Probucol treatment reverses antioxidant and functional deficit in diabetic cardiomyopathy

Earlier we reported that probucol treatment subsequent to the induction of diabetes can prevent diabetes-associated changes in myocardial antioxidants as well as function at 8 weeks. In this study, we examined the efficacy of probucol in the reversal of diabetes induced myocardial changes. Rats were made diabetic with a single injection of streptozotocin (65 mg/kg, i.v.). After 4 weeks of induction of diabetes, a group of animals was treated on alternate days with probucol (10 mg/kg i.p.), a known lipid lowering agent with antioxidant properties. At 8 weeks, there was a significant drop in the left ventricle (LVSP) and aortic systolic pressures (ASP) in the diabetic group. Hearts from these animals showed an increase in the thiobarbituric acid reacting substances (TBARS), indicating increased lipid peroxidation. This was accompanied by a decrease in the myocardial antioxidant enzymes activities, superoxide dismutase (SOD) and glutathione peroxidase (GSHPx). Myocardial catalase activity in the diabetic group was higher. In the diabetic + probucol group both LVSP and ASP showed significant recovery. This was also accompanied by an improvement in SOD and GSHPx activities and there was further increase in the catalase activity. Levels of the TBARS were decreased in this group. These data provide evidence that diabetic cardiomyopathy is associated with an antioxidant deficit which can be reversed with probucol treatment. Improved cardiac function with probucol may be due to the recovery of antioxidants in the heart.     

Free radical activity during development of insulin-dependent diabetes mellitus in the rat.

Free radical-induced lipid peroxidation was quantified by measuring expired pentane from diabetic prone BB Wistar rats of 45-90 d of age. Insulin-dependent diabetes mellitus was manifest at the age of 71 +/- 8 d. Expired pentane increased from 2.1 +/- 0.7 to 5.0 +/- 3.0 pmol/100g/min (p less than 0.01) at manifestation of the disease and remained high throughout the test period. In healthy age-matched control rats it persisted low. In rats made diabetic with streptozotocin, expired pentane remained low. The changes in expired pentane suggest that the development of endogenous insulin-dependent diabetes mellitus in BB rats is associated with increased free radical activity. This is not due to hyperglycemia or ketosis per se, and reflects a fundamental difference in the free radical activity between the spontaneously diabetic BB rats and the disease produced by streptozotocin. Development of spontaneous insulin-dependent diabetes in BB rats is associated with increased free radical activity that persists after the manifestation of the disease.     

Diabetes-induced decrease in rat brain microsomal Ca2+-ATPase activity

The Ca(2+)-ATPase activity of rat brain microsomes was studied in streptozotocin (STZ)-induced diabetes. Male rats, 200-250 g, were rendered diabetic by injection of STZ (45 mg kg(-1) body weight) via the teil vein. Brain tissues were collected at 1, 4 and 10 weeks after diabetes was induced for determination of Ca(2+)-ATPase activity, lipid peroxidation and tissue calcium levels. Diabetic rats had significantly elevated blood glucose levels compared to controls. Blood glucose levels were 92.92 +/- 1.22 mg dl(-1) (mean +/- SEM) for the control group, 362.50 +/- 9.61 mg dl(-1) at 1 week and >500 mg dl(-1) at 4, 8 and 10 weeks for the diabetics. Enzyme activities were significantly decreased at 1, 4, 8 and 10 weeks of diabetes relative to the control group (p < 0.001). Ca(2+)-ATPase activity was 0.084 +/- 0.008 U l(-1), 0.029 +/- 0.005 U l(-1), 0.029 +/- 0.006 U l(-1), 0.033 +/- 0.003 U l(-1) and 0.058 +/- 0.006 U l(-1) (mean +/- SEM) at control, 1, 4, 8 and 10 week of diabetes respectively. The change in calcium levels in diabetic rat brain at 8 and 10 weeks of diabetes was significantly higher than that of the control group (p < 0.05). On the other hand lipid peroxidation measured as TBARS (thiobarbituric acid reactive substances) was significantly higher at 8 and 10 weeks of diabetes (p < 0.05). The increase in lipid peroxidation observed in diabetic rat brain may be partly responsible for the decrease in calcium ATPase activity.     

Free and lipid myo-inositol in tissues from rats with acute and less severe streptozotocin-induced diabetes.

Acute diabetes with ketosis was induced in rats by intraperitoneal streptozotocin and also a milder form of diabetes without ketosis by injecting less of the drug. The acutely diabetic rats were killed 72h after injection and the others after either 2 or 13 weeks. Free and lipid myo-inositol was then measured in various tissues and body fluids by g.l.c. of the trimethylsilyl ether. Serum inositol was increased in the acutely diabetic group, whereas liver inositol was decreased. Brain and kidney inositol concentrations were increased in the mildly diabetic animals at 13 weeks and there was a progressive decrease in sciatic-nerve inositol. Lipid inositol of sciatic nerve was decreased in the acutely diabetic group only. Brain lipid inositol concentration was decreased in mild diabetes at 13 weeks. Possible implications of these findings in relation to diabetic neuropathy was discussed.     

Fetal rat islet insulin deficiency following maternal administration of streptozotocin

Pancreatic islets were isolated from the fetuses of normal rats and rats made diabetic by the iv administration of streptozotocin (STZ) on either Day 3 or 5 of pregnancy. Of the rats made diabetic on Day 3, one group also received insulin injections at the appearance of glucosuria. Maternal blood glucose on Day 20 of gestation was significantly different in the diabetic rats (405 +/- 27 mg/dl) from the normal (97 +/- 1 mg/dl) and insulin-treated diabetic rats (69 +/- 9 mg/dl). While fetal weight was significantly decreased in the STZ-treated rats (2.64 +/- 0.13 g vs 3.52 +/- 0.05 g for the control group, P less than 0.005), fetal glucose was significantly higher in the STZ-treated than in normal pups (342 +/- 11 vs 35 +/- 1 mg/dl, P less than 0.005). Both fetal weight and glucose were normalized by insulin treatment: 3.16 +/- 0.18 g and 31 +/- 7 mg/dl, respectively. Insulin release from fetal islets of diabetic dams was blunted after a week in culture both in basal and stimulated conditions. After 2 weeks in culture, there was partial recovery in the insulin response to glucose but it did not equal to that measured in fetal islets from the normal and insulin-treated diabetic rats. These data suggest maternal hyperglycemia severely impairs fetal weight and insulin release from fetal rat islets in vitro, and correction of the hyperglycemia by insulin treatment not only improves fetal weight and glucose concentrations, but it also normalizes insulin release from fetal rat islets in vitro.     

Gfat1基因在2型糖尿病大鼠肺组织中的表达

观察2型糖尿病大鼠不同时期肺组织谷氨酰胺果糖转移酶1(Gfat1)的表达情况.方法 SD大鼠随机分为正常对照组和模型组,对照组18只,模型组28只.模型组高脂饲料喂养2个月后,腹腔注射链脲佐菌素(STZ 15mg/kg)复制糖尿病模型,统计体重变化及空腹血糖值.RT-PCR方法检测造模成功后2周、4周和6周肺组织Gfat1 mRNA表达.结果 模型组大鼠体重增长较快,造模开始第28天,第42天,第56天和第70天高脂模型组与对照组体重差异有显著性(P＜0.05).注射STZ的高脂模型组空腹血糖值较高(FBG≥10.0),和对照组比较,FBG差异有极显著性(P＜0.01).糖尿病大鼠造模成功后2周,模型组肺组织Gfat1的表达低于对照组,与对照组比较差异无显著性(P＞0.05),4周模型组Gfat1的表达高于对照组,模型组与对照组比较差异有显著性(P＜0.05).6周模型组Gfat1的表达高于对照组,但模型组与对照组比较差异无显著性(P＞0.05).结论 大鼠饲喂高脂饲料结合腹腔注射STZ可成功建立2型糖尿病大鼠模型;在不同时期2型糖尿病大鼠肺组织中,Gfat1表达水平发生改变.     

2型糖尿病大鼠的尿液代谢组学改变

目的 通过检测2型糖尿病大鼠尿液代谢谱的变化.探讨代谢组学在糖尿病研究中的应用.方法 SD大鼠高糖高脂饲料喂养6周后,腹腔注射链脲菌素(Streptozotocin,STZ)37 mg/kg建立2型糖尿病模型,动态检测空腹血糖(FBG)变化,检测甘油三酯(TC)、总胆固醇(TC)、游离脂肪酸(FFA)及胰岛素(INS)...     

Protective effect of caffeic acid phenethyl ester (CAPE) on lipid peroxidation and antioxidant enzymes in diabetic rat liver

The aim of this study was to examine the effect of caffeic acid phenethyl ester (CAPE) on lipid peroxidation (LPO) and the activities of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in the liver of streptozotocin (STZ)-induced diabetic rats. Twenty-seven rats were randomly divided into three groups: group I, control non-diabetic rats (n = 9); group II, STZ-induced, untreated diabetic rats (n = 8); group III, STZ-induced, CAPE-treated diabetic rats (n = 10), which were intraperitoneally injected with CAPE (10 microM kg(-1) day(-1)) after 3 days followed by STZ treatment. The liver was excised after 8 weeks of CAPE treatment, the levels of malondialdehyde (MDA) and the activities of SOD, CAT, and GSH-Px in the hepatic tissues of all groups were analyzed. In the untreated diabetic rats, MDA markedly increased in the hepatic tissue compared with the control rats (p < 0.0001). However, MDA levels were reduced to the control level by CAPE. The activities of SOD, CAT, and GSH-Px in the untreated diabetic group were higher than that in the control group (p < 0.0001). The activities of SOD and GSH-Px in the CAPE-treated diabetic group were higher than that in the control group (respectively, p < 0.0001, p < 0.035). There were no significant differences in the activity of CAT between the rats of CAPE-treated diabetic and control groups. Rats in the CAPE-treated diabetic group had reduced activities of SOD and CAT in comparison with the rats of untreated diabetic group (p < 0.0001). There were no significant differences in the activity of GSH-Px between the rats of untreated diabetic and CAPE-treated groups. It is likely that STZ-induced diabetes caused liver damage. In addition, LPO may be one of the molecular mechanisms involved in STZ-induced diabetic damage. CAPE can reduce LPO caused by STZ-induced diabetes.     

Decreased RhoA expression in myocardium of diabetic rats

Diabetic cardiomyopathy is 1 of the major causes of death in diabetic patients, but the pathogenesis is unclear. There is evidence that RhoA, a small GTPase, might be involved in cardiac function. This study, therefore, analyzed RhoA expression and activation in hearts of diabetic rats. Male Sprague-Dawley rats were divided into control and diabetic groups of 18 each. Diabetes was induced by intravenous injection of streptozotocin (55 mg/kg). Rats were studied 3 weeks after induction of diabetes. Heart rate, which was measured 24 h/day, decreased by 93 +/- 7 beats/min in diabetic rats. There was a 62% decrease (p < 0.01) in RhoA mRNA expression in heart tissues (left ventricle) of diabetic rats (38.5 +/- 6.7 x 106 molecules/microg total RNA) compared with controls (101 +/- 10.3 x 106 molecules/microg total RNA). Western blot showed a 33% decrease in total RhoA protein expression in heart tissues of diabetic rats compared with controls (p < 0.05). A reduced RhoA translocation in heart tissues of diabetic rats was determined by a 64% decrease in membrane-bound RhoA (p < 0.01 vs. control group), indicating that the activation of RhoA is markedly reduced in diabetic myocardium. Our data suggest that down-regulated RhoA may be involved in cardiomyopathy in diabetic rats.     

普罗布考对糖尿病大鼠肾组织氧化应激的影响

目的研究普罗布考（Probucol）对糖尿病大鼠肾组织氧化应激的影响。方法采用腹腔注射链脲佐菌素（STZ）建立糖尿病大鼠模型。30只Wistar大鼠分为正常对照组（NC）、糖尿病组（DM）、糖尿病普罗布考治疗组（DP）。8周末称取体重、肾重、计算肾肥大指数（肾重/体重）,检测尿白蛋白排泄率（UAER）;测定各组生化指标包括血糖（BG）、胆固醇（TC）、三酰甘油（TG）、血清肌酐（SCr）、血尿素氮（BUN）;检测肾组织中丙二醛（MDA）的含量及超氧化物歧化酶（SOD）、过氧化氢酶（CAT）与谷胱甘肽过氧化物酶（GSH-Px）活性;肾组织切片行PAS染色分析肾小球面积及肾小球体积。结果 DM组大鼠肾重、肾重/体重、UAER、TC、TG、SCr、BUN、肾小球面积、肾小球体积较NC组均明显增加,DP组上述改变较DM组均明显减轻（P〈0.05）。DP组肾组织中MDA含量明显低于DM组,SOD、CAT、GSH-Px活性明显高于DM组（P〈0.05）。结论普罗布考可能部分通过减轻肾组织氧化应激反应实现对糖尿病大鼠肾脏的保护作用。     

人脐带间充质干细胞移植对糖尿病大鼠血清学的影响

目的:观察人脐带间充质干细胞(hu MSCs)移植对糖尿病大鼠血糖、胰岛素和血清因子表达的影响。方法:随机选择12只Wistar大鼠通过腹腔注射链脲佐菌素50 mg/kg,血糖高于16.7 mmol/L者定为糖尿病大鼠,再将其随机分为糖尿病组和干细胞组,每组6只,同时选择6只雄性Wistar大鼠为正常组。干细胞组大鼠腹腔注射hu MSCs细胞悬液,糖尿病组注射PBS液。分别于注射2周、4周和6周后测定和比较各组大鼠的血糖、血清胰岛素、肿瘤坏死因子(TNF-α)和白介素-6(IL-6)的表达。结果:与正常组比较,糖尿病组和干细胞组大鼠的血糖水平均显著升高,胰岛素水平均显著降低(P0.01)。与糖尿病组比较,干细胞组大鼠注射hu MSCs后的血糖水平明显降低,胰岛素水平明显升高(P0.05),血清TNF-α和IL-6 m RNA水平均显著降低(P0.01)。结论:hu MSCs移植能显著降低糖尿病大鼠的血糖,促进其胰岛素分泌,同时降低血清TNF-α和IL-6的表达。     

Adenosine triphosphatase activity of streptozotocin-induced diabetic rat brain microsomes. Effect of vitamin E

Hyperglycemia causes protein glycosylation, oxidation and alterations in enzyme activities, which are the underlying causes of diabetic complications. This study was undertaken to test the role of vitamin E treatment on Ca2+-ATPase activity, protein glycosylation and lipid peroxidation in the brain of streptozotocin (STZ)-induced diabetic rats. Male rats weighing about 250-300 g were rendered diabetic by a single STZ injection of 50 mg/kg via the tail vein. Both the diabetic and non-diabetic rats were fed a vitamin E supplemented diet (500 IU/kg/day). Ca2+-ATPase activity was significantly reduced at week 10 of diabetes compared to the control group (p < 0.05), with 0.225+/-0.021 U/I (mean +/- S.E.M.) in the control group and 0.072 +/- 0.008 U/l (mean +/- S.E.M.) in the diabetic group. Vitamin E treatment prevented the enzyme activity from decreasing. The activities observed were 0.226 +/- 0.020 U/l and 0.172 +/- 0.011 U/I (mean +/- S.E.M.) in the vitamin E-treated control and diabetic group, respectively. STZ-induced diabetes resulted in an increased protein glycosylation and lipid peroxidation. Vitamin E treatment led to a significant inhibition in blood glucose, protein glycosylation and lipid peroxidation, which in turn prevented abnormal activity of the enzyme in the brain. This study indicates that vitamin E supplementation may reduce complications of diabetes in the brain.     

Maternal low-carbohydrate high-protein diet affects mandibular growth in diabetic newborn rats

Dams with 7 pups each were randomly assigned to two different diets. Twelve dams were fed a normal (20%) protein diet and were divided into two groups of 4 and 8 animals. Pups from group 1 (n = 28) were injected with citrate buffer as a control. Pups from group 2 (n = 56) were injected with streptozotocin. Twelve additional dams were fed a 40% protein diet. They were also divided into two groups of 4 and 8 animals. Pups from group 3 (n = 28) were injected with citrate buffer as a control. Pups from group 4 (n = 56) were injected with streptozotocin. Forty-eight hours later, diabetic status was determined using Dextrostix. On Day 15, pups were injected with [14C]proline to determine collagen synthesis and 45Ca to study mineralization. After the pups were killed, blood glucose levels were determined. Then mandibles were removed. Milk from each dam was also collected after injection of oxytocin. At the time of killing, blood glucose levels in diabetic pups were less than earlier levels, though still higher than those of controls on either diet. The weights of body and mandible, collagen contents, and the total calcium contents in the diabetic group were in general less than those of the nondiabetic group on the 20 and 40% protein diets. 45Ca uptake in the diabetic group was significantly increased compared with those of the nondiabetic rats on both diets. The percentage reduction in the mandibles of diabetic rats from those of nondiabetic rats on the 40% protein diets was consistently less than that of animals on the 20% protein diets. The higher protein contents of the maternal milk in the 40% protein group may partly be responsible for the smaller impairment of mandibular development in the diabetic over nondiabetic animals. It is concluded that maternal low-carbohydrate high-protein diets will play indirectly a beneficial role in the development of the mandibles of diabetic newborns.     

Insulin receptors on erythrocytes and hepatocytes from streptozotocin induced diabetic rats

Insulin receptors on hepatocytes and erythrocytes were studied in rats two and eight weeks after the injection of streptozotocin (50 mg/kg) to see if erythrocyte insulin receptors change parallel with hepatocyte insulin receptors in response to hypoinsulinemia. Insulin binding to hepatocytes increased two (14.0 +/- 2.5% v.s. 7.7 +/- 0.7%; P less than 0.025) and eight weeks (15.9 +/- 1.9% v.s. 6.6 +/- 1.1%; P less than 0.005) after the streptozotocin injection. Scatchard analysis revealed that this increase was due to a rise in both the receptor concentration and affinity. The number of receptors was comparable in the two- and eight-week-streptozotocin rats while the increase in the affinity was more pronounced in the latter group. Insulin binding to the erythrocytes was also increased in both two- (5.0 +/- 0.7% v.s. 4.2 +/- 0.6%) and eight-week- (4.3 +/- 0.6% v.s. 2.7 +/- 1.2%) streptozotocin rats. This increase was due to a rise in the receptor concentration rather than the affinity. However, compared to hepatocytes, these changes were inconsistent and statistically not significant. Furthermore, no correlation was obtained between the binding and plasma insulin concentration. These results indicate that insulin receptors on rat erythrocytes are less sensitive to a change in the plasma insulin concentration and do not always reflect accurately the receptor state on hepatocytes.     

Increased steady-state levels of laminin B1 mRNA in kidneys of long-term streptozotocin-diabetic rats. No effect of an aldose reductase inhibitor

The steady-state levels of mRNAs coding for two components of basement membranes, the alpha 1 chain of type IV collagen and the B1 chain of laminin, were measured in the kidneys of male CDF rats following the induction of diabetes with streptozotocin for periods of between 2 days and 28 weeks. The concentration of mRNA for the alpha 1 chain of type IV collagen/microgram of RNA decreased markedly with age in control and diabetic rats. The diabetic level was significantly lower than control after 2 and 11 weeks of diabetes. After 28 weeks, however, there was no significant difference from the levels in control animals. Treatment of control and diabetic rats with the aldose reductase inhibitor Statil (350 mg/kg diet) did not affect the levels of the mRNA for the alpha 1 chain of type IV collagen. In contrast to the continuous decline in the concentration of mRNA for the alpha 1 chain of type IV collagen, the level of mRNA for the B1 chain of laminin increased two-fold between 11 and 28 weeks after induction of diabetes. This increase occurred as aging of control rats reduced the level of laminin B1 mRNA by approximately 50%. Treatment with Statil had no effect on laminin B1 mRNA levels. In control rats there was no change in the ratio of the levels of mRNAs for laminin B1: alpha 1 (IV) collagen with age. The mean ratio was 0.97 +/- 0.10 at 19 weeks and 1.0 +/- 0.10 at 36 weeks of age. In diabetic rats there was a marked increase in the ratio from 0.85 +/- 0.11 at 19 weeks to 3.2 +/- 1.2 at 36 weeks of age. The increased abundance of mRNA for laminin B1 raises the possibility that increased synthesis of laminin contributes to the thickening and abnormal function of renal basement membranes in streptozotocin-diabetic rats.     

The use of xanthine oxidase for a specific and sensitive fluorimetric determination of 6-mercaptopurine in serum

Excretion of urinary N-acetyl-beta-D-glucosaminidase has been found to be elevated in diabetic humans and rats. This urinary glycosidase may reflect blood sugar control over time, since it has been significantly and positively correlated with hemoglobin A1 in children with insulin-dependent diabetes. Other studies have suggested that urinary NAG may predict diabetic nephropathy. In order to more carefully define the relationship between urinary NAG excretion and blood and urine sugars, hemoglobin A1, and microalbuminuria, 48 rats were made diabetic by the use of streptozotocin. All rats were uninephrectomized at 3 weeks. Of these, 23 were treated with daily insulin injections, 25 were untreated, and both groups were compared to 13 control, nondiabetic rats. Urine volume, glucose, albumin, and blood sugar were all significantly (P less than 0.05) elevated in the untreated rats compared to the treated and control groups. Urinary NAG:UCr was significantly (P less than 0.01) elevated in the untreated group with lower but still elevated levels (P less than 0.05) in the treated rats. To further define the time course of the increase in UNAG:UCr 12 rats were followed serially at 12-hr intervals for 92 hr after streptozotocin. Urinary NAG increased significantly (P less than 0.05) at 12 hr after streptozotocin injection and reached a plateau at 36 hr while hemoglobin A1 did not rise until 2 weeks after onset of hyperglycemia. Urinary NAG increases more rapidly than hemoglobin A1 after onset of hyperglycemia and glycosuria.(ABSTRACT TRUNCATED AT 250 WORDS)     

高糖高脂饮食联合注射STZ制备2型糖尿病大鼠缺血性心脏病模型

目的：制备2型糖尿病缺血性心脏病大鼠模型。方法：雄性Wistar大鼠20只,随机分为正常组和糖尿病模型组（n=10）。糖尿病模型组给予高糖高脂饮食饲喂4周后,一次性腹腔注射链脲佐菌素40mg/kg,制备糖尿病大鼠模型。每周常规监测血糖、血清胰岛素、体重的变化。糖尿病模型组与正常组大鼠,使用BL-41O生物机能试验系统,每周测定肢体2导联心电图。最后检测血清中的肌酸激酶和乳酸脱氢酶的含量。结果：高糖高脂饲料饲喂4周后胰岛素升高至4．05ng/ml,糖尿病模型组注射SIZ后空腹血糖迅速升高,达到17．9mmol/L。在第14周,糖尿病模型组出现S-T段抬高,并且与正常组比较,血清肌酸激酶（creatine kinase,CK）和乳酸脱氢酶（lactate dehydrogenase,LDH）均升高。结论：本实验成功建立的2型糖尿病缺血性心脏病大鼠模型,为研究糖尿病缺血性心脏病提供理想的动物模型。     

Histological evidence that metformin reverses the adverse effects of diabetes on orthodontic tooth movement in rats

This study evaluated the effects of metformin on orthodontic tooth movement in a rat model of type 2 diabetes mellitus. Rats were fed a high-fat diet for 4 weeks to induce fat accumulation and insulin resistance, and then injected with a low dose of streptozotocin (35 mg/kg) intraperitoneally to induce type 2 diabetes. An orthodontic appliance was placed in normoglycemic, type 2 diabetes, and type 2 diabetes with metformin-administrated rats. After 14 days, type 2 diabetes rats exhibited greater orthodontic tooth movement and had a higher number of tartrate-resistant acid phosphatase-positive osteoclasts, stronger cathepsin K expression, and weaker alkaline phosphatase immunostaining than normoglycemic rats. Metformin administration resulted in normalization of osteoclast numbers, cathepsin K immunostaining, and of tooth movement as well as partly recovery of alkaline phosphatase expression in diabetic rats. Metformin also reduced sclerostin expression and improved the immunolocalization of dentin matrix protein 1 in osteocytes of type 2 diabetes rats. These results suggest that metformin administration reversed the adverse effects of diabetes on orthodontic tooth movement.     

The longitudinal effect of inhibiting fatty acid oxidation in diabetic rats fed a high fat diet.

This study was designed to examine the time-course of response to inhibition of fatty acid (FA) oxidation in rats rendered mildly diabetic with streptozotocin and fed a high fat diet (50% of energy derived from fat). Etomoxir, a specific carnitine palmitoyltransferase (CPT-1) inhibitor, was administered subcutaneously (12.5 mg/kg) to inhibit long chain fatty acid oxidation. Diabetic and non-diabetic control rats were maintained on the high fat diet. Following an overnight fast, glucose, free fatty acid (FFA) and triglyceride (TG) concentrations were determined after three days, one week and four weeks of treatment. The effect of Etomoxir treatment in reducing fasting glucose concentrations was not evident until after one week, while fasting FFA and TG concentrations were already reduced after three days treatment. All of these changes were maintained over the four week period (P less than 0.001), resulting in reduced levels of fasting plasma glucose (17.6 +/- 2.4 vs 22.3 +/- 1.9 mmol/l), fasting plasma TG (0.32 +/- 0.07 vs 0.98 +/- 0.14 mmol/l) and fasting serum FFA (1.52 +/- 0.26 vs 3.51 +/- 0.69 mEq/l). In addition, the improvements in glucose and lipid levels were accompanied by restored rates of growth towards that of non-diabetic control rats. These results suggest that the short term inhibition of FA oxidation improves fasting glucose, FFA and TG concentrations in diabetic rats fed a high fat diet.     

Effects of streptozotocin-induced diabetes and insulin on calcium responsiveness of the rat vas deferens

In the present study, effects of streptozotocin-induced diabetes and insulin treatment on the reactivity of rat vas deferens to KCl and calmidazolium, a calmodulin antagonist, were evaluated and calmodulin levels in vas deferens tissue from diabetic and insulin-treated rats were determined. Diabetes was induced in rats by a single injection of streptozotocin. Five weeks after the induction of diabetes, one group of diabetic rats was injected with insulin for 3 weeks. After 8 weeks, vas deferens tissues on one side of diabetic and insulin-treated diabetic rats and their controls were mounted in organ bath to measure isometric tension, while the tissues on the other side of rats were homogenized to determine calmodulin levels by radioimmunoassay. Concentration-response curves to KCl were obtained in vas deferens tissues in the absence and presence of calmidazolium. The effects of KCl and calmidazolium on vas deferens isolated from 8-weeks diabetic rats were decreased. Calmodulin levels were also found to be decreased in vas deferens from diabetic rats. Decreased calmodulin levels in diabetic rat vas deferens were not corrected by insulin treatment. Only a partial correction following insulin treatment was observed in contractile effect of KCl on diabetic rat vas deferens, whereas insulin treatment increases the affinity of calmodulin in this muscle. Experimental diabetes causes an impairment in calcium/calmodulin-dependent contractile process of vas deferens, which is correctable partially following insulin therapy. The changes in the function of rat vas deferens due to streptozotocin diabetes seem to be related to impaired sexual functions in human diabetes.