Zucker糖尿病肥胖模型大鼠的焦虑样行为学研究

目的 观察Zucker糖尿病肥胖（ZDF）大鼠的行为学特征,探讨2型糖尿病与焦虑症的关系。方法 8周龄雄性ZDF大鼠和Zucker健康对照（ZLC）大鼠（n = 8）,分别以Purina 5008高脂饲料和普通饲料饲养至12周,观察动物在旷场试验（OFT）和高架十字迷宫（EPM）中的行为变化,以OFT和EPM的总体路程和平均速度评价动物整体运动情况,分别以OFT中央区和EPM开闭区的路程百分率（D%）和停留时间百分率（T%）评价动物的焦虑样行为变化。结果 经过4周饲养,ZDF大鼠的体质量［ZLC 与 ZDF分别为（185.00±12.96）和（341.68±9.88） g,P＜0.01］和血糖值［ZLC 与ZDF分别为（4.94±0.24）和（13.06±0.89） mmol/L,P＜0.01］符合2型肥胖型糖尿病判断标准。与ZLC大鼠相比,ZDF大鼠OFT（P＜0.01）和EPM（P＜0.05）中的总路程和平均速度显著降低,ZDF大鼠分别在OFT中央区和EPM开臂区的D%（P＜0.01）以及OFT中央区和EPM开臂区的T%（P＜0.05）则显著升高。结论 ZDF大鼠由于疾患和肥胖导致行动迟缓,并呈现较低水平的焦虑状态,提示2型糖尿病病理过程可能并未直接与焦虑症发生发展有关。     

Dietary L-arginine supplementation reduces fat mass in Zucker diabetic fatty rats

This study was conducted to test the hypothesis that dietary supplementation of arginine, the physiologic precursor of nitric oxide (NO), reduces fat mass in the Zucker diabetic fatty (ZDF) rat, a genetically obese animal model of type-II diabetes mellitus. Male ZDF rats, 9 wk old, were pair-fed Purina 5008 diet and received drinking water containing arginine-HCl (1.51%) or alanine (2.55%, isonitrogenous control) for 10 wk. Serum concentrations of arginine and NO(x) (oxidation products of NO) were 261 and 70% higher, respectively, in arginine-supplemented rats than in control rats. The body weights of arginine-treated rats were 6, 10, and 16% lower at wk 4, 7, and 10 after the treatment initiation, respectively, compared with control rats. Arginine supplementation reduced the weight of abdominal (retroperitoneal) and epididymal adipose tissues (45 and 25%, respectively) as well as serum concentrations of glucose (25%), triglycerides (23%), FFA (27%), homocysteine (26%), dimethylarginines (18-21%), and leptin (32%). The arginine treatment enhanced NO production (71-85%), lipolysis (22-24%), and the oxidation of glucose (34-36%) and octanoate (40-43%) in abdominal and epididymal adipose tissues. Results of the microarray analysis indicated that arginine supplementation increased adipose tissue expression of key genes responsible for fatty acid and glucose oxidation: NO synthase-1 (145%), heme oxygenase-3 (789%), AMP-activated protein kinase (123%), and peroxisome proliferator-activated receptor gamma coactivator-1alpha (500%). The induction of these genes was verified by real-time RT-PCR analysis. In sum, arginine treatment may provide a potentially novel and useful means to enhance NO synthesis and reduce fat mass in obese subjects with type-II diabetes mellitus.     

Exercise training decreases proinflammatory profile in Zucker diabetic (type 2) fatty rats

ObjectiveIn the present study we evaluated the effect of exercise on the plasma levels of proinflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), and the anti-inflammatory molecule uric acid in the Zucker diabetic fatty (ZDF) rats that are more prone to develop type 2 diabetes mellitus.MethodsSixteen obese ZDF (Gmi fa/fa) rats (8 wk old, 228.40 ± 4.05 g) were randomly assigned to one of two groups (n = 8 each): an exercise-trained group and a sedentary one. In addition, 16 lean ZDF (Gmi +/+) rats (8 wk old, 199.00 ± 3.50 g) were subjected to identical sedentary and exercise conditioning (n = 8 each). Initially, rats swam 15 min/d (5 d/wk) in a 36°C bath. The exercise protocol was gradually increased by 15 min/d until a swimming period of 1 h/d (1 wk) was attained. Thereafter, rats swam 1 h/d, 3 d/wk, for an additional period of 11 wk. Rats were sacrificed 48 h after the last training period and the blood and pancreas were collected. Circulating levels of glucose, glycosylated hemoglobin, total cholesterol, triglycerides, insulin, uric acid, IL-6, and TNF-α were assessed. The concentrations of proinflammatory cytokines in the pancreas were also evaluated.ResultsIn the diabetic ZDF (fa/fa) rats, exercise decreased hyperuricemia (?37.3%) and IL-6 and TNF-α levels (?16.9% and ?12.7% respectively) and maintained the weight of the pancreas at near normal. Immunohistochemistry revealed a marked decrease in the expression of TNF-α and IL-6 in the pancreatic islet cells of ZDF (fa/fa) rats.ConclusionThese results indicate that aerobic exercise is anti-inflammatory in nature.     

Glycemic index in the diet of European outpatients with type 1 diabetes: relations to glycated hemoglobin and serum lipids

BACKGROUND: Little is known about the variation of the glycemic index (GI) in the diet of European outpatients with type 1 diabetes and how the GI of a commonly consumed diet is associated with metabolic control. OBJECTIVE: The present study examined the calculated dietary GI of European outpatients with type 1 diabetes for possible relations to glycated hemoglobin (Hb A(1c)) and serum lipid concentrations. DESIGN: The relation of the GI (calculated from a 3-d dietary record) to Hb A(1c), serum cholesterol (total, LDL, and HDL), and fasting triacylglycerol was analyzed in 2810 people with type 1 diabetes from the EURODIAB Complications Study. RESULTS: The GI was independently related to Hb A(1c) (P = 0.0001). Compared with the highest GI quartile (median GI: 89), adjusted Hb A(1c) in the lowest GI quartile (median GI: 75) was 11% lower in patients from southern European centers and 6% lower in patients from northern, western, and eastern European centers. Of the serum lipids, only the HDL cholesterol in patients from these European centers was independently related to the GI (P = 0.002). In southern European centers, the consumption of pasta, temperate-climate fruit, white bread, and potatoes largely determined the patients' dietary GI, whereas in the northern, western, and eastern European centers, consumption of bread, potatoes, and temperate-climate fruit was most relevant. CONCLUSIONS: This study in European patients with type 1 diabetes showed that a lower dietary GI is related to lower Hb A(1c) concentrations, independently of fiber intake. The consumption of bread and pasta had the biggest effect on the overall dietary GI of European outpatients.     

Establishment of a model to assess mumps virus neurovirulence in neonatal Wistar rats

Mumps virus (MuV) is highly neurotropic and neurovirulent, hence, the neurovirulence of virus seeds used in the production of mumps vaccines must be tested. The previous neurovirulence evaluation method involves measuring the area of the cavity in the Lewis neonatal rat brain caused by MuV through paraffin sectioning and hematoxylin-eosin (HE) staining. However, the processes of paraffin sectioning and HE staining are time consuming and complicated. To solve this problem, in this study, a vibratome sectioning system was first deployed to evaluate MuV neurovirulence in the rat brain instead of paraffin sectioning and HE staining. The results showed that the vibratome sectioning method could assess the neurovirulence potential of MuV more objectively and efficiently. In addition, the effects of different MuV doses and the ages of the rats in days on this evaluation method were explored. The results indicate that MuV at no less than 10 50 % cell culture infective dose (CCID₅₀) could cause obvious cavity formation in 1-day-old rat brains. The neonatal rat model developed in this study could evaluate the neurovirulence of different MuV strains with high sensitivity and good repeatability.     

Dietary supplementation with watermelon pomace juice enhances arginine availability and ameliorates the metabolic syndrome in Zucker diabetic fatty rats

Watermelon is rich in L-citrulline, an effective precursor of L-arginine. This study was conducted to determine whether dietary supplementation with watermelon pomace juice could ameliorate the metabolic syndrome in the Zucker diabetic fatty (ZDF) rat, an animal model of noninsulin-dependent diabetes mellitus. Nine-week-old ZDF rats were assigned randomly to receive drinking water containing 0% (control) or 0.2% L-arginine (as 0.24% L-arginine-HCl), 63% watermelon pomace juice, 0.01% lycopene, or 0.05% citrus pectin (n = 6 per treatment). At the end of the 4-wk supplementation period, blood samples, aortic rings, and hearts were obtained for biochemical and physiological analyses. Feed or energy intakes did not differ among the 5 groups of rats. However, dietary supplementation with watermelon pomace juice or L-arginine increased serum concentrations of arginine; reduced fat accretion; lowered serum concentrations of glucose, free fatty acids, homocysteine, and dimethylarginines; enhanced GTP cyclohydrolase-I activity and tetrahydrobiopterin concentrations in the heart; and improved acetylcholine-induced vascular relaxation. Compared with the control, dietary supplementation with lycopene or citrus pectin did not affect any measured parameter. These results provide the first evidence to our knowledge for a beneficial effect of watermelon pomace juice as a functional food for increasing arginine availability, reducing serum concentrations of cardiovascular risk factors, improving glycemic control, and ameliorating vascular dysfunction in obese animals with type-II diabetes.     

Use of 3,4-didehydroretinol to assess vitamin A status in rats

The acetate and palmitate esters of 3,4-didehydroretinol (DR; vitamin A2 alcohol) have been synthesized and characterized. When administered orally in corn oil to female rats, DR was present in the serum as the alcohol, but primarily as esters in the liver. As total stores of retinol (R; vitamin A1 alcohol) decrease, the ratio of DR to R in the serum markedly increases. The ratio of DR to R in serum was greater than 0.27 at liver vitamin A1 palmitate values of less than 3 micrograms/g, 0.05-0.14 at 3-19 micrograms/g, and less than 0.04 at greater than or equal to 20 micrograms/g. Thus, the ratio of DR to R in the serum at a suitable interval after the administration of dehydroretinyl acetate may aid in assessing marginal vitamin A status. DR was not demonstrably converted to R in these studies.     

2型糖尿病门诊患者血糖控制状况及影响因素分析

[目的] 评价2型糖尿病门诊患者血糖控制情况,了解该人群血糖控制的影响因素。[方法] 采用单纯随机抽样的方法,在上海市某三级甲等医院糖尿病中心抽取2型糖尿病患者677例,收集患者的基本人口学特征、体格检查以及实验室检测资料等。运用单因素分析和非条件Logistic回归分析探讨血糖控制的影响因素。[结果] 677例2型糖尿病患者的糖化血红蛋白（HbAlc）平均值为7.27%,HbAlc ≥ 7.00%的患者有313例,占46.23%。非条件Logistic回归分析结果显示,影响血糖控制效果的因素有舒张压（DBP）、体质指数（BMI）和三酰甘油（TG）,OR值分别为1.03、1.17和1.40。[结论] 2型糖尿病门诊患者的血糖控制现状不容乐观,血糖控制状况受多种因素影响。     

Dietary single cell protein reduces fatty liver in obese Zucker rats

There is growing evidence that dietary proteins may interfere with lipid metabolism. We therefore examined the effects of feeding obese Zucker rats a single cell protein (SCP) with low ratios of methionine:glycine and lysine:arginine for 6 weeks. SCP feeding reduced the hepatic steatosis and lowered the plasma transaminase levels when compared with casein-fed rats (controls). The fatty acid oxidation was increased in liver mitochondria and peroxisomes, whereas the activities of enzymes involved in lipogenesis and TAG biosynthesis were unaffected. SCP feeding affected the fatty acid composition of liver lipids and plasma, and reduced the mRNA levels of the fatty acid desaturases. The decreased gene expression of stearoyl-CoA desaturase suggested that the fatty acids were directed towards oxidation rather than esterification as TAG. The decreased mRNA levels of VLDL-receptor and lipoprotein lipase in the liver after SCP feeding suggested that the uptake of TAG-rich lipoprotein to the liver was decreased. To conclude, the reduced fatty liver by SCP feeding may be caused by the increased capacity for fatty acid beta-oxidation in the liver, combined with changed fatty acid composition and possibly a reduced hepatic clearance of circulating VLDL. An increased awareness of the effect of dietary proteins on lipid metabolism could be of relevance in future dietary treatment of non-alcoholic fatty liver disease.     

Caloric intake and hypothalamic neurotransmitters in Zucker rats made acutely diabetic with streptozocin

Zucker rats, lean and obese, treated with low dose intraperitoneal injections of streptozocin become hyperglycemic within 24h. Insulin levels fall, although the obese animal remains hyperinsulinemic. Associated with these changes in glucose and insulin there are transient decreases in caloric intake. Macronutrient selection studies show that protein consumption decreases. There is a trend for fat intake to decrease. The levels of hypothalamic neurotransmitters in the lean animals are not altered by streptozocin. The levels of 5-hydroxyindoleacetic acid increases in the streptozocin-treated obese animal in the paraventricular region, ventromedial region and the raphe. Serotonin is also significantly increased in the paraventricular region of the obese rat. These results suggest that acutely, treatment with streptozocin injures pancreatic islets, causing, in turn, decreases in insulin levels so that hyperglycemia ensues in both phenotypes. Associated with these perturbations are decreases in caloric intake. The magnitude of change in insulin levels is much greater in the obese rat. It is hypothesized that in the obese Zucker rat decrements in food intake are mediated by increase in serotonin turnover in the hypothalamus and these changes are related to changes of insulin levels. These data support the concept that circulating insulin affects hypothalamic neurotransmitters.     

Supplementation of coenzyme Q10 and α-tocopherol lowers glycated hemoglobin level and lipid peroxidation in pancreas of diabetic rats

The importance of nutritional supplementation in diabetes remains an unresolved issue. The present study was undertaken to examine the effects of α-tocopherol and CoQ₁₀, powerful antioxidants, on metabolic control and on the pancreatic mitochondria of GK rats, a model of type 2 diabetes. We also evaluated the efficacy of these nutrients in preventing the diabetic pancreatic lesions observed in GK rats. Rats were divided into 4 groups, a control group of diabetic GK rats and 3 groups of GK rats administered with α-tocopherol and CoQ₁₀ alone or both in association, during 8 weeks. Fasting blood glucose levels were not significantly different between the groups, nor were blood glucose levels at 2 hours after a glucose load. HbA1c level was significantly reduced in the group supplemented with both antioxidants. Diabetes induced a decrease in coenzyme Q plasma levels that prevailed after treatment with antioxidants. In addition, the plasma α-tocopherol levels were higher after treatment with the antioxidants. An increment in some components of the antioxidant defense system was observed in pancreatic mitochondria of treated GK rats. Moreover, the antioxidants tested either alone or in association failed to prevent the pancreatic lesions in this animal model of type 2 diabetes. In conclusion, our results indicate that CoQ₁₀ and α-tocopherol decrease glycated HbA1c and pancreatic lipid peroxidation. These antioxidants increase some components of the antioxidant defense system but do not prevent pancreatic lesions. Thus, we cannot rule out the potential benefit of antioxidant treatments in type 2 diabetes in the prevention of their complications.     

Supplemental fructose attenuates postprandial glycemia in Zucker fatty fa/fa rats

Experiments were conducted to evaluate the effects of supplemental fructose on postprandial glycemia. After overnight food deprivation, Zucker fatty fa/fa rats were given a meal glucose tolerance test. Plasma glucose response was determined for 180 min postprandially. At a dose of 0.16 g/kg body, fructose reduced (P < 0.05) the incremental area under the curve (AUC) by 34% when supplemented to a glucose challenge and by 32% when supplemented to a maltodextrin (a rapidly digested starch) challenge. Similarly, sucrose reduced (P = 0.0575) the incremental AUC for plasma glucose when rats were challenged with maltodextrin. Second-meal glycemic response was not affected by fructose supplementation to the first meal, and fructose supplementation to the second meal reduced (P < 0.05) postprandial glycemia when fructose had been supplemented to the first meal. In a dose-response study (0.1, 0.2, and 0.5 g/kg body), supplemental fructose reduced (P < 0.01) the peak rise in plasma glucose (linear and quadratic effects). In the final experiment, a low dose of fructose (0.075 g/kg body) reduced (P < 0.05) the incremental AUC by 18%. These data support the hypothesis that small amounts of oral fructose or sucrose may be useful in lowering the postprandial blood glucose response.     

Glycemic control of type 2 diabetic patients after short-term zinc supplementation

This study was carried out to determine whether a short-term zinc supplementation contributes to beneficial changes in glycemic control among type 2 diabetic patients. Seventy-six diabetic subjects and 72 normal adults participated in this study. Subjects were divided into supplemented and control groups. Forty-four diabetic patients and 34 normal subjects were supplemented with 50 mg zinc daily as zinc gluconate for 4 weeks. Zinc status was assessed from fasting plasma levels and urinary excretion. The effects of zinc supplementation on fasting blood glucose, HbA_1c, insulin, and C-peptide were measured at the beginning of the study and after 4 weeks of supplementation. The changes in glycemic control indicators were compared between diabetic groups, classified by baseline HbA_1c levels, and by diabetic duration. At baseline, the incidence of marginal zinc deficiency in the diabetic group, as determined by plasma zinc level, was approximately twice as high as in the normal adult group. The changes of HbA_1c concentration, and fasting blood glucose following supplementation were not statistically significant in diabetic subjects. In normal subjects, a significant decrease of HbA_1c occurred only in the zinc supplemented group. No significant changes were observed for serum insulin and C-peptide in diabetic as well as normal subjects. However, when the changes were compared by baseline HbA_1c level, we found that diabetic subjects with HbA_1c ≥ 7.5% showed significantly improved levels of HbA_1c and fasting glucose after Zn supplementation. While such improvement in fasting blood glucose was significant among diabetics with shorter diabetic duration, significant levels of increase in serum insulin and C-peptide were observed in zinc supplemented subjects with longer diabetic duration. Fasting blood glucose was significantly decreased, whereas serum insulin and C-peptide were increased in diabetics with marginal zinc status. Therefore, we suggest that Zn supplementation for a short-term period may improve glycemic control in diabetic patients with higher HbA_1c levels and marginal zinc status.     

Postprandial hypoglycemic effect of mulberry leaf in Goto-Kakizaki rats and counterpart control Wistar rats

Postprandial hypoglycemic effect of mulberry leaf (Morus alba L.) was compared in two animal models: Goto-Kakizaki (GK) rats, a spontaneous non-obese animal model for type II diabetes, and their counterpart control Wistar rats. First, the effect of a single oral administration of mulberry leaf aqueous extract (MLE) on postprandial glucose responses was determined using maltose or glucose as substrate. With maltose-loading, MLE reduced peak responses of blood glucose significantly in both GK and Wistar rats (P < 0.05), supporting the inhibition of α-glucosidase by MLE in the small intestine. With glucose-loading, MLE also significantly reduced blood glucose concentrations, measured at 30 min, in both animal models (P < 0.01), proposing the inhibition of glucose transport by MLE. Next, dried mulberry leaf powder (MLP) was administered for 8 weeks by inclusion in the diet. By MLP administration, fasting blood glucose was significantly reduced at weeks 4 and 5 (P < 0.05), but then returned to values that were similar to those of the control at the end of experimental period in GK rats. Insulin, HOMA-IR, C-reactive protein, and triglycerides tended to be decreased by MLP treatment in GK rats. All other biochemical parameters were not changed by MLP administration in GK rats. Collectively, these findings support that MLE has significant postprandial hypoglycemic effect in both non-obese diabetic and healthy animals, which may be beneficial as food supplement to manage postprandial blood glucose. Inhibitions of glucose transport as well as α-glucosidase in the small intestine were suggested as possible mechanisms related with the postprandial hypoglycemic effect of MLE.     

Antioxidant activity of melatonin in diabetes in relation to the regulation and levels of plasma Cu,Zn, Fe,Mn, and Se in Zucker diabetic fatty rats

ObjectiveTo study the antioxidant activity of melatonin in diabetes in relation to the regulation and levels of plasma copper (Cu), zinc (Zn), iron (Fe), manganese (Mn), and selenium (Se) in Zucker diabetic fatty (ZDF) and lean (ZL) rats.MethodsAt 6 wk of age, both ZDF (n = 30) and ZL (n = 30) animals were subdivided into three groups: control (C) (n = 10), vehicle (V) (n = 10), and melatonin-treated (M) (10 mg/kg/d; n = 10) rats for a 6-wk period. At the end of treatment period, plasma mineral levels were measured by flame (Cu, Zn, and Fe), electrothermal (Mn), and hydride generation (Se) atomic absorption spectrometry.ResultsZDF rats had significantly higher Cu, Fe, and Mn plasma levels than did ZL rats (P < 0.05). No significant differences were found between control and vehicle groups (P > 0.05). Melatonin treatment did not influence plasma levels of these antioxidant minerals (Cu, Zn, Fe, and Mn) in ZDF groups (M-ZDF versus C-ZDF group) and ZL (M-ZL versus C-ZL group) rats with the exception of Zn, whose mean plasma level was lower in the M-ZL versus C-ZL group. However, plasma Se levels increased significantly (P < 0.05) after melatonin supplementation in both groups (M-ZDF and M-ZL).ConclusionThe higher mean plasma Cu, Fe, and Mn levels in the ZDF group are related to the enhanced oxidative stress in diabetes and obesity. Melatonin administration significantly enhanced plasma Se levels in both groups (M-ZDF and M-ZL). This is the first study to report that melatonin treatment increases plasma Se levels.