Comparison of experimental diabetes induced by streptozotocin and cyproheptadine

It is generally accepted that Diabetes mellitus is caused by the endocrinological functional disturbance of the pancreas, decreasing available insulin for carbohydrate metabolisms. Diabetes mellitus is not necessarily related to hypoinsulinemia, and some senile subjects show diabetic symptoms although the insulin levels in their blood are within the normal range. Therefore, in order to examine the cause of Diabetes mellitus, the glucose tolerance test is usually given as a routine laboratory method to monitor the pancreatic endocrine functions. The pattern of decreasing glucose level in blood will tell us what is the cause of the disease. In testing the effects of anti-diabetic drugs, experimental diabetic conditions have been prepared by various methods, and recently streptozotocin (STZ) and cyproheptadine (CPH) have been successfully used to induce diabetic conditions of various degrees. In the present study, degree of disturbance of the pancreatic functions by STZ and CPH were compared, and in addition, disturbance of organs other than the pancreas was also examined biochemically. When a high dose of STZ was given, irreversible disfunction of glucose level normalizing and insulin secreting abilities was observed. Serum GOT, GPT, lysosomal enzyme activities and lysosomal enzyme activity in the liver and pancreas decreased in high dose STZ administered rats. Low dose STZ disturbed the pancreatic endocrine function less than that in high dose STZ, and the blood glucose level normalizing function was reversibly disturbed. Insulin secretion decreased, and normalized on discontinuation of low dose STZ administration. Low dose STZ also disturbed organs other than the pancreas as in high dose STZ.(ABSTRACT TRUNCATED AT 250 WORDS)     

Protective effect of boldine on oxidative mitochondrial damage in streptozotocin-induced diabetic rats.

Increased oxidative stress has been suggested to be involved in the pathogenesis and progression of diabetic tissue damage. Several antioxidants have been described as beneficial for oxidative stress-associated diseases. Boldine ([s]-2,9-dihydroxy-1, 10-dimethoxyaporphine) is a major alkaloid found in the leaves and bark of boldo (Peumus boldus Molina), and has been shown to possess antioxidant activity and anti-inflammatory effects. From this point of view, the possible anti-diabetic effect of boldine and its mechanism were evaluated. The experiments were performed on male rats divided into four groups: control, boldine (100 mg kg(-1), daily in drinking water), diabetic [single dose of 80 mg kg(-1)of streptozotocin (STZ), i.p.] and diabetic simultaneously fed with boldine for 8 weeks. Diabetic status was evaluated periodically with changes of plasma glucose levels and body weight in rats. The effect of boldine on the STZ-induced diabetic rats was examined with the formation of malondialdehydes and carbonyls and the activities of endogenous antioxidant enzymes (superoxide dismutase and glutathione peroxidase) in mitochondria of the pancreas, kidney and liver. The scavenging action of boldine on oxygen free radicals and the effect on mitochondrial free-radical production were also investigated. The treatment of boldine attenuated the development of hyperglycemia and weight loss induced by STZ injection in rats. The levels of malondialdehyde (MDA) and carbonyls in liver, kidney and pancreas mitochondria were significantly increased in STZ-treated rats and decreased after boldine administration. The activities of mitochondrial manganese superoxide dismutase (MnSOD) in the liver, pancreas and kidney were significantly elevated in STZ-treated rats. Boldine administration decreased STZ-induced elevation of MnSOD activity in kidney and pancreas mitochondria, but not in liver mitochondria. In the STZ-treated group, glutathione peroxidase activities decreased in liver mitochondria, and were elevated in pancreas and kidney mitochondria. The boldine treatment restored the altered enzyme activities in the liver and pancreas, but not the kidney. Boldine attenuated both STZ- and iron plus ascorbate-induced MDA and carbonyl formation and thiol oxidation in the pancreas homogenates. Boldine decomposed superoxide anions, hydrogen peroxides and hydroxyl radicals in a dose-dependent manner. The alkaloid significantly attenuated the production of superoxide anions, hydrogen peroxide and nitric oxide caused by liver mitochondria. The results indicate that boldine may exert an inhibitory effect on STZ-induced oxidative tissue damage and altered antioxidant enzyme activity by the decomposition of reactive oxygen species and inhibition of nitric oxide production and by the reduction of the peroxidation-induced product formation. Boldine may attenuate the development of STZ-induced diabetes in rats and interfere with the role of oxidative stress, one of the pathogeneses of diabetes mellitus.     

Beneficial effect of 17β-estradiol on hyperglycemia and islet β-cell functions in a streptozotocin-induced diabetic rat model

The modulating effect of estrogen on glucose homeostasis remains a controversial issue at present. In this study, we sought to determine the beneficial effect of 17β-estradiol (E₂) on hyperglycemia and islet β-cell functions in streptozotocin (STZ)-induced diabetic rats. Male Sprague-Dawley rats were injected i.p. with STZ to induce a relatively mild diabetic condition. The rats were then treated with E₂ orally at 500 μg/kg body weight/day for 15 days to evaluate the modulating effect on hyperglycemia, insulin secretion, and islet β-cell proliferation. E₂ administration for 10 days significantly lowered plasma glucose levels, increased plasma insulin levels, and improved glucose tolerance by attenuating insulin response to oral glucose loading. These beneficial effects of E₂ were accompanied by increases in islet number and volume, rate of islet cell proliferation, and the amount of insulin secreted. The growth-stimulatory effect of E₂ on islet cells was linked to the functions of the estrogen receptor α. Notably, these protective effects of E₂ on diabetic conditions were basically not observed when the STZ-treated rats had a more severe degree of islet damage and hyperglycemia. Taken together, we conclude that E₂ can promote the regeneration of damaged pancreatic islets by stimulating β-cell proliferation in diabetic rats, and this effect is accompanied by improvements in glucose tolerance and a decrease in plasma glucose levels. These findings suggest that oral administration of E₂ may be beneficial in diabetic patients with an accelerated loss of islet β-cells.     

Antidiabetic activity of γ-sitosterol isolated from Lippia nodiflora L. in streptozotocin induced diabetic rats

Lippia nodiflora L. (Verbenaceae) is a creeping perennial herb widely used in traditional system of medicine to treat ulcers, bronchitis and heart diseases; it also possesses antidiabetic property. In the present study, γ-sitosterol isolated from Lippia nodiflora was screened for its antidiabetic property in streptozotocin (STZ) induced diabetic rats. Insulin secretion in response to glucose was evaluated in isolated rat islets. Oral administration of γ-sitosterol (20 mg/kg body weight) once daily for 21 days in STZ-induced diabetic rats resulted in a significant decrease in blood glucose and glycosylated hemoglobin with a significant increase in plasma insulin level, body weight and food intake. Furthermore γ-sitosterol showed antihyperlipidemic activity as evidenced by significant decrease in serum total cholesterol, triglycerides and very low density lipoprotein-cholesterol levels coupled with elevation of high density lipoprotein-cholesterol levels in treated rats. A significant decrease in the activities of alanine aminotransaminase, aspartate aminotransaminase, alkaline phosphatase and acid phosphatase in γ-sitosterol treated rats when compared to diabetic control rats indicated its protective role against liver damage. γ-Sitosterol increased insulin secretion in response to glucose. Immunohistochemical study of pancreas also confirmed the biochemical findings. These results indicated that γ-sitosterol, the compound isolated from L. nodiflora, possessed antihyperglycemic activity.     

小剂量阿司匹林对糖尿病大鼠胰腺功能和凋亡相关蛋白的研究

目的研究小剂量阿司匹林对糖尿病大鼠胰腺功能和凋亡相关蛋白的影响。方法雄性SD大鼠,尾静脉注射链脲佐菌素30mg/kg,造成1型糖尿病动物模型,随机分为糖尿病模型组和9 mg/kg阿司匹林治疗组(ASA治疗组),每组8只,另选8只健康雄性大鼠为正常对照组。各组大鼠灌服给药12周后,检测各组大鼠空腹血糖、血清胰岛素水平,免疫组化法检测分析Caspase-3、Bax和Bcl-2的表达情况。结果与正常对照组比较,糖尿病模型组大鼠空腹血糖提高、血清胰岛素水平降低,胰岛素抵抗指数升高;胰腺组织Caspase-3、Bax表达增强,Bcl-2的表达减弱,Bcl-2/Bax比值降低;ASA治疗组大鼠,血糖减低,胰岛素提高,减低Caspase-3、Bax表达,提升Bcl-2的表达,并明显提高Bcl-2/Bax比值。结论小剂量阿司匹林对糖尿病大鼠胰岛素分泌功能有保护作用,可能与调节胰腺细胞凋亡相关蛋白表达有关。     

Insulin-induced immunohistochemical and morphological changes in pancreatic beta-cells of streptozotocin-treated diabetic rats

This study was undertaken to investigate insulin-induced changes in the immunohistochemistry and morphometry of pancreatic beta-cells, plasma insulin and blood glucose concentrations of streptozotocin (STZ)-treated diabetic rats. Fifty male Wistar rats (200-250 g) were randomly divided into three experimental groups (viz., A: control group, B: STZ-treated group, and C: STZ+insulin-treated group). Diabetes was induced in group B and group C rats by single intraperitoneal injections of STZ (75 mg/kg body weight), while each animal in the "control" group A received equal volume of citrate buffer solution (pH 6.3) intraperitoneally. STZ+insulin-treated group C diabetic rats were additionally treated with subcutaneous injections of lente insulin (0.5 U/kg body weight) daily from Day 10 to Day 30 of our 40-day study period. The rats used were sacrificed at different time intervals (10th, 20th, 30th and up to the 40th day) following STZ treatment. Fragments of endocrine pancreas of each rat were randomly processed for immunohistochemistry staining and pancreatic insulin content. In diabetic state, pancreatic beta-cells showed a weak immunostaining for insulin on Day 10. Thereafter, insulin administration (in the group C rats) caused a significant decrease (p < 0.05) in the elevated blood glucose levels, and a significant increase (p < 0.05) in the serum insulin concentrations. The surviving beta-cells regenerated and virtually regained their normal immunostaining and functional status for insulin. On the 30th day, the pancreatic insulin contents of the insulin-treated group C rats showed approximately 45-fold increase in immunoreactivity when compared with the immunoreactivity of the same STZ+insulin-treated rats on Day 10 of the 40-day study period. The present study illustrates the sequence of morphological changes that occur in the islets of Langerhans following STZ administration and subsequent insulin treatment. The study also suggests that administration of a moderate single dose of STZ in Wistar rats produces specific necrosis of beta-cells, typical of type 1 insulin-dependent diabetes. The experimental evidence obtained in this study appears to suggest that induction of regenerative stimulus (by insulin treatment) in diabetic state triggers pancreatic regenerative processes, thereby restoring functional activities of the pancreas.     

Correction of hyperglycemia and insulin sensitivity by T-1095, an inhibitor of renal Na+-glucose cotransporters, in streptozotocin-induced diabetic rats

We investigated the effects of T-1095 (3-(benzo[b]furan-5-yl)-2',6'-dihydroxy-4'-methylpropiophenone 2'-O-(6-O-methoxycarbonyl)-beta-D-glucopyranoside), an orally active inhibitor of Na+-glucose cotransporter, on hyperglycemia and insulin resistance in skeletal muscle of streptozotocin (STZ)-induced diabetic rats. Chronic (4 weeks) administration of T-1095 as food admixture (0.01 -0.1% wt/wt) suppressed the blood glucose level without affecting the food intake and body weight. In addition, the reduced 2-deoxyglucose uptake and lactate release in the soleus muscle of STZ rat was ameliorated by chronic treatment of T-1095. These data suggest that T-1095 improves insulin sensitivity in skeletal muscle through correction of hyperglycemia and has novel therapeutic potential for treatment of diabetes mellitus through removing glucose toxicity.     

Antihyperglycemic Activity of Aqueous Root Extract of Rubia cordifolia. in Streptozotocin-Induced Diabetic Rats

Abstract

The aim of the current study was to examine the antidiabetic action of Rubia cordifolia. Linn (Rubiaceae) aqueous root extract (RCAREt) in streptozotocin (STZ)-induced diabetic rat model. STZ-induced diabetic rats were treated with RCAREt for 8 weeks (1 g kg^?1 b.w., orally per day). Serum glucose, total cholesterol and triglycerides, hematological parameters, and liver and kidney transaminases in normal, STZ diabetic, and RCAREt-treated diabetic rats were measured. The observed hyperglycemia, hypertriglyceridemia, enhanced transaminases of liver and kidney, hypochromic microcytic anemia, and loss of body weight in STZ diabetic rats were normalized by RCAREt treatment, whereas the hypercholesterolemia was not rectified. The beneficial effect of RCAREt treatment might be due to different types of active principles, each with a single or a diverse range of biological activities.     

Glucose- and Metabolically Regulated Hepatic Insulin Gene Therapy for Diabetes

Purpose The purpose of this study was to examine glucose- and metabolically modulation of insulin secretion by rAAV-mediated gene delivery in vitro and in vivo. Materials and methods A recombinant adeno-associated virus vector (rAAV) containing a furin-mutated human insulin gene, driven by the rat insulin I promoter, was used in this study. Glucose-responsive secretion of human insulin was determined by treating rAAV-transduced Huh7 human hepatoma cells with varying concentrations of glucose, with or without insulin secretagogues. Glucose- and metabolically modulated secretion of human insulin in the streptozotocin (STZ)-induced diabetic mice was assessed by intrahepatic administration of rAAV-polyethylenimine (PEI) complexes, followed by intraperitoneal glucose tolerance test (IPGTT), with or without theophylline. Results Glucose- and metabolically controlled human insulin secretion was obtained in the rAAV-transduced Huh7 cells. Treatment of STZ-induced diabetic animals with rAAV–polyethylenimine (rAAV-PEI) complexes resulted in production of human insulin and amelioration of hyperglycemia. Co-administration of glucose and theophylline in these animals augmented the secretion of human insulin, demonstrating metabolic modulation of insulin secretion in vivo. Immunohistochemical examination of the liver sections of rAAV-treated mice confirmed the production of human insulin. Conclusions Glucose- and metabolically controlled hepatic insulin gene therapy was obtained both in vitro and in vivo.     

Streptozotocin-induced elevation of pancreatic taurine content and suppressive effect of taurine on insulin secretion

The role of taurine in pancreatic insulin secretion was studied. The administration of the pancreato-toxic streptozotocin (STZ) induced a significant increase of pancreatic taurine content in ddY and CD-1 strains of mice in addition to a remarkable hyperglycemia which resulted from significant damage to the beta-cells of this organ. The increase in pancreatic taurine content was invariably observed under both the transient and the continuous hyperglycemic conditions induced by STZ. It was also shown by analysing lyophilized pancreatic sections that this elevation of taurine content in the pancreas induced by STZ was due to the rise of taurine level in the exocrine tissues, whereas that in the islets of Langerhans was not affected by STZ. On the other hand, the in vitro addition of taurine (1-10 mM) significantly suppressed the glucose-stimulated and Ca2+-dependent secretion of insulin (IRI) from the isolated islets of Langerhans without affecting the Ca2+-independent secretion of this hormone. Considering the results described above, it seems possible that the action site of taurine may be at the exterior of islet cells, perhaps at the cellular membranes of the islets of Langerhans. The present results suggest that pancreatic taurine may play a significant physiological role in the regulation of insulin secretion from the islets of Langerhans and of the serum level of glucose.     

Antihyperglycaemic action of diosmin,a citrus flavonoid,is induced through endogenous β‐endorphin in type I‐like diabetic rats

Diosmin is one of the flavonoids contained in citrus and has been demonstrated to improve glucose metabolism in diabetic disorders. However, the mechanism(s) of diosmin in glucose regulation remain obscure. Therefore, we investigated the potential mechanism(s) for the antihyperglycaemic action of diosmin in streptozotocin‐induced diabetic rats (STZ‐diabetic rats). Diosmin lowered hyperglycaemia in a dose‐dependent manner in STZ‐diabetic rats. This action was inhibited by naloxone at a dose sufficient to block opioid receptors. Additionally, we determined the changes in plasma β‐endorphin‐like immunoreactivity (BER) using enzyme‐linked immunosorbent assay (ELISA). Diosmin also increased BER dose‐dependently in the same manner. Repeated treatment of STZ‐diabetic rats with diosmin for 1 week resulted in an increase in the expression of the glucose transporter subtype 4 (GLUT 4) in the soleus muscle and a reduction in the expression of phosphoenolpyruvate carboxykinase (PEPCK) in the liver. These effects were also inhibited by naloxone at a dose sufficient to block opioid receptors. Bilateral adrenalectomy in STZ‐diabetic rats eliminated the actions of diosmin, including both the reduction in hyperglycemia and the elevation of plasma BER. In conclusion, our results suggest that diosmin may act on the adrenal glands to enhance the secretion of β‐endorphin, which can stimulate the opioid receptors to attenuate hepatic gluconeogenesis and increase glucose uptake in soleus muscle, resulting in reduced hyperglycemia in STZ‐diabetic rats.     

Intervention of D-glucose ameliorates the toxicity of streptozotocin in accessory sex organs of rat

Streptozotocin (STZ) is a naturally occurring compound isolated from Streptomyces achromogens. It is used extensively for inducing diabetes in experimental animals. Diabetes mellitus is known to have proven adverse effects on male sexual organs and their reproductive functions. The atrophy of prostate gland and other organs of the genitourinary tract were observed in experimental diabetic animals. STZ exhibits a structural resemblance to D-glucose due to the presence of sugar moiety in its structure. Pancreatic beta-cells mainly contain GLUT1 and GLUT2 glucose transporters. Possibly due to structural resemblance, STZ and d-glucose, share a common recognition site for entry into the beta-cells. The objective of the present study is to evaluate the effect of D-glucose on STZ-induced toxicity in accessory sex organs of male rats. Animals were kept on overnight fasting. One group received vehicle and served as negative control, while all other groups were given STZ (45 mg/kg). Animals that received only STZ served as positive control. The effect of D-glucose was studied on STZ treated animals with different dosage of D-glucose (250, 500, 1000 and 2000 mg/kg). Restoration of body weight, plasma glucose and plasma insulin was evident only at 1000 and 2000 mg/kg of D-glucose. The protective effect of D-glucose is evident only when it is administered simultaneously with STZ. In the present investigation, we report that simultaneous administration of D-glucose along with STZ ameliorates STZ-induced toxicity. This is evident from the restoration of accessory sex organ's weight, cellular morphology as well as insulin level.     

Beneficial role of telmisartan on cardiovascular complications associated with STZ-induced type 2 diabetes in rats

We studied the effect of an eight-week treatment with telmisartan (5 mg kg(-1)day(-1)) on cardiovascular complications that are associated with type 2 diabetes in a neonatal rat model. Type 2 diabetes was induced by the administration of 90 mg/kg streptozotocin (STZ), ip, in two-day-old rats. The development of diabetes was checked 12 weeks after STZ administration, and the animals were divided into different groups. Telmisartan treatment was given for eight weeks. At the end of the eight-week treatment, various biochemical and cardiac parameters were measured. Diabetic rats exhibited hyperglycemia, hyperinsulinemia, hyperlipidemia, increased blood pressure and heart rate, increased creatinine, cardiac enzyme and C-reactive protein (CRP) levels, a reduction in the rate of pressure development and decay, cardiac hypertrophy and oxidative stress. Chronic treatment with telmisartan significantly prevented STZ-induced hypertension and tachycardia and elevated fasting glucose and insulin levels. It significantly prevented the dyslipidemia and significantly reduced the elevated creatinine and CRP levels and the levels of other cardiac enzyme markers, like lactate dehydrogenase and creatinine kinase, in diabetic rats. There was an increase in rate of blood pressure development and decay with telmisartan treatment. Telmisartan also produced beneficial effects by preventing cardiac hypertrophy, which was evident from left ventricular collagen levels, the cardiac hypertrophy index and the left ventricular hypertrophy index in diabetic rats. Telmisartan successfully prevented oxidative stress, which was evidenced by a decrease in malondialdehyde and an increase in glutathione, catalase, superoxide dismutase levels. In conclusion, our data suggest that telmisartan prevented STZ-induced metabolic abnormalities and cardiovascular complications in type 2 diabetes.     

咖啡对糖尿病大鼠胰岛素分泌、敏感性及氧化应激影响

目的评价咖啡对链脲佐菌素（STZ）诱导的糖尿病大鼠胰岛素敏感性、氧化应激指标及胰腺内胰岛素含量的影响。方法 Wistar大鼠48只,随机分为正常对照组（NC组）、含咖啡因咖啡灌胃组（CC）、去咖啡因咖啡灌胃组（DC）、STZ模型组（S）。CC组和DC组分别以咖啡和去咖啡因咖啡每日灌胃,8周后CC组、DC组、S组均腹腔注射STZ 10 mg kg-1,行口服葡萄糖耐量试验（OGTT）及胰岛素耐量试验（ITT）,测定血浆8-异前列腺素F2α（8-isoPGF2α）和8-羟脱氧鸟苷（8-OHDG）水平,检测胰腺内胰岛素含量。结果 OGTT CC组、DC组、S组均较NC组血糖明显升高。ITT结果 DC组和CC组ITT 30、60、120 min血糖下降比例明显高于S组、与NC组比较血糖下降比例无显著差异。CC组、DC组、S组血浆8-isoPGF2α和8-OHDG水平较NC组明显升高,CC组和DC组8-isoPGF2α和8-OHDG水平显著低于S组。CC组、DC组、S组胰腺内胰岛素含量较NC组显著降低,CC组胰腺内胰岛素水平明显高于DC组和S组。结论含咖啡因咖啡和去咖啡因咖啡均可增加糖尿病大鼠胰岛素敏感性、改善氧化应激;含咖啡因咖啡可增加内源性胰岛素分泌。本研究结果提示含咖啡因和去咖啡因咖啡都可能通过影响氧化应激参与调节糖代谢,含咖啡因咖啡可改善糖尿病大鼠B细胞分泌功能。     

Effects of atorvastatin and pravastatin on glucose tolerance in diabetic rats mildly induced by streptozotocin

Effects of atorvastatin and pravastatin on glucose tolerance in mildly induced diabetic rats by streptozotocin at 24 mg/kg, i.v. were studied. Non-diabetic and diabetic rats were given orally 0.5% carboxymethylcellulose (control), 8 mg/kg atorvastatin or 8 mg/kg pravastatin once a day for 6 weeks. An oral glucose tolerance test (OGTT) was carried out 1, 2, 3, and 6 weeks after the administration. The blood glucose and plasma insulin levels measured before OGTT in the diabetic rats were not different from those in the non-diabetic rats. However, the hyperglycemic response to OGTT in the diabetic rats significantly exceeded that in the non-diabetic rats. The plasma insulin increased by OGTT in the diabetic rats appeared to be lower than that in the non-diabetic rats. Statin treatments for 1 week did not modify the OGTT-induced hyperglycemia appreciably, although there were some significant differences. More than 2 weeks after administration, the blood glucose levels at several time points after a glucose intake in the atorvastatin-treated diabetic rats were significantly higher than the respective levels in the control diabetic rats. Neither atorvastatin nor pravastatin modified the OGTT-induced insulin secretion. Statins, especially atorvastatin, may influence the glucose tolerance in mildly induced diabetic rats without alterations of insulin secretion.     

Adrenergic receptors and the onset of streptozotocin-induced diabetes in mice

Treatment with yohimbine, an alpha 2-adrenergic blocker, prior to the injection of a subdiabetogenic dose of streptozotocin (STZ) produced hyperglycemia and hypoinsulinemia in mice 7 days later. Prazosin, an alpha 1-adrenergic blocker, was ineffective. The capacity of phentolamine and phenoxybenzamine to potentiate the diabetogenic effect of STZ was intermediate between that of yohimbine and prazosin. Propranolol and hexamethonium inhibited the potentiating action of yohimbine. Yohimbine enhanced the potentiating effect of isoproterenol on the STZ-induced diabetes. Acute changes in phase glucose and insulin levels induced by STZ were potentiated by yohimbine but not by prazosin. The insulin releasing ability of the pancreatic islets 7 days after STZ was all but lost in mice pretreated with yohimbine but not with prazosin. These results suggest that the beta- and alpha 2-, not alpha 1-adrenergic system which modulates insulin release from pancreatic islets influences the response to the diabetogenic action of STZ in mice.     

Effects of red mold dioscorea with pioglitazone,a potentially functional food,in the treatment of diabetes

The prevalence of type 2 diabetes mellitus is increasing rapidly, and its treatment with pioglitazone is likely to induce rhabdomyolysis. We aimed to determine the effect of cotreatment with pioglitazone and red mold dioscorea (RMD) produced by Monascus purpureus NTU 568 on pancreas function in streptozotocin (STZ)-induced diabetic rats. In diabetic rats fed RMD, RMD with pioglitazone, and pioglitazone alone, insulin concentrations increased significantly by 18.6–40.4%, 64.0–100.0%, and 52.8%, respectively, compared with that in the diabetic group (p < 0.05). Oral glucose tolerance was impaired in the STZ-induced diabetic group within 4 weeks, however, oral glucose tolerance in rats treated with RMD or RMD with pioglitazone improved after 4 weeks, 6 weeks, and 8 weeks. Findings from this study might lend support to the use of RMD as a novel functional food for the prevention of diabetes.     

The influence of rutin on the extracellular matrix in streptozotocin-induced diabetic rat kidney

We previously reported that rutin administration to streptozotocin (STZ)-induced diabetic rats decreased plasma glucose and increased plasma insulin levels. In this study, we have examined the role of rutin on matrix remodelling in the kidney of STZ-induced diabetic rats. STZ was administered intraperitoneally (50 mg kg(-1)) to male albino Wistar rats to induce experimental diabetes. Rutin (100 mg kg(-1)) was orally administered to normal and STZ-induced diabetic rats for a period of 45 days and its influence on the content of hydroxyproline and collagen and on the activity of matrix metalloproteinases (MMPs) were studied. We have also studied the levels of tissue inhibitors of metalloproteinases (TIMPs) in the kidney. STZ-induced diabetic control rats showed increased content of hydroxyproline and collagen, decreased activity of MMPs and increased levels of TIMPs in the kidney. These changes were positively modulated by rutin treatment in STZ-induced diabetic rats, thereby protecting the kidney. In normal rats treated with rutin, none of the parameters studied were significantly altered. From the results obtained, we could conclude that rutin influences MMPs and effectively protects kidney against STZ-induced damage in rats. The effects observed are due to the reduction of plasma glucose levels by rutin.     

Sopungsungi-won (SP) prevents the onset of hyperglycemia and hyperlipidemia in Zucker diabetic fatty rats

Sopungsungi-won (SP) is a known formula for senile constipation and diabetes mellitus, based on traditional Korean medicine. The preventive effect of SP on the development of overt diabetes in Zucker diabetic fatty (ZDF) rats was evaluated. When administered orally through a diet for 8 weeks, diabetic conditions such as hyperglycemia, polydipsia and hypertriglyceridemia were all ameliorated in SP-treated rats. In parallel with the onset and progression of hyperglycemia in the ZDF control rats; there was a marked decline in plasma insulin concentrations from 26.1 microU/ml, at age 7 weeks, to 14.8 microU/ml at age 15 weeks. In the SP-treated rats, however, the plasma insulin concentrations did not decline, and SP at a dose of 5 g/kg significantly increased the insulin levels to 31.9 microU/ml. Early normalization of plasma insulin and a retained ability to subsequently increase plasma insulin were indicative of a pancreatic beta cell protective action by the SP formula. In addition, expressions of an insulin-responsive gene and corresponding protein, glucose transporter 4 (GLUT4), in skeletal muscle, were also determined in SP- and rosiglitazone-treated ZDF rats. mRNA and protein levels of GLUT4 in SP-treated rats were upregulated in a dose dependent manner. Furthermore, when ZDF rats were treated with 2 g/kg of the SP formula, the activity of glucose-6-phosphatase was decreased by 49%, whereas the activity of glucokinase was increased by 196%, compared to the ZDF control rats. Taken together, these data provide evidence that the SP formula markedly lowered the plasma glucose levels, probably through an effect not only on improvement of insulin action, but through a combined stimulation of glycolysis and an inhibition of gluconeogenesis in the liver, and also suggest the validity of SP's clinical use in the treatment of type 2 diabetes mellitus following further toxicological investigation.     

Depression of glucose levels and partial restoration of pancreatic β-cell damage by melatonin in streptozotocin-induced diabetic rats

Diabetes mellitus is a common but serious metabolic disorder associated with many functional and structural complications. Glucose metabolism is disturbed due to an absolute or relative insulin deficiency. The experiment was carried out to determine the effect of melatonin on blood glucose and insulin concentrations, and histopathology of pancreatic β-cells in streptozotocin (STZ)-induced diabetic rats. The rats were randomly allocated into one of the four experimental groups: group A (control), group B (diabetic untreated), group C (diabetic treated with melatonin for 6 weeks) and group D (diabetic treated with melatonin for 8 weeks); each group contained ten animals. Diabetes was induced in B, C and D groups by a single intraperitoneal (i.p.) injection of STZ (50 mg/kg, freshly dissolved in 5 mmol/l citrate buffer, pH 4.5). The rats in melatonin-treated groups were subjected to the daily i.p injection of 10 mg kg⁻¹ of melatonin for 6 or 8 weeks starting the day after STZ injection. Control and diabetic untreated rats were injected with the same volume of isotonic NaCl as the melatonin treated groups. Almost all insulin-positive β-cells were degranulated, degenerated or necrotic in the STZ-treated rats leading to decrease in insulin secretion and an increase in blood glucose concentration. Melatonin treatment caused a sharp decrease in the elevated serum glucose, a slight increase in the lowered serum insulin concentrations and small partial regeneration/proliferation of β-cells of islets. It is concluded that the hypoglycemic action of melatonin could be partly due to small amelioration in the β-cells of pancreatic islets causing a slight increase in insulin secretion, it is mostly due to the extrapancreatic actions of the melatonin.