Long-term changes in the diabetic state induced by different doses of streptozotocin in rats.

The long-term effects of different doses (0, 25, 35, 45, 55, 65 and 100 mg/kg) of streptozotocin (STZ) in male Wistar rats had been followed over a 16 week period. The weight-gain curve and the epididymal fat pad weight were significantly different (P less than 0.05) from control after 1 week with the 65 and 100 mg/kg doses and after 4 weeks with the 45 and 55 mg/kg doses; there were no significant changes with the 25 and 35 mg/kg doses even after 16 weeks. An i.v. glucose tolerance test (0.5 g/kg) was performed at 1, 4 or 16 weeks after the injection of STZ. The basal levels of glucose were significantly elevated (P less than 0.05) after 1 week with the greater than or equal to 55 mg/kg doses, and after 16 weeks with the greater than or equal to 45 mg/kg doses; there was also an overall increase in the basal glucose levels between 1 and 16 weeks in rats treated with the greater than or equal to 45 mg/kg doses. The basal insulin levels were significantly decreased (P less than 0.05) after 1 week with the greater than or equal to 65 mg/kg doses, after 4 weeks with the greater than or equal to 55 mg/kg doses and after 16 weeks with the greater than or equal to 35 mg/kg doses. The insulin peak 2 min after the glucose load was significantly less (P less than 0.05) after 1 week with the greater than or equal to 35 mg/kg doses and after 16 weeks with the greater than or equal to 25 mg/kg doses. The use of an insulinogenic index to assess the insulin secretory capacity showed a significant decrease (P less than 0.05) for the greater than or equal to 35 mg/kg doses at each tested time; with the 45 mg/kg dose, there was a further significant decrease (P less than 0.01) between the first and sixteenth week. The present long-term studies showed that there is a progressive deterioration in the glucose tolerance and insulin secretion after the injection of different doses of STZ. Furthermore, changes in glucose-insulin interrelationships over time suggest that the insulin insensitivity previously described in STZ diabetic rats might be only an early transient phenomenon.     

A new animal model of non-insulin-dependent diabetes mellitus with hypertension: neonatal streptozotocin treatment in spontaneously hypertensive rats.

Streptozotocin (STZ) treatment on neonatal rats produces a non-insulin-dependent diabetes mellitus (NIDDM) model in adulthood. Applying this model to spontaneously hypertensive rats (SHR), we designed the present study to develop a new model of NIDDM with genetic hypertension. Two-day-old male and female SHR were intraperitoneally injected with 25.0-75.0mg/kg STZ, and two-day-old Wistar Kyoto rats (WKY) of both sexes, which are a normotensive control strain for SHR, were similarly injected with 75.0-150.0mg/kg STZ. Control rats received vehicle alone. The relationships between the doses of the STZ injected and the changes of the metabolic variable and blood pressure were examined for 12 weeks following the treatment. Plasma glucose levels in male SHR increased in a dose-dependent manner at 12 weeks, control 122 +/- 8 (SEM) mg/dl, 25.0mg/kg STZ 139 +/- 13mg/dl (ns), 37.5mg/kg STZ 240 +/- 51mg/dl (ns), 50.0mg/kg STZ 359 +/- 39mg/dl (p less than 0.01), 62.5mg/kg STZ 419 +/- 33mg/dl (p less than 0.001) and 75.0mg/kg STZ 513 +/- 10mg/dl (p less than 0.001), whereas in male WKY, only mild hyperglycemia developed in case of the higher doses of STZ given, control 112 +/- 4mg/dl, 75.0mg/kg STZ 136 +/- 18mg/dl (ns), 100.0mg/kg STZ 204 +/- 40mg/dl (ns), 125.0mg/kg STZ 219 +/- 37mg/dl (p less than 0.05), and 150.0mg/kg STZ 177 +/- 12mg/dl (p less than 0.01). The development of hypertension was not affected by the neonatal STZ treatment in male SHR at 11 weeks, systolic blood pressure being control 210 +/- 7mmHg, 25.0mg/kg STZ 217 +/- 5mmHg (ns), 37.5mg/kg STZ 202 +/- 3mmHg (ns), 50.0mg/kg STZ 216 +/- 6mmHg (ns), 62.5mg/kg STZ 210 +/- 6mmHg (ns), and 75.0mg/kg STZ 209 +/- 5mmHg (ns). For the long-term observation, STZ-treated male SHR were divided into mild diabetes group (plasma glucose at 12 weeks less than 300mg/dl, mean 195 +/- 21mg/dl) and severe diabetes group (greater than or equal to 300mg/dl, mean 445 +/- 18mg/dl). Hyperglycemia in both groups was maintained until 28 weeks, plasma glucose being control 112 +/- 4mg/dl, mild diabetes group 161 +/- 10mg/dl (p less than 0.01), and severe diabetes group 419 +/- 25mg/dl (p less than 0.001) but it later gradually ameliorated, plasma glucose at 52 weeks being control 120 +/- 3mg/dl, mild diabetes group 131 +/- 7mg/dl (ns), and severe diabetes group 220 +/- 43mg/dl (ns). However, hypertension persisted in both diabetes groups until 52 weeks, systolic blood pressure being control 209 +/- 6mmHg, mild diabetes group 199 +/- 9mmHg (ns), and severe diabetes group 221 +/- 6mmHg (ns).(ABSTRACT TRUNCATED AT 400 WORDS)     

一种建立小鼠2型糖尿病心肌病模型的方法

目的:采用连续喂养高脂饮食(high-fat diet,HFD)结合单次腹腔注射链脲佐菌素(streptozotocin,STZ)的方法建立小鼠2型糖尿病心肌病模型。方法:将40只5~6周龄C57BL/6J雄性小鼠随机分成2组(每组各20只):对照(control)组,持续以普通饲料喂养;HFD+STZ组,持续以HFD喂养,并于造模第5周注射STZ(100mg/kg)。于造模实验开始(第0周)、第5周、第6周、第11周和第16周,测量体重和血糖,并于第11周和第16周分别对control组和HFD+STZ组小鼠进行心功能检测、胰岛素水平检测、组织学观察和心肌细胞凋亡分析。结果:造模过程中HFD+STZ组小鼠各时期的体重均大于control组(P0.05),注射完STZ后小鼠体重略有下降,但仍高于control组。注射STZ 1周后,HFD+STZ组小鼠空腹血糖值均持续高于13.89 mmol/L。在造模第11周和16周时,HFD+STZ组小鼠胰岛素水平与control组相比均有降低(P0.05)。心功能检测、组织学观察和心肌细胞凋亡分析显示,造模第11周时,HFD+STZ组小鼠的超声、心肌细胞面积和凋亡率等指标与control组相比变化不明显;造模第16周,HFD+STZ组小鼠出现心室功能障碍,心肌细胞肥大,心肌细胞的面积和心肌细胞凋亡率明显大于control组(P0.05)。结论:采用连续喂养HFD结合单次注射STZ可成功建立小鼠2型糖尿病心肌病模型。     

mTOR/S6K1在2型糖尿病Wistar大鼠肝脏和肌肉的表达

目的应用Wistar大鼠制备2型糖尿病的动物模型,观察肝脏和肌肉组织mTOR/Rps6kb1(S6K1)表达的变化。方法雄性Wistar成年大鼠高脂饲料喂养8周,腹腔注射链脲佐菌素(STZ)25mg/kg,注射后第4周检测空腹血糖、胰岛素水平,对结果进行统计分析;解剖大鼠,取肝脏和肌肉组织,应用RT-PCR和Western blot检测肝脏和肌肉组织mTOR及S6K1表达。结果与正常对照组比较,模型组大鼠血糖值升高(0.05),胰岛素水平下降(0.05),肝脏和肌肉中的mTOR/S6K1蛋白和mRNA表达均升高(0.05)。结论 mTOR及S6K1在2型糖尿病大鼠肝脏和肌肉过表达,提示其可能参与2型糖尿病发病过程。     

Early administration of an immunomodulator and induction of remission in insulin-dependent diabetes mellitus

A clinical trial was undertaken to determine whether intensive thymopentin administration enhances remission of insulin-dependent diabetes (IDDM) during the first year after diagnosis. Dosage with insulin was minimized with target control of blood glucose levels less than or equal to 7.8 mmol/l before meals. Remission was defined as a prolonged period after IDDM onset (not less than 3 months) characterized by a non-insulin-receiving (NIR) state in which target metabolic control was reached without administration of insulin and with a valid C-peptide response, evaluated after standard breakfast. Sixteen IDDM patients aged 12-31 years, recruited within 2 weeks of initiation of insulin therapy and within 5 weeks of onset of symptoms, were treated with intravenous (i.v.) thymopoietin32-36 pentapeptide (Thy) (1 mg/kg/body weight) for 7 days and twice per week for up to 3 months. A control IDDM group without initial significant differences in metabolic control parameters was also studied. No difference was observed between the two IDDM groups regarding the after-diagnosis normalization curve of HbA1c; mean daily glycemic level rates and ICA titer decreased during the observation. A reduction in anti-insulin antibodies (AIA) in Thy-treated patients was observed in comparison to conventionally treated IDDM starting from 6 months and reaching a reduction peak at 1 year (P less than or equal to 0.02). As regards the NIR remission rate, it was significantly more accelerated in Thy-treated patients, reaching 43% at 6 months and 57% at 1 year vs 12% and 6.7% respectively in the control IDDM group (P range less than or equal to 0.05-0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

完全脾切除增加了小鼠胰岛对STZ的敏感性

目的: 探讨脾脏对链脲菌素(STZ)损伤胰岛β细胞是否具有保护作用。方法: 以外科手术切除小鼠全脾。60只脾切除小鼠随机分为3组,分别以80 mg/kg、160 mg/kg STZ给小鼠腹腔注射,另一组腹腔注射生理盐水。60只正常小鼠做同样分组及处理。1周后,测定各组小鼠空腹血糖、血清胰岛素水平,免疫组化分析各组胰岛β细胞总量,ELISA法分析胰岛细胞凋亡,Luminol化学发光法测定各组胰腺活性氧簇(ROS)水平。结果: 80 mg/kg STZ处理脾切除组空腹血糖浓度显著升高,血清胰岛素显著降低;同剂量STZ处理的正常小鼠血糖及胰岛素水平则正常;此外, 80 mg/kg STZ处理的脾切除小鼠β细胞总量、胰岛凋亡细胞核小体聚集值及胰腺组织ROS的产生与同剂量STZ处理的正常小鼠相比均有显著差异。结论: 脾可以阻止低剂量STZ对正常小鼠胰岛β细胞的破坏作用。完全脾切除增加了胰岛对STZ的敏感性,这一作用与胰腺组织ROS增加相关。     

ACEI和ARB治疗改善糖尿病大鼠胰岛素分泌功能的研究

目的：研究血管紧张素转换酶抑制剂ACEI和血管紧张素II受体拮抗剂ARB对高脂喂养链脲佐菌素（STZ）诱导的糖尿病大鼠胰岛素和胰高糖素分泌及氧化应激功能的影响。方法：应用Enalaprial和Losartan对高脂喂养STZ诱导的糖尿病大鼠进行干预,放免法测定胰岛素和胰高糖素,ELISA检查氧化应激指标8-isoPGF-2α水平。并通过静脉葡萄糖耐量实验了解ACEI和ARB治疗对一相胰岛素分泌的影响。结果：ACEI或ARB治疗可以减少氧化应激,保护一相胰岛素分泌。结论：ACEI或ARB治疗对维持正常的胰岛素分泌可能起到了重要保护作用,从而降低血糖和减少糖尿病的发生。这可能是大规模临床研究中ACEI和ARB使血糖回归至正常水平或减少新发的糖尿病的发生率的深层机制之一。     

Defective glucose counterregulation after strict glycemic control of insulin-dependent diabetes mellitus

We infused small doses of insulin (0.3 mU per kilogram of body weight per minute; range, 0.9 to 1.7 U per hour) for three hours into 8 subjects who did not have diabetes, 11 patients with well-controlled diabetes (hemoglobin A1, 7.6 +/- 0.7 percent), and 10 patients with poorly controlled diabetes (hemoglobin A1, 11.5 +/- 1.7 percent) to simulate the mild peripheral hyperinsulinemia observed during insulin treatment. Normoglycemia was established in the patients during the night before study. During the insulin infusion, the plasma glucose level stabilized at 60 to 70 mg per deciliter (3.3 to 3.9 mmol per liter) in the subjects without diabetes and the patients with poorly controlled diabetes, because of a rebound increase in hepatic glucose production. In contrast, hypoglycemia developed in the patients with well-controlled diabetes (42 +/- 2 mg of glucose per deciliter, or 2.3 +/- 0.1 mmol per liter, P less than 0.01) as glucose production remained suppressed. The hypoglycemia in the patients with well-controlled diabetes was associated with a lowering of the plasma threshold of glucose that triggered a release of epinephrine (less than 45 mg of glucose per deciliter, or 2.5 mmol per liter, vs. greater than 55 mg per deciliter, or 3.1 mmol per liter, in the other groups, P less than 0.01) as well as an enhanced sensitivity to the suppressive effects of insulin on hepatic glucose production. Nearly identical disturbances in glucose counterregulation and decreased perception of hypoglycemia developed when four of the subjects with poorly controlled diabetes were restudied after intensive treatment. We conclude that strict control of diabetes induces physiologic alterations (delayed release of epinephrine and persistent suppression of glucose production) that impair glucose counterregulation to doses of insulin in the therapeutic range. These defects may contribute to the increased incidence of severe hypoglycemia reported during intensive insulin therapy.     

重组腺相关病毒介导的VLDLR基因对2型糖尿病大鼠脂代谢紊乱的作用

目的： 探索增加极低密度脂蛋白受体 (VLDLR) 基因表达对2型糖尿病大鼠脂代谢紊乱和动脉粥样斑块的影响。方法: 构建携带人VLDLR基因的重组腺相关病毒载体（rAAV-VLDLR）。高脂高糖饮食8周后尾静脉注射小剂量链脲佐菌素(STZ)造2型糖尿病动物模型,VLDLR治疗组大鼠注射rAAV-VLDLR,糖尿病对照组注射rAAV-0。RT-PCR及Western blotting分别检测大鼠骨骼肌、心脏、主动脉、肝脏、脂肪VLDLR mRNA及蛋白表达水平。检测VLDLR基因对血糖、胰岛素、稳态模型胰岛素抵抗指数（HOMA-IR）、甘油三酯（TG）、胆固醇（TC）、脂蛋白脂酶（LPL）活性及主动脉粥样斑块的影响。结果: rAAV-0组大鼠骨骼肌、主动脉、脂肪VLDLR mRNA及蛋白水平低于正常组,VLDLR治疗组VLDLR mRNA及蛋白水平较rAAV-0组有不同程度增加。VLDLR治疗后4、8周的TG及4、8、12周的TC明显降低（P＜0.05）,8周HOMA-IR明显降低(P＜0.05),LPL活性明显增强(P＜0.05),主动脉内膜损伤减轻。结论: 增加VLDLR基因表达对改善2型糖尿病大鼠脂代谢紊乱效果显著,并可在此基础上减轻主动脉粥样斑块程度。     

Difference in glucose intolerance between C57BL/6J and ICR strain mice with streptozotocin/nicotinamide-induced diabetes

Blood glucose and plasma insulin levels between C57BL/6J and ICR strain mice with nicotinamide (NA) and streptozotocin (STZ)-induced diabetes were compared to establish a suitable strain of the experimental diabetic mouse model. The mice were intraperitoneally treated twice with STZ (100 mg/kg) 15 min after injection of NA (120 mg/kg) at a 1-day interval, and non-fasting blood glucose level was then weekly monitored for 5 weeks. The blood glucose level in ICR mice gradually increased and was about 2-times higher than that in C57BL/6J mice at the end of the observation. The plasma insulin level in ICR mice was comparatively low, compared with that in C57BL/6J mice. ICR mice were also markedly glucose-intolerant when oral glucose tolerance test was performed. These results indicate that ICR strain is more sensitive than C57BL/6J strain as a mouse model with NA/STZ-induced mild diabetes.     

神经型一氧化氮合酶在1型糖尿病大鼠肾皮质中的表达

目的观察1型糖尿病大鼠肾皮质内神经型一氧化氮合酶(nNOS)的表达变化。方法采用一次性腹腔注射大量链脲佐菌素(STZ)的方法建立1型糖尿病大鼠模型。分别在成模后的第1,2,4周3个时间点处死动物,采用亚硝酸还原酶法检测一氧化氮(NO)的含量;采用免组织化学染色法观察nNOS在肾皮质的表达;采用Western blot方法测定nNOS在肾皮质含量的变化。结果1周病程时糖尿病模型组大鼠肾皮质NO表达水平低于对照组(P<0.05),2周病程时高于对照组(P<0.05),4周病程时显著高于对照组(P<0.01)。nNOS在肾皮质中的表达部位主要在致密斑,在肾小管中也有少量的表达。糖尿病模型组大鼠肾皮质nNOS含量在1周病程时低于正常对照组,2周病程时与正常对照组无显著性差异,4周病程时高于正常对照组。结论在1型糖尿病大鼠肾脏病变的早期,肾皮质内NO的减少主要是由于nNOS合成减少造成的。     

Glucose intolerance and insulin resistance accompany immobilization

Physical activity is known to increase glucose tolerance and insulin sensitivity. To examine the influence of physical inactivity on insulin sensitivity, we measured oral glucose tolerance (OGTT) and insulin response to glucose in 18 patients immobilized to bed for six weeks after acute spine fracture. The results were compared to those of nine chronically immobilized spinal cord injury patients and to eight healthy mobile controls. During the first week after trauma both glucose and insulin responses in the OGTT were two- to three-fold above normal (p less than 0.01). The index of insulin resistance (glucose area X insulin area) was seven-fold greater than in healthy controls (p less than 0.001). After three weeks' immobilization insulin resistance had declined by 30-35% (p less than 0.05) being then at the level observed in chronically immobilized subjects. After remobilization the insulin resistance was further decreased but remained still 2.3 times higher than in controls. Thus, trauma causes a manifold increase in insulin resistance, which is reduced but not normalized during the subsequent immobilization and remobilization.     

Characterization of pancreatic islet cell tumors and renal tumors induced by a combined treatment of streptozotocin and nicotinamide in male SD rats

We herein investigated the histopathological features, including proliferative activity and immunoexpression, of pancreatic islet cell tumors (ICTs) in male SD rats induced by streptozotocin (STZ) and nicotinamide (NA), and discussed their relevance to biological behaviors and prognoses. A total of 70 and 43% of rats developed ICTs 37–45 weeks after the treatment with STZ (50 or 75 mg/kg, i.v.) and NA (350 mg/kg, twice, p.o.), respectively. Among the islet tumors observed in the STZ/NA-treated groups, 75% were adenomas, while 25% were carcinomas. Most STZ/NA-induced carcinomas were characterized by well-differentiated tumor cells with/without local invasion into the surrounding tissues, and weak proliferative activity. No outcome such as distance metastasis and death was noted. All of the ICTs strongly expressed insulin, part of which had hormone productivity; however there were no hypoglycemia-related clinical signs such as convulsion in these rats 36 weeks after the treatment. These results suggested that rat ICTs induced STZ/NA have small impact on biological activity or prognosis. STZ/NA treatment significantly increased of focal proliferative lesions in the kidney, liver and adrenal glands other than pancreatic islets. Of the STZ/NA-induced kidney tumors, more than 60% were renal cell adenomas, and many of them were basophilic type. The incidence of eosinophilic or clear cell type of tumors was less than 10%, respectively. Immunohistochemical analyses revealed that many of the STZ/NA-induced basophilic type of renal tumors were derived from proximal tubules, whereas the clear cell and eosinophilic types were derived from collecting tubules.     

2型糖尿病大鼠阴茎海绵体内皮细胞PKC-α的表达

目的:观察高脂喂养联合小剂量链脲佐菌素(STZ)注射制备的2型糖尿病(T2DM)大鼠阴茎海绵体内皮细胞蛋白激酶C-α(PKC-α)的表达。方法:6周龄勃起功能正常的SD大鼠60只,分为对照组(10只)和实验组(50只),后者高脂喂养8周后腹腔注射STZ35mg/Kg,第9周末与对照组平行尾静脉采血,测定空腹血糖(FBG)、胰岛素(FINS)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、游离脂肪酸(FFA);计算胰岛素敏感性指标Homa-IR和Homa-β;并取阴茎海绵体组织进行HE染色观察组织学变化,以及免疫组化方法测定内皮细胞PKC-α的表达。结果:实验组大鼠高脂喂养8周后体重增加,注射STZ后成功复制T2DM模型。其FFA、TG、LDL-C水平显著高于对照组(P<0.05)。光镜下,实验组大鼠阴茎海绵体结构疏松,免疫组化显示阴茎海绵体内皮细胞PKC-α表达较对照组丰富(P<0.05)。结论:T2DM模型大鼠阴茎海绵体内皮细胞的PKC-α表达增加,可能与高血糖、高血脂、胰岛素抵抗、游离脂肪酸升高有关。     

Hepatic uptake of insulin in man

The hepatic uptake of unlabeled insulin (5--50 mU/kg) was determined in 45 nondiabetic patients without hepatic disease. Thirty patients were studied at normoglycemia and 15 at moderate steady hyperglycemia, induced by intraportal infusion of 80 or 200 mg glucose per h and per kg. The first pass fractional hepatic uptake of insulin (FH) was estimated by comparing the results after a portal and a peripheral infusion of unlabeled insulin in each patient. It varied negatively with the amount of insulin given, decreasing about 50% after a tenfold increase in dose. FH was markedly smaller during steady hyperglycemia than at normoglycemia, regardless of insulin dose. For low doses (5--10 mU/kg), giving insulin concentrations within the physiological range, FH was 0.43 (5 mU/kg) and 0.40 (10 mU/kg) at normoglycemia and 0.16 (10 mU/kg) at hyperglycemia. FH did not vary with the fasting or the glucose-stimulated, endogenous insulin levels recorded before insulin infusion. It is suggested that glucose is more important than insulin in modulating the fractional hepatic uptake of insulin.     

Glucose intolerance following chronic metabolic acidosis in man.

The effect of chronic metabolic acidosis (0.1 g/(kg . day) X 3 days) on carbohydrate metabolism was examined with the glucose-clamp technique in 16 healthy volunteers. Hyperglycemic clamp. Plasma glucose concentration is acutely raised and maintained 125 mg/dl above the basal level. Because the glucose concentration is held constant, the glucose infusion rate is an index of glucose metabolism (M). Following NH4Cl, M decreased from 8.95 +/- 1.12 to 7.35 +/- 0.76 (P less than 0.05) despite an increased plasma insulin concentration (I) 23 +/- 9%, P less than 0.05). Consequently the M/I ratio, an index of tissue sensitivity to insulin, decreased by 32 +/- 5% (P less than 0.005). Euglycemic clamp. Plasma insulin concentration is acutely raised and maintained 101 +/- 3 microU/ml above basal and plasma glucose is held constant at the fasting level by a variable glucose infusion (M). Following NH4Cl both M and M/I decreased by 15 +/- 4% (P = 0.005) and 15 +/- 5% (P = 0.01), respectively. Metabolic acidosis had no effect on basal [3-3H]glucose production or the percent of decline (91 +/- 4%) following hyperinsulinemia. Both hyperglycemic and euglycemic clamp studies indicate that impaired glucose metabolism following metabolic acidosis results from impaired tissue sensitivity to insulin.     

The influence of training-detraining upon the heart, muscle and adipose tissue of female rats.

The purpose of this study was to measure the effects of a 10 week training, 3 week detraining cycle upon heart, muscle and adipose tissue of the rat. Specific pathogen-free female Wistar rats, 175 g at the onset of the experiments, were separated into three treatment groups; Sedentary Control (SC), Trained (T) and Detrained (DT). Animals from the T group were killed at 2, 4, 6, 8 and 10 weeks and animals from the DT group were killed at 7, 14 and 21 days after the last day of training. Unweighted swimming--6 h/day, 5 day/week, was the form of training employed. The animals, after being sacrificed, were anesthetized with nembutal (45 mg/kg body wt.) and muscle samples and heart removed. These tissues were frozen and analyzed at a later date for succinate dehydrogenase (SDH) activity (muscles), total protein (TP), total hydroxylprotein (TH) and wet and dry weight (heart). Adipose tissue was removed last, digested in collagenase (5 mg/ml) and the isolated cells used to measured 2-[3H]deoxyglucose uptake (DOG) and the conversion of D-[1-14C]glucose (C-1) and D-[6-14C]glucose (C-6) to CO2. The results of this study show that 10 weeks of endurance training induced myocardial hypertrophy (P less than 0.05) which involved increases in both TP and TH, the heart of the trained animals having 20.8% more protein and a 28.5% more hydroxlprotein than the sedentary controls. With detraining hypertrophy was lost within 21 days. Training maintained fat cell size at its pre-trained diameter, while inactivity allowed growth in the adipocytes of the control animals. The uptake of DOG and the conversion of glucose C-1 and glucose C-6 to CO2, were significantly (P less than 0.05) higher in the adipocytes of trained animals indicating that they were more responsive to insulin than the sedentary controls, which corresponded to increases in the respiratory enzyme levels of the muscles. During the first 7 days of detraining DOG uptake and both C-1 and C-6 glucose oxidation remained elevated. In conclusion the results of this study clearly demonstrate that there is a direct relationship between adiposity and training that can be related to the insulin responsiveness of the adipose tissue.     

The effect of riluzole and mannitol on cerebral oedema after cryogenic injury in the mouse.

A cryogenic lesion was produced under halothane anaesthesia in the mouse by placing a cotton swab soaked in liquid nitrogen onto the surface of the cranium. This provoked an oedematous lesion which developed within the hour after the insult and evolved over the following week. Treatment with mannitol at 3 g/kg i.v. caused a significant 22% reduction in oedema 1 h later, when administered immediately after lesion, but not when administered 23-h post lesion. Likewise riluzole (16 mg/kg, i.v.) significantly reduced oedema by 17% when administered immediately after lesion, or 13% (P < 0.05) when administered 23 h after lesion. Repeated doses (2 x 16 mg/kg, i.p.) of riluzole were also able to reduce oedema significantly (24%, P < 0.05) at 24 h post lesion. Riluzole, in four repeated doses of 8 mg/kg i.p. was also able to reduce lesion surface size by 16% (P < 0.05) 48 h after lesion.     

Complex maze performance in young and aged rats: response to glucose treatment and relationship to blood insulin and glucose.

In aged rats and humans, impaired glucose regulation has been correlated with poor memory performance, and glucose treatment can result in improved performance. We tested this glucose hypothesis with rats in a 14-unit T-maze that has provided robust evidence of age-related performance decline. Aged (24-25 month) and young (6-7 month) male F-344 rats were pretrained for one-way active avoidance before receiving complex maze training (4 daily trials over 5 days) with the contingency of moving through each of 5 segments to avoid footshock. Ten min before daily training, aged rats received either saline or glucose in doses of 10, 100, or 500 mg/kg IP, while young rats received saline. Significant (ps less than 0.05) age-related increases in errors, runtime, and shock duration were observed. Glucose treatment had no significant effect on the number of maze errors committed; however, performance variables such as runtime and shock duration appeared to be reduced in rats receiving glucose. About 4-6 weeks later, a sample of these rats was fasted overnight, injected IP with glucose (150 mg/kg), and bled at various postinjection intervals to obtain estimates of blood glucose and insulin levels. Significant correlations (ps less than 0.05) were observed between maze errors and baseline glucose levels, r(21) = -.62, and peak glucose response, r(19) = .49. However; within the aged group, significant correlations (ps less than 0.01) with maze errors emerged only for baseline glucose, r(13) = -.69, and peak insulin response, r(13) = -.65. Thus, regulation of insulin, but not glucose, appeared related to learning abilities among aged rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Low-dose streptozotocin induces sustained hyperglycemia in Macaca nemestrina

The potential for using macaques to create a nonhuman primate diabetic model was investigated. The significant objectives were to determine a) prognosis of STZ induced permanent beta cell destruction in nonhuman primates, and b) the potential to use STZ treated animals in a model of autoimmune diabetes by following adoptively transferred lymphocytes into MHC identical macaques. Beta cell impairment was achieved by a single intravenous, low dose (10-40 mg/kg body weight) streptozotocin injection in a majority of pigtailed macaques (Macaca nemestrina). Multiple injections, even at low doses at close intervals affected liver and kidney functions in addition to beta cell destruction. Abnormal IVGTT were observed in all streptozotocin-treated animals, in some within a week to 10 days. The fasting blood glucose levels rose from <70 mg/dl in pre-STZ stage to above 400 mg/dl in severely diabetic macaques. Histological evidence suggests loss of beta cells when animals were euthanized within two to four weeks post-STZ treatment. Near complete destruction of beta cells was observed in animals maintained longer than three months on insulin. Donor T cells from STZ-treated animals were incubated overnight with 10U/ml IL-2 and 2.5 ug/ml PHA and then injected iv into a MHC-identical non-diabetic sibling. Three weeks later a second injection of donor PMBC labeled with vital dye Cell Tracker Green was given and the animal was euthanized after 24 hours. The recipient showed labeled donor T cells in the pancreas, spleen and peripheral blood, consistent with specific homing of activated lymphocytes from the diabetic donor.