Ovarian dysfunction in streptozotocin-induced diabetic rats

The effect of streptozotocin diabetes on some ovarian functions in adult rats was examined. Diabetic diestrus animals showed reduced ovary weight and lower circulating levels of progesterone. Scatchard plots of binding data derived from ovarian particulate fractions of normal and streptozotocin diabetic rats revealed the presence of one class of binding sites with high affinity for 125I-hCG. The apparent association constant of the hCG receptors of diabetic ovaries was comparable to that of normal gonads. However, a marked decrease (42%) in the number of hCG binding sites was found in diabetic animals. With isolated luteal cells similar results were obtained, and the administration of insulin to streptozotocin diabetic rats restored to normality the number of hCG binding sites. The maximal response of progesterone production by luteal cells from control ovaries was obtained with 10(-10) M hCG. A 100-fold higher concentration of hCG was required for the maximum stimulation of cAMP synthesis. The cAMP response of cells from diabetic rats was significantly higher than that of control cells. However, luteal cells from diabetic rats showed some loss of sensitivity in the synthesis of progesterone during incubation with hCG. Most of the alterations seen in diabetic female rats could be restored with insulin therapy, indicating that insulin plays an important role in the regulation and maintenance of normal reproductive functions. It is suggested that the diminution of the LH receptor population causes the disruption of normal luteal cell function. This fact could be responsible for some of the reproductive alterations in the diabetic female rat.     

3,5-Diiodo-l-thyronine ameliorates diabetic nephropathy in streptozotocin-induced diabetic rats

3, 5-Diiodothyronine (T2), a natural metabolite of triiodothyronine (T3) from deiodination pathway, can mimic biologic effects of T3 without inducing thyrotoxic effects. Recent studies revealed T3 acted as a protective factor against diabetic nephropathy (DN). Nevertheless, little is known about the effect of T2 on DN. This study was designed to investigate whether and how T2 affects experimental models of DN in vivo and in vitro. Administration of T2 was found to prevent significant decrease in SIRT1 protein expression and activity as well as increases in blood glucose, urine albumin excretion, matrix expansion, transforming growth factor-β1 expression, fibronectin and type IV collagen deposition in the diabetic kidney. Concordantly, similar effects of T2 were exhibited in the cultured rat mesangial cells (RMC) exposed to high glucose and that could be abolished by a known SIRT1 inhibitor, sirtinol. Moreover, enhanced NF-κB acetylation and JNK phosphorylation present in both diabetic rats and high glucose-treated RMC were distinctly dampened by T2. Collectively, these results suggested that T2 was a protective agent against renal damage in diabetic nephropathy, whose action involved regulation of SIRT1.     

Effect of glycine in streptozotocin-induced diabetic rats

Inadequate utilization of glucose in diabetes mellitus favors diverse metabolic alterations that play a relevant role in the physio-pathology of chronic complications of this disease. Streptozotocin-induced diabetic rats were treated daily with glycine (130 mM as optimal concentration) or taurine (40 mM) for six months. Groups of diabetic rats without treatment were used as controls. Glucose, total cholesterol, triacylglycerol, and glycated hemoglobin were determined periodically after inducing diabetes. Rats were killed after 6 months of treatment and histological analyses were performed. Diabetic groups that received glycine or taurine showed significant lower concentrations of glucose, total cholesterol, triacylglycerol, and glycated hemoglobin than diabetic control rats (P<0.05) after 6 months treatment. Histological analyses of diabetic rats showed pancreatic atrophy and necrosis, vacuolization, decrease of beta cells, and diffuse glomerulosclerosis. Diabetic rats treated with glycine or taurine showed less enlargement of the glomerular basal membrane than control diabetic rats. Our results suggest that glycine and taurine reduced the alterations induced by hyperglycemia in streptozotocin-induced diabetic rats probably due to inhibition of oxidative processes.     

间断性低氧对大鼠淋巴细胞转化的影响

目的: 探讨间断性低氧对机体免疫反应的影响.方法: 以模拟海拔高度间断性低氧(4 h/d)模型观察大鼠脾淋巴细胞对丝裂原(Con A)的反应性.结果: 与对照相比,5 km急性低氧4 h大鼠淋巴细胞的转化率下降25.43%(P<0.05) ,间断性低氧2、5、15 d后淋巴细胞转化率分别为97.03%、104.5%和99.55%,与对照组无明显差异.2 km间断性低氧(4 h/d)1、2、5、15 d,大鼠脾淋巴细胞转化率分别为93.19%、96.43%、99.03%和100.54%,与对照组无明显差异.脾单个核细胞DNA含量显示, 5 km急性低氧4 h DNA含量明显下降(76.22%±7.06%,P<0.05),间断性低氧5 d和15 d后与对照组无显著差异.结论: 急性低氧抑制淋巴细胞的转化,并随低氧的加重而增加,重复间断性低氧暴露其抑制作用减弱,引起大鼠淋巴细胞转化产生适应.推测免疫适应与HPA轴的适应有关.     

Oral glycine administration attenuates diabetic complications in streptozotocin-induced diabetic rats

Diabetes mellitus is a disease characterized by impaired glucose metabolism that leads to retinopathy, brain micro-infarcts and other complications. We have previously shown that oral glycine administration to diabetic rats inhibits non-enzymatic glycation of hemoglobin and diminishes renal damage. In this work, we evaluated the capacity of the amino acid glycine (1% w/v, 130 mM) to attenuate diabetic complications in streptozotocin (STZ)-induced diabetic Wistar rats and compared them with non-treated or taurine-treated (0.5% w/v, 40 mM) diabetic rats. Glycine-treated diabetic rats showed an important diminution in the percentage of animals with opacity in lens and microaneurysms in the eyes. Interestingly, there was a diminished expression of O-acetyl sialic acid in brain vessels compared with untreated diabetic rats (P<0.05). Additionally, peripheral blood mononuclear cells isolated from glycine-treated diabetic rats showed a better proliferative response to PHA or ConA than those obtained from non-treated diabetic rats (P<0.05). Glycine-treated rats had a less intense corporal weight loss in comparison with non-treated animals. Our results suggest that administration of glycine attenuates the diabetic complications in the STZ-induced diabetic rat model, probably due to inhibition of the non-enzymatic glycation process.     

Changes in liver gangliosides in streptozotocin-induced diabetic rats

Diabetes mellitus is associated with various structural and functional liver abnormalities that affect the glycogen and lipid metabolisms. The effects of streptozotocin-induced diabetes and of insulin supplementation to Sprague-Dawley diabetic rats on ganglioside patterns in liver were determined. Diabetic livers showed a tendency to hepatomegaly 3 weeks after STZ-induction of diabetes. The concentration of total gangliosides in diabetic and non-diabetic livers was similar, but the concentration of total gangliosides in the liver of insulin-stabilized rats was slightly increased. Bidimensional TLC chromatographic analysis of gangliosides isolated from normal diabetic and insulin-stabilized diabetic livers showed quantitative and qualitative changes. In comparison with normal controls, the densitometric analyses of diabetic liver ganglioside patterns had increased amounts of GM3, GM1, GD1b, and GT1b gangliosides, while GM2 could not be detected. The hepatic ganglioside pattern of insulin-stabilized diabetic rats was partially restored, resembling the profile of normal rats. The activity of GalNAcT, GalT-2 and SialT-4 transferases was measured in liver microsomal fractions of the different groups of animals. Diabetic rats showed an increased activity of GalNAcT and a decrease in the activity of GalT-2 and SialT-4 compared with the controls. The enzymatic activities found in insulin-treated rats showed a tendency to return to the values observed in normal control animals. The results evidenced that streptozotocin-induced diabetes affects the liver ganglioside pattern and the ganglioside synthesis enzyme activity. The alterations found in ganglioside metabolism could represent one of the earliest changes associated with the diabetic pathology.     

Iuteolin对糖尿病大鼠心脏功能的保护作用及其可能机制

目的：研究Iuteolin对链脲佐菌素诱导的Ⅰ型糖尿病大鼠心功能及心肌线粒体氧化应激的影响。方法：雄性SD大鼠,随机分成正常对照组,Iuteolin对照纽,糖尿病模型组,低剂量Iuteolin（10ms／（kg·d））灌胃治疗组,高剂量Iuteolin（100ms／（kg·d））灌胃治疗组。各组大鼠饲养8周后,测体重、血糖、心功能、左心室重量、心肌胶原含量及活性氧自由基（ROS）水平,分离心肌线粒体检测ROS水平、超氧化物歧化酶（SOD）活性及线粒体肿胀程度。结果：Iuteolin处理对糖尿病大鼠血糖无明显影响,但可减少糖尿病引起的体重下降。高剂量Iuteolin可显著减小糖尿病大鼠心室与体重比值,提高左室发展压,降低左室舒张末压。高剂量Iuteolin治疗后,糖尿病大鼠心肌ROS及胶原含量。心肌线粒体ROS水平与肿胀程度均明显下降,心肌线粒体SOD活性明显增加。结论：Iuteolin处理可显著改善糖尿病大鼠心功能．其机制可能与减轻心肌线粒体氧化应激及抑制线粒体肿胀有关。     

Changes of acute-phase proteins in streptozotocin-induced diabetic rats

Quantitative and qualitative changes of serum proteins, apart from glycation, have not been sufficiently studied in streptozotocin-induced diabetic rats (D), the most common experimental model for diabetes. Thus, we decided to analyze the serum of diabetic rats by concanavalin A-blotting in comparison with rats with acute inflammation induced by fermented yeast (Y), in which characteristic alterations of serum proteins have been described. Two months after the streptozotocin treatment, the blood glucose levels were highly elevated (456+/-24 vs. 124+/-10 mg/dl, p<0.001, n=12), the body weight was significantly lower than normal (279+/-10 vs. 392+/-6 g, p<0.001, n=12), and serum proteins appeared to be highly glycated (p<0.001) when analyzed by the fructosamine assay, without any significant change in the total serum protein concentration. Analysis by concanavalin A-blotting, revealed a significant decrease of alpha1-inhibitor-3 (alpha1-I3, p<0.05) and an increase of the beta chain of haptoglobin (beta-Hp, p<0.05) in both D and Y rats (n=3) compared with control animals. However, acute inflammation caused a marked rise of two prominent acute phase proteins, alpha2-macroglobulin and hemopexin, which did not change appreciably in diabetic rats. Further work will be necessary to evaluate the physiopathological significance of these phenomena which could result from changes of both concentration and glycosylation of the aforementioned proteins.     

Glial and neuronal dysfunction in streptozotocin-induced diabetic rats

Neuronal dysfunction has been noted very soon after the induction of diabetes by streptozotocin injection in rats. It is not clear from anatomical evidence whether glial cell dysfunction accompanies the well-documented neuronal deficit. Here, we isolate the Müller cell driven slow-P3 component of the full-field electroretinogram and show that it is attenuated at 4 weeks following the onset of streptozotocin-hyperglycaemia. We also found a concurrent reduction in the sensitivity of the phototransduction cascade, as well as in the components of the electroretinogram known to indicate retinal ganglion cell and amacrine cell integrity. Our data support the idea that neuronal and Müller cell dysfunction occurs at the same time in streptozotocin-induced hyperglycaemia.     

Stereospecific disposition of fluvastatin in streptozotocin-induced diabetic rats

The study reports on the stereoselective pharmacokinetics of fluvastatin, a racemic mixture of (-)-(3S,5R)- and (+)-(3R,5S)-enantiomers, in streptozotocin-induced diabetic rats. Wistar (control) and streptozotocin-induced diabetic rats (n = 6/time point) received by oral gavage racemic fluvastatin (5 mg/kg), and blood samples were collected until 24 h. The enantiomers were analysed by chiral HPLC with fluorescence detection. The pharmacokinetic parameters were analysed by Wilcoxon and Mann-Whitney tests. The results are reported as means (95% CI). The following differences (p < 0.05) were observed between the control and diabetic groups, respectively: maximum plasma concentration (Cmax) of (-)-(3S,5R), 410.0 (310.0-510.0) versus 532.6 (463.5-601.8) ng x mL(-7); area under the plasma concentration versus time curve (AUC(0-infinity)) for (-)-(3S,5R), 4342A (3,775.7-4,909.0) versus 3025.2 (2,218.9-3,831.5) ng x h x mL(-1); apparent total clearance (Cl/f) of (-)-(3S,5R), 0.6 (0.5-0.7) versus 0.9 (0.6-1.1) L x h(-1) x kg(-1); AUC(0-infinity) for (+)-(3R,5S), 493.5 (376.9-610.1) versus 758.5 (537.1-980.0) ng x h x mL(-1); and Cl/f of (+)-(3R,5S), 5.3 (3.9-6.8) versus 3.5 (2.6-4.4) L x h(-1) x kg(-1). Streptozotocin-induced diabetes in rats alters the pharmacokinetics of fluvastatin in a stereoselective manner.     

Altered tail-skin temperature responsiveness in streptozotocin-induced diabetic rats

We evaluated the tail-skin temperature response to administration of several doses of isoproterenol in streptozotocin-induced diabetic rats after 48 h and after 4 weeks of diabetes. Blood glucose concentrations were significantly increased over controls 48 hours after administration of streptozotocin (65 mg/kg, i.v.) and remained elevated to a similar degree in the 4-week group. Basal rectal temperature and tail-skin temperature (TST) were not different between controls and the diabetic groups and were not affected by administration of saline. However, administration of isoproterenol (25 micrograms/kg, s.c.) caused a significant rise in TST in the control group, but not in the rats diabetic for 4 weeks. A similar but exaggerated response was observed in the controls after subcutaneous administration of 40 micrograms/kg and 100 micrograms/kg of isoproterenol. The TST response in the 4-week diabetic rats still remained negligible with the two higher doses of isoproterenol. When the data were summarized as area under the TST curve, a dose-dependent increase was observed in the control groups and a significant absence of response was observed in the 4-week group. The rats studied 48 h after streptozotocin injection had a similar TST response to the control group after administration of 40 micrograms/kg of isoproterenol. Colonic temperatures did not significantly change between the two groups in any of the studies, although the colonic temperatures tended to rise in the control groups following administration of isoproterenol. We conclude from this study that the absence of a tail-skin temperature response in rats diabetic for 4 weeks results from either a reduced beta-adrenergic receptor mediated response or an altered neural thermoregulatory reflex response, or both. These changes are probably not due to streptozotocin treatment or increases in blood glucose.     

Impaired ascorbic acid metabolism in streptozotocin-induced diabetic rats

Ascorbic acid (AA) metabolism in streptozotocin (STZ)-induced diabetic rats was determined by examining urinary excretion, renal reabsorption, reductive regeneration, and biosynthesis of AA at 3 and 14 days after STZ administration. AA concentrations in the plasma, liver, and kidney of the diabetic rats were significantly lower than those of controls on d 3, and decreased further as the diabetic state continued. Hepatic AA regeneration significantly decreased in the diabetic rats on d 3 in spite of increased gene expressions of AA regenerating enzymes and was further reduced on d 14. Hepatic activity of L-gulono-gamma-lactone oxidase, a terminal enzyme of hepatic AA biosynthesis, also decreased significantly on d 3 and decreased further on d 14. Urinary excretion of AA was significantly increased on d 3, with an increase in urine volume but no change in gene expressions of renal AA transporters (SVCT1 and SVCT2). Urinary excretion of AA was normalized on d 14. The results suggest that impaired hepatic and renal regeneration, as well as increased urinary excretion and impaired hepatic biosynthesis of AA, contributed to the decrease in AA in plasma and tissues of STZ-induced diabetic rats.     

Enhanced testicular antioxidant capacity in streptozotocin-induced diabetic rats

Diabetes mellitus is associated with diabetic impairment of testicular function, ultimately leading to reduced fertility. Its etiology may involve oxidative damage by reactive oxygen substances, and protection against this damage can be offered by antioxidant supplementation. The aim of this study was to investigate the effects of intraperitoneal administration of vitamin C and E, selenium (Se), and vitamin E plus Se (COM) on concentrations of lipid peroxide (as malondialdehyde; MDA), reduced glutathione (GSH), and vitamin E concentrations and glutathione peroxidase (GSH-Px) activity in the testes of rats with diabetes induced by streptozotocin (STZ). Sixty groups were used (10 animals each) and these animals were initially allocated to two groups: control group and diabetic group. The diabetic group was subdivided into five groups as follows: diabetic control (DC), vitamin E, Se, COM, and vitamin C. Animals in the DC group and vitamin C, vitamin E, Se, and COM groups were made diabetic by the injection of STZ on 4 d after an injection of vitamins C and E, Se, and COM. Those vitamins and Se were also administered for 21 consecutive days. The MDA, vitamin E, GSH levels, and GSH-Px activities in testes were determined. Although the vitamin E concentration was higher in the control than in the DC group, the MDA levels were found to be lower in the control than in the DC group. The MDA levels in the testes samples of vitamin C, vitamin E, Se, and COM groups were lower than the DC group. However, GSH-Px activity and GSH levels in the testes were not significantly different between the control and DC groups. Vitamin E concentrations in the vitamin C, vitamin E, Se, and COM groups and GSH levels and GSH-Px activities in the Se, COM, and vitamin C groups were higher than either the control or DC group. The results indicate that reactive oxygen substances may be involved in possible testicular complications in diabetes of rats. Administration of vitamins C and E and Se reduced the testicular lipid peroxidation; these vitamins and Se had significant protective effects on testes of rats against oxidative damage in diabetes. Abstract of the study was presented at the conference Trace Elements in Men and Animals-11. June 2–6, 2002; Dr. Naziroğlu has been awarded a TEMA11 Investigative Scientist Award.     

Testicular mitochondrial alterations in untreated streptozotocin-induced diabetic rats

Diabetes-induced complications are associated with mitochondrial dysfunction and increasing evidence suggests that diabetes has an adverse effect on male reproductive function. The STZ-induced diabetic rat was used as an animal model for the type 1 form of the disease with the aim of determining its effects in spermatogenesis and testicular mitochondrial function. Several aspects of mitochondrial function were measured, including respiratory and electric potential function, as well as mitochondrial calcium loading capacity. Additionally oxidative stress production, antioxidant levels and possible apoptotic alterations were also evaluated. We observed that diabetic animals present alterations in spermatogenesis in both the testis and epidydimus. However, and surprisingly, the overall results in mitochondrial parameters failed to reveal severe testicular mitochondrial dysfunction in diabetic animals, with the exception of a decrease in calcium load. Taken together, results suggest that in animal models that mimic untreated type 1 diabetes the severe effects of the condition on spermatogenesis are not directly mitochondrial-mediated.     

Effects of sleeve gastrectomy in neonatally streptozotocin-induced diabetic rats

Background

Sleeve gastrectomy (SG) has emerged recently as a stand-alone bariatric procedure to treat morbid obesity and enhance glucose homeostasis. The aim of the study was to evaluate its effects in neonatally streptozotocin (STZ)-induced diabetic rats (n-STZ diabetic rats).

Methodology and Principal Findings

To induce diabetes, STZ (90 mg/kg) was administered intraperitoneally to 2-day-old male pups. When 12 weeks old, diabetic rats were randomized into sleeve operation group (SLG, n = 6) and sham operation group (SOG, n = 6). Body weights were monitored weekly, and daily consumption of water and food were followed for eight consecutive weeks postoperatively. Serum glucose levels were measured periodically at the 4th and 8th week after surgery. Insulin, ghrelin, glucose-dependent insulinotropic polypeptide (GIP) and Glucagon-like peptide-1 (GLP-1) levels were assayed at the end of the study. Our data showed that SLG rats exhibited significantly lower body weight gain in addition to reduced food and water intakes postoperatively compared to their sham-operation counterparts. However, resolution of diabetes was not observed in our study. Correspondingly, there were no significant differences between SOG rats and SLG rats in glucose metabolism-associated hormones, including insulin, GIP and GLP-1. In contrast, ghrelin level significantly decreased (P<0.01) in SLG group (58.01±3.75 pg/ml) after SG surgery compared to SOG group (76.36±3.51 pg/ml).

Conclusions

These observations strongly suggest that SG is effective in controlling body weight. However, SG did not achieve resolution or improvement of diabetes in n-STZ diabetic rats.     

Antidiabetic effect of Lactobacillus GG in streptozotocin-induced diabetic rats

Neonatally streptozotocin-induced diabetic (n-STZ) rats were given food containing Lactobacillus GG cells (GG) or a control diet (control), from 9 to 18 weeks of age. The GG cells significantly lowered the blood hemoglobin A(1C) (HbA(1C)) level and improved glucose tolerance in n-STZ rats (p<0.05). In the GG group, the serum insulin level at 30 min after glucose loading was significantly higher than in the control group (p<0.05).     

Gender-dependent expression of pancreatic proteins in streptozotocin-induced diabetic rats

To elucidate gender-dependent protein regulation and molecular abnormalities in streptozotocin (STZ)-induced diabetes, we compared differentially expressed pancreatic proteins between male and female diabetic rats and their healthy controls using a 2-DE-based proteomic approach. In animal experiments, we found that females exposed to STZ displayed greater susceptibility towards diabetes development due to lower insulin secretion and severe β-cell damage. It was also accompanied with more impaired regulation of sex hormones, lower glucose tolerance, and higher blood glucose levels compared to male diabetic rats. Among 748 detected protein spots ranging in mass from 6 to 240 kDa between pH 3 and 10, a total of 42 proteins showed significant sexually-dimorphic regulation patterns between male and female diabetic rats. Proteomic data revealed that male and female rats displayed prominent gender-dimorphic differential regulation of pancreatic proteins involved in glycolysis, the citric acid cycle, amino acid synthesis, lipid metabolism, insulin biosynthesis, β-cell regeneration, cell signaling, as well as antioxidative and cellular stress defense. In conclusion, the current proteomic study revealed that severely impaired protein regulation in the pancreas, at least in part, is responsible for increased susceptibility of female rats to STZ-induced diabetes.     

Remodeling of liver phospholipidomic profile in streptozotocin-induced diabetic rats

Lipid homeostasis in liver is known to be altered with diabetes mellitus, ultimately leading to liver damage and related complications. The present work aimed to evaluate changes in the liver phospholipid profile after 4 months of uncontrolled hyperglycemia. Twenty Wistar rats were divided into two groups: control and streptozotocin-treated (T1DM). After 4 months, animals were sacrificed and morphological characterization of liver was performed and related with serum markers of hepatic damage. Lipid extracts were obtained from liver and phospholipid (PL) classes were quantified. Lipid molecular species were determined by LC–MS and LC–MS/MS, and fatty acids by GC–MS. Concomitantly with signs of hepatic damage we found variations in the relative amount of phospholipid classes in T1DM, characterized by a decrease in PLs with choline head group, and by an increase in the relative content of other PL classes. A remodeling in PL fatty acyl chains was observed in T1DM liver, with a similar pattern to all the PL classes, and consisting in the reduction of 16:0 and an increase of 18:0 and 18:2 acyl chains. The observed changes in T1DM lipid profile may contribute to the altered membrane properties underlying hepatic damage, worsening the metabolic alterations that characterize T1DM.