、b5含量,氨基吡啉-N-脱甲基酶(AND)和苯胺-4-羟化酶(AH)活性在各个时间点随染锰剂量的增加,基本呈降低趋势,且高剂量组均极显著(P0.01)低于正常组,低、中剂量组有高于正常组的情况。NADPH-细胞色素C还原酶(CR)和红霉素-N-脱甲基酶(ERND)的活性的变化规律不明显,30和60 d NADPH-细胞色素C还原酶活性呈降低趋势,而90 d时呈升高趋势,且高剂量组极显著(P0.01)高于正常组。红霉素-N-脱甲基酶在30 d时呈升高趋势,60和90 d时呈波动性降低变化,且高剂量组均极显著(P0.01)低于正常组。在各个时间点,CYP2H1 mRNA的转录水平除30 d低、高剂量组,60 d中剂量组,90 d低剂量组高于正常组外,其他组均低于正常组。结果提示,锰中毒可影响鸡肝脏细胞色素P450酶系以及CYP2H1 mRNA的转录水平。  相似文献   

14.
In the present study, modifying effects of diabetes on carcinogenesis induced in type 2 diabetes mellitus model Zucker diabetic fatty (ZDF) rats were investigated using a multiorgan carcinogenesis bioassay. Our re sults demonstrated enhancement of urinary bladder, colon and liver carcinogenesis in ZDF rats treated with five types of carcinogens (DMBDD). Elevated insulin and leptin and decreased adiponectin levels in the serum may be responsible for the high susceptibility of type 2 diabetes mellitus model rats to carcinogenesis in these organs. Possible mechanisms of increased susceptibility of diabetic rats to bladder carcinogenesis could be activation of the PI3K pathway and suppression of p53 in the urothelium in consequence of the above serum protein alterations.  相似文献   

15.
Cytochrome P450 2E1 (CYP2E1) and 2A (CYP2A) are the main enzymes involved in the metabolism of skatole in pigs. In this study, physiological concentrations of androstenone, 17β‐oestradiol and testosterone were tested for their ability to regulate CYP2E1 and CYP2A activity in liver microsomes isolated from entire male and female pigs as well as in microsomes from Saccharomyces cerevisiae expressing either human recombinant CYP2E1 or CYP2A6. We found that physiological concentrations of androstenone and oestradiol had the ability to inhibit CYP2E1 activity. The magnitude of this inhibition (approximately 30%) was similar in recombinant human CYP2E1 and microsomes from entire male pigs. This inhibition was only seen when adding the steroid to the assay 15 min before the substrate. Interestingly, CYP2E1 activity in the microsomes from female pigs was not affected. None of the investigated steroids modified the activity of recombinant human CYP2A6. However, CYP2A activity was slightly increased in the microsomes from female pigs in the presence of oestradiol, but the magnitude of this increase was very low (below 10%) and probably irrelevant. Overall, these results indicate that physiological concentrations of androstenone and oestradiol have a potential to inhibit CYP2E1 activities in vitro, and that this inhibition is gender‐specific. Further studies are needed to investigate the biochemical mechanisms underlying those differences between the genders.  相似文献   

16.
Dogs do not appear to progress from obesity-induced insulin resistance to type 2 diabetes mellitus. Both postprandial hyperglycemia and postprandial hypertriglyceridemia have been proposed to cause or maintain beta cell failure and progression to type 2 diabetes mellitus in other species. Postprandial glucose, triglyceride, and insulin concentrations have not been compared in lean and obese dogs. We measured serum glucose, triglyceride, and insulin concentrations in nine naturally occurring obese and nine age- and gender-matched lean dogs. After a 24-h fast, dogs were fed half their calculated daily energy requirement of a standardized diet that provided 37% and 40% of metabolizable energy as carbohydrate and fat, respectively. Fasting and postprandial glucose and triglyceride concentrations were greater in the obese dogs (P < 0.001), although the mean insulin concentration for this group was five times greater than that of the lean group (P < 0.001). Most of the 0.6 mM (11 mg/dL) difference in mean postprandial glucose concentrations between lean and obese dogs was attributable to a subset of persistently hyperglycemic obese dogs with mean postprandial glucose concentrations 1.0 mM (18 mg/dL) greater than that in lean dogs. Persistently hyperglycemic obese dogs had lower triglyceride (P = 0.02 to 0.04) and insulin (P < 0.02) concentrations than other obese dogs. None of the dogs developed clinical signs of diabetes mellitus during follow-up for a median of 2.6 yr. We conclude that pancreatic beta cells in dogs are either not sensitive to toxicity because of mild hyperglycemia or lack another component of the pathophysiology of beta cell failure in type 2 diabetes mellitus.  相似文献   

17.
To induce diabetes mellitus in 8 steers, they were fasted for 96 hours and given 110 mg of alloxan/kg of body weight (IV, in 1 dose) immediately before refeeding. Subsequently, 4 of the steers were treated with insulin (0.1 to 3 U/kg) to control hyperglycemia and 4 were not given insulin. Four control steers were fasted and refed. Fasting increased serum phosphorus, total protein, and bilirubin and decreased serum magnesium and potassium. Refeeding returned serum values of magnesium, potassium, total protein, and bilirubin toward base-line values, regardless of treatment group. However, serum phosphorus remained increased in steers with alloxan-induced diabetes and was not lowered by insulin injections. Sodium and chloride values were depressed in steers with alloxan-induced diabetes; these values remained significantly (P less than 0.05) lower than base-line values, even in steers given insulin. Fat infiltration was evident in the pancreas, liver, and to some extent, kidneys of steers with alloxan-induced diabetes, but was occasionally present in tissues of steers given insulin.  相似文献   

18.
A propionate tolerance test (PTT) was used to determine the pathophysiology of a Japanese Black steer with hyperglycemia. In the hyperglycemic steer, a low insulin secretion was confirmed by a glucose tolerance test (GTT), so that the hyperglycemic steer was diagnosed as insulin-dependent diabetes mellitus. Although the plasma insulin concentration in the control cattle increased in response to propionate stimulation, a low insulin response to PTT was observed in the diabetic steer. The fact that both PTT and GTT determined that the diabetic steer had low insulin secretion suggests that the PTT might be an effective diagnostic tool for diabetes mellitus in cattle.  相似文献   

19.
Cytochrome P450 2E1 (CYP2E1) is one of the body's metabolite of drugs and low molecular weight compounds mainly enzymes, and the increasing of activity or expression of CYP2E1 is closely related with the clinical variety of diseases. This paper reviews the research progress of protein structure, function, positioning mechanism and other aspects of genetic polymorphisms of CYP2E1 at home and abroad. Thereby the paper could lay the foundation for further exploration of the biological effects of CYP2E1 and its relationship with clinical disease.  相似文献   

20.
试验旨在研究汤阴北艾精油对CYP450酶各亚型活性和表达的影响。采用水蒸馏提取法提取北艾精油,通过GC-MS检测北艾精油成分。为研究北艾精油对CYP450酶活性的影响,将SD大鼠随机分为对照组（CON）和北艾精油组（EO）,分别灌胃0.1%吐温-80 100 μL/g和0.1%吐温-80稀释的北艾精油（5%）100 μg/g,灌胃后给予20 μg/g各探针药物,采用鸡尾酒探针法分别对给药后5、10、20、30 min及1、2、3、6、12、24、36、48 h血浆中3种探针底物的浓度进行检测,考察北艾精油对CYP1A2、CYP2E1和CYP2D6酶活性的影响;为探究北艾精油对CYP450酶基因和蛋白表达的影响,将昆明小鼠随机分为对照组和北艾精油组,分别灌胃0.1%吐温-80 100 μL/g和0.1%吐温-80稀释的北艾精油（5%）100 μg/g,连续灌胃3日,每日2次,末次给药24 h后提取总mRNA及肝微粒体,采用实时荧光定量PCR和蛋白免疫印迹法（Western blotting）测定CYP1A2、CYP2E1和CYP2D6 mRNA和蛋白表达含量。结果表明：①北艾精油主要成分为Eucalyptol;3-Cyclohexen-1-ol,4-methyl-1-（1-methylethyl）-3;（+）-2-Carene,4-.alpha.-isopropenyl-2;m-Mentha-4,8-diene,（1S,3S）-（+）-;Benzoic acid,2,4,6-trimethyl-2,4,6-trimethylphenyl ester。②对血液中非那西汀（CYP1A2底物）、右美沙芬（CYP2D6底物）和氯唑沙宗（CYP2E1底物）进行药代动力学分析可知,北艾精油具有抑制CYP2D6和CYP2E1酶活性的作用,而对CYP1A2酶活性无显著作用。③实时荧光定量PCR和Western blotting测定结果表明,北艾精油可显著抑制CYP2E1和CYP2D6酶的表达。综上,北艾精油对CYP2E1和CYP2D6酶活性和表达均具有明显的抑制作用,提示艾草精油不能同时与以CYP2D6和CYP2E1为主要代谢酶的药物同食。该研究结果可为北艾精油的合理用药提供数据基础。  相似文献   

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