A new prostaglandin E1 analogue (TFC-612) prevents a decrease in motor nerve conduction velocity in streptozocin-diabetic rats

A new prostaglandin E1 analogue (TFC-612) was orally given to streptozocin-diabetic rats for 4 weeks after the induction of diabetes and its effects on motor nerve conduction velocity were studied. The compound significantly prevented a decrease of the velocity but did not reverse abnormal sorbitol and myo-inositol contents of the sciatic nerve. The results suggest that TFC-612 has a potent effect on diabetic nerve dysfunction via other mechanism than the correction of sorbitol and myo-inositol metabolisms and could be a potential compound for therapy of diabetic polyneuropathy.     

Effects of magnolol (5,5'-diallyl-2,2'-dihydroxybiphenyl) on diabetic nephropathy in type 2 diabetic Goto-Kakizaki rats

We investigated the effect of magnolol (5,5'-diallyl-2,2'-dihydroxybiphenyl), a marker compound isolated from the cortex of Magnolia officinalis, in non-obese type 2 diabetic Goto-Kakizaki (GK) rats. The rats were treated orally with magnolol (100 mg/kg body weight) once a day for 13 weeks. In magnolol-treated GK rats, fasting blood glucose and plasma insulin were significantly decreased, and the pancreatic islets also showed strong insulin antigen positivity. Urinary protein and creatinine clearance (Ccr) were significantly decreased. Pathological examination revealed the prevention of the glomeruli enlargement in magnolol-treated GK rats. The overproduction of renal sorbitol, advanced glycation endproducts (AGEs), type IV collagen, and TGF-beta1 mRNA were significantly reduced in magnolol-treated GK rats. Thus based on our findings, the use of magnolol could result in good blood glucose control and prevent or retard development of diabetic complications such as diabetic nephropathy.     

The effects of zenarestat, an aldose reductase inhibitor, on minimal F-wave latency and nerve blood flow in streptozotocin-induced diabetic rats

The effects of zenarestat, 3-(4-bromo-2-fluorobenzyl)-7-chloro-3,4-dihydro-2,4-dioxo-1(2H)-quinazolineacetic acid, an aldose reductase inhibitor (ARI), on F-wave conduction abnormalities, nerve blood flow (NBF) reduction and sorbitol accumulation were studied in streptozotocin-induced diabetic rats. Two weeks after the induction of diabetes, zenarestat was given once a day for two weeks. In diabetic control rats, marked accumulation of sorbitol, reduction of NBF and prolongation of minimal F-wave latency (FWL) were observed as compared to normal rats. Zenarestat, at a dose of 32 mg/kg, inhibited sorbitol concentration to nearly the normal rat level and significantly improved not only NBF but also minimal FWL. At a dose of 3.2 mg/kg, sorbitol accumulation was inhibited by approximately 40% and there was a tendency to increase in NBF; however, minimal FWL was not improved at all. These data suggest that a highly inhibition of the nerve sorbitol accumulation is requisite for the treatment of diabetic peripheral neuropathy.     

Sorbitol, inositol and nerve conduction in diabetes

Motor nerve conduction velocity was lower in streptozotocin-diabetic rats than in controls. Treatment with the aldose reductase inhibitor Sorbinil restored conduction velocity to normal. Diabetic rats had an increased concentration of sorbitol and reduced free inositol in sciatic nerve. Sorbinil corrected both defects. Inositol administration to diabetic rats also restored conduction velocity to normal. Genetically diabetic mice had reduced concentrations of inositol in sciatic nerve but fructose and sorbitol were normal. Glucose concentration was considerably increased.     

Arctigenic acid,the key substance responsible for the hypoglycemic activity of Fructus Arctii

We have reported the antidiabetic activity of the total lignans from Fructus arctii (TLFA) against alloxan-induced diabetes in mice and rats. In this study, arctigenic acid was found to be the main metabolite in rat plasma detected by UPLC/MS and HPLC/MS/MS after oral administration of TLFA. For the first time, its hypoglycemic activity and acute oral toxicity were evaluated in Goto-Kakizaki (GK) rats, a spontaneous type 2 diabetic animal model, and ICR mice respectively.GK rats were orally given arctigenic acid (50 mg/kg) twice daily before each meal for 12 weeks. The treatment reduced the elevated plasma glucose, glycosylated hemoglobin and showed significant improvement in glucose tolerance in glucose fed hyperglycemic GK rats. We found that the hypoglycemic effect of arctigenic acid was partly due to the stimulation on insulin secretion, whereas the body weight was not affected by arctigenic acid administration in GK rats. Meanwhile, there was no observable acute toxicity of arctigenic acid treatment at the dosage of 280 mg/kg body weight daily in the acute 14-day toxicity study in mice.This study demonstrates that arctigenic acid may be the main metabolite in the rat serum after oral administration of TLFA, which showed significant hypoglycemic effect in GK rats, and low acute toxicity in ICR mice. The result prompts us that arctigenic acid is the key substance responsible for Fructus Arctii antidiabetic activity and it has a great potential to be further developed as a novel therapeutic agent for diabetes in humans.     

Effects of pycnogenol treatment on oxidative stress in streptozotocin-induced diabetic rats

Free radicals and oxidative stress have been implicated in the etiology of diabetes and its complications. This in vivo study has examined whether subacute administration of pycnogenol, a French pine bark extract containing procyanidins that have strong antioxidant potential, alters biomarkers of oxidative stress in normal and diabetic rats. Diabetes was induced in female Sprague-Dawley rats by a single injection of streptozotocin (90 mg/kg body weight, ip), resulting (after 30 days) in subnormal body weight, increased serum glucose concentrations, and an increase in liver weight, liver/body weight ratios, total and glycated hemoglobin, and serum aspartate aminotransferase activity. Normal and diabetic rats were treated with pycnogenol (10 mg/kg body weight/day, ip) for 14 days. Pycnogenol treatment significantly reduced blood glucose concentrations in diabetic rats. Biochemical markers for oxidative stress were assessed in the liver, kidney, and heart. Elevated hepatic catalase activity in diabetic rats was restored to normal levels after pycnogenol treatment. Additionally, diabetic rats treated with pycnogenol had significantly elevated levels of reduced glutathione and glutathione redox enzyme activities. The results demonstrate that pycnogenol alters intracellular antioxidant defense mechanisms in streptozotocin-induced diabetic rats.     

Effect of Aegle marmelos Correa. (Bael) fruit extract on tissue antioxidants in streptozotocin diabetic rats

A study was undertaken to evaluate the anti-lipid peroxidative activity of an aqueous extract of A. marmelos fruits (AMFEt) in streptozotocin diabetic rats in heart and pancreas. Oral administration of AMFEt for 30 days (125 and 250 mg kg(-1) body weight twice daily) produced a significant decrease in the elevated levels of peroxidation products, viz. thiobarbituric acid reactive substances and hydroperoxides in the tissues of diabetic rats. The depressed activities of superoxide dismutase, catalase and glutathione peroxidase and lowered glutathione content in the heart and pancreas of diabetic rats were found to increase on treatment with AMFEt. AMFEt at a dose of 250 mg kg(-1) was more effective than glibenclamide (300 microg kg(-1)) and both reversed all the values significantly. Thus AMFEt exhibits anti-oxidative activity in streptozotocin diabetic rats.     

Formononetin Ameliorates Diabetic Neuropathy by Increasing Expression of SIRT1 and NGF

Diabetic neuropathy is commonly observed complication in more than 50 % of type 2 diabetic patients. Histone deacetylases including SIRT1 have significant role to protect neuron from hyperglycemia induced damage. Formononetin (FMNT) is known for its effect to control hyperglycemia and also activate SIRT1. In present study, we evaluated effect of FMNT as SIRT1 activator in type 2 diabetic neuropathy. Type 2 diabetic neuropathy was induced in rats by modification of diet for 15 days using high fat diet and administration of streptozotocin (35 mg/kg/day, i. p.). FMNT treatment was initiated after confirmation of type 2 diabetes. Treatment was given for 16 weeks at 10, 20 and 40 mg/kg/day dose orally. FMNT treatment‐controlled hypoglycemia and reduced insulin resistance significantly in diabetic animals. FMNT treatment reduced oxidative stress in sciatic nerve tissue. FMNT treatment also reduced thermal hyperalgesia and mechanical allodynia significantly. It improved conduction velocity in nerve and unregulated SIRT1 and NGF expression in sciatic nerve tissue. Results of present study indicate that continuous administration of FMNT protected diabetic animals from hyperglycemia induced neuronal damage by controlling hyperglycemia and increasing SIRT1 and NGF expression in nerve tissue. Thus, FMNT can be an effective candidate for treatment of type 2 diabetic neuropathy.     

Effect of TFC-612, a 7-thia prostaglandin E1 derivative, on a peripheral arterial occlusive disease model in rats

TFC-612, methyl 6-({(1R,2S,3R)-3-hydroxy-2-{(1E,3S,5R)-3-hydroxy-5-methyl-1-nonenyl}-5-oxocyclopentyl}-thio]-hexanoate, inhibited the progression of the lesion in a lauric acid-induced peripheral arterial occlusive model at 1.0 mg/kg p.o. or 1.0 μg/rat/h s.c. in rats. Aspirin (32 mg/kg, p.o.), an anti-platelet drug, did not suppress the lesion growth. On the other hand, ketanserin (10 mg/kg, p.o.), a 5-HT₂ antagonist, also inhibited the progression of the lesion. In vitro, TFC-612 inhibited rat platelet aggregation induced by collagen and ADP with IC₅₀ values of 5.4 ng/mL and 9.5 ng/mL, respectively. Aspirin also inhibited collagen-induced aggregation with an IC₅₀ value of 6.3 μg/mL, but not ADP-induced aggregation at 180 μg/mL. Ketanserin had no effect on either aggregation at 40 μg/mL. In ex vivo experiments, aspirin inhibited platelet aggregation induced by collagen at 10 and 32 mg/kg in rats. However, TFC-612 showed significant inhibition only at 10 mglkg. TFC-612 and ketanserin increased dermal blood flow in the rat paw at 1.0 μg/kg i.v. and 100 μg/kg Lv., respectively. Aspirin had no effect on blood flow at 3.2 mg/kg i.v. These results suggest that the improvement of microcirculation, in addition to anti-platelet action by TFC-612, contributes to its inhibitory effect in a peripheral arterial occlusive model in rats.     

Human C-peptide Dose Dependently Prevents Early Neuropathy in the BB/Wor-rat

In order to explore the neuroprotective and crossspecies activities of.C-peptide on type 1 diabetic neuropathy, spontaneously diabetic BB/W-rats were given increasing doses of human recombinant Cpeptide (hrC-peptide). Diabetic rats received 10, 100, 500, or 1000 μg of hrC-peptide/kg body weight/ day from onset of diabetes. After 2 months of hrC-peptide administration, 100 μg and greater doses completely prevented the nerve conduction defect, which was associated with a significant but incomplete prevention of neural Na⁺/K⁺-ATPase activity in diabetic rats with 500 μg or greater C-peptide replacement. Increasing doses of hrC-peptide showed increasing prevention of early structural abnormalities such as paranodal swelling and axonal degeneration and an increasing frequency of regenerating sural nerve fibers. We conclude that hrC-peptide exerts a dose dependent protection on type 1 diabetic neuropathy in rats and that this effect is probably mediated by the partially conserved sequence of the active C-terminal pentapeptide     

Haematopoietic properties of ethanolic extract of Ageratum conyzoides (Goat weed) in Albino rats.

The potential haematological effects associated with the administration of ethanolic leaf extract of Ageratum conyzoides was investigated in rats. 27 rats were randomly divided into four groups. The first group had 6 rats and served as control, the remaining 3 experimental groups and had 7 rats each. These later groups were gavaged with the extract of Ageratum conyzoides in concentrations of 200 mg/kg, 400 mg/kg and 500 mg/kg respectively for 30 days at a dose of 0.1 ml/body weight. The control group was gavaged with 0.9% sodium chloride at a dose of 0.1 m1/body weight as placebo. The extract at the doses administered was found to increase in a dose-related fashion PCV and Hb ([P < 0.01] for 200 mg/kg and [P < 0.001] for 400 mg/kg and 500 mg/kg), RBC ([P < 0.05] for 400 mg/Kg and 500 mg/kg) and marginal increases that were not significant for 200 mg/kg); MCH and MCV ([P < 0.05] and [P < 0.01] for 400mg/kg and 500mg/kg respectively) 200 mg/kg was not significant. MCHC recorded no significant change. WBC recorded marginal increases that were not significant, similarly, the differential white blood cell recorded marginal increases that were not significant, except lymphocytes that recorded significant increase in group 4 [P < 0.05]. Marginal Decreases in body weight were also observed, these decreases were however not significant. The result of this study thus indicate haematopoietic potentials of the extract and could possibly remedy anaemia.     

Chromium picolinate supplementation improves insulin sensitivity in Goto-Kakizaki diabetic rats

Chromium picolinate (CrP) supplementation has been studied as a potential therapy of insulin resistance and lipid abnormalities. There have been some reports involving chromium supplementation in patients with diabetes, but the results are varied. The present study was conducted to assess the effects of CrP on insulin sensitivity and body weight in Goto-Kakizaki (GK) diabetic rats. We supplemented normal Sprague-Dawley (SD) rats and GK diabetic rats with supplemental CrP, 100 mg/kg/day once a day for 4 weeks. In the normal SD rats, the mean body weight of the control group increased by 50.5%, whereas that of the CrP-treated group increased by 65.9% (P < 0.05 vs control). Similarly, in the diabetic GK rats, CrP supplementation showed increased weight gain compared to the control group (133.4% vs 119.6% of the baseline weight, P < 0.01). Glucose tolerance tests (GTT) [ip injection of glucose; 2 g/kg] and insulin sensitivity tests [SQ injection of insulin (5 U/kg) plus ip injection of glucose (30 min after insulin injection)] were conducted. During insulin sensitivity tests at the end of treatment, the glucose levels were significantly lower in CrP-treated rats compared with the control rats (AUC_0→120; 113.1 ± 32.0 vs 170.5 ± 49.0 mg-min/mL, P < 0.05). During GTTs, the glucose levels and insulin concentrations in the CrP-treated rats were not different from those in the control rats.

The results of these studies suggest that CrP supplementation in GK diabetic rats leads to increase of weight gain and improvement of insulin sensitivity. This raises the possibility that CrP supplementation can be considered to improve carbohydrate metabolism in patients with type 2 diabetes mellitus.     

Ameliorating effect of eugenol on hyperglycemia by attenuating the key enzymes of glucose metabolism in streptozotocin-induced diabetic rats

Epidemiological studies have demonstrated that diabetes mellitus is a serious health burden for both governments and healthcare providers. This study was hypothesized to evaluate the antihyperglycemic potential of eugenol by determine the activities of key enzymes of glucose metabolism in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced into male albino Wistar rats by intraperitoneal administration of STZ (40 mg/kg body weight (b.w.)). Eugenol was administered to diabetic rats intragastrically at 2.5, 5, and 10 mg/kg b.w. for 30 days. The dose 10 mg/kg b.w. significantly reduced the levels of blood glucose and glycosylated hemoglobin (HbA1c) and increased plasma insulin level. The altered activities of the key enzymes of carbohydrate metabolism such as hexokinase, pyruvate kinase, glucose-6-phosphate dehydrogenase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, and liver marker enzymes (AST, ALT, and ALP), creatine kinase and blood urea nitrogen in serum and blood of diabetic rats were significantly reverted to near normal levels by the administration of eugenol. Further, eugenol administration to diabetic rats improved body weight and hepatic glycogen content demonstrated the antihyperglycemic potential of eugenol in diabetic rats. The present findings suggest that eugenol can potentially ameliorate key enzymes of glucose metabolism in experimental diabetes, and it is sensible to broaden the scale of use of eugenol in a trial to alleviate the adverse effects of diabetes.     

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。     

Ultrastructural study of the effect of insulin dosage on the myocardium of spontaneously diabetic BB rats

Cardiac ultrastructure was studied in spontaneously diabetic BB rats maintained on two different regimens of insulin daily. For 3 months from the onset of overt diabetes, one diabetic group was well controlled with daily subcutaneous administration of sufficient insulin to prevent glycosuria (9.0-13.0 U/kg). Approximately half of this dose (4.5 U/kg) of insulin was given daily to a second group of diabetic rats. Normal Wistar rats and nondiabetic BB rats were used as controls. Blood glucose values were three- to four-fold higher with respect to these controls in the diabetic BB rats receiving the smaller dose of insulin but were significantly lower than controls in diabetic animals receiving the higher insulin dose. A 30% difference in body weight with respect to the Wistar controls, obvious hyperliposis, and some nerve degeneration were seen in the low dose insulin group of diabetics. Such changes did not occur in the well-controlled insulin-treated group. Electron microscopic examination of the left ventricular tissue revealed mild damage in both groups of diabetics consisting of small focal lesions and mild edema along the sarcoplasmic reticulum and sometimes adjacent to the sarcolemma. Thus, insulin treatment, which prevented glycosuria, resulted in normal tissue lipid levels and prevented nerve damage but had little effect on the other diabetes-induced ultrastructural alterations in the myocardium of these rats.     

Antihyperglycemic effect of fraxetin on hepatic key enzymes of carbohydrate metabolism in streptozotocin-induced diabetic rats

Epidemiological studies have demonstrated that the diabetes mellitus is a serious health burden for both governments and healthcare providers. The present study was hypothesized to evaluate the antihyperglycemic potential of fraxetin by determining the activities of key enzymes of carbohydrate metabolism in streptozotocin (STZ) – induced diabetic rats. Diabetes was induced in male albino Wistar rats by intraperitoneal administration of STZ (40 mg/kg b.w). Fraxetin was administered to diabetic rats intra gastrically at 20, 40, 80 mg/kg b.w for 30 days. The dose 80 mg/kg b.w, significantly reduced the levels of blood glucose and glycosylated hemoglobin (HbA1c) and increased plasma insulin level. The altered activities of the key enzymes of carbohydrate metabolism such as glucokinase, glucose-6-phosphate dehydrogenase, glucose-6-phosphatase, fructose-1,6-bisphosphatase and hepatic enzymes (aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP)) in the liver tissues of diabetic rats were significantly reverted to near normal levels by the administration of fraxetin. Further, fraxetin administration to diabetic rats improved body weight and hepatic glycogen content demonstrated its antihyperglycemic potential. The present findings suggest that fraxetin may be useful in the treatment of diabetes even though clinical studies to evaluate this possibility may be warranted.     

Alterations of Inositol Lipid Metabolism of Rat Sciatic Nerve in Streptozotocin-Induced Diabetes

Abstract: The composition and metabolism of rat sciatic nerve phospholipids were studied 20 weeks after induction of chronic diabetes by intraperitoneal injection of streptozotocin (50 mg/kg). On a wet weight basis the nerves from the diabetic animals showed a 7% decrease in total phospholipid from that of controls and a relative decrease in phosphatidylinositol. Incubations of isolated sciatic nerves of diabetic rats in a medium containing [³³P]orthophosphate gave decreased labeling of phosphatidylinositol and substantial changes in the labeling pattern of phosphatidylinositol phosphate and 4,5-bisphosphate from that of controls. The ratio of label in these polyphosphoinositides decreased from 2.5 for normal nerve to about 1.0 for diabetic nerve within a 2-h incubation period. These metabolic alterations were not observed in acutely diabetic animals 5 days after streptozotocin (100 mg/kg) administration. Because polyphosphoinositides may be involved in the control of membrane permeability during axonal conduction, alterations in their relative amounts or turnover rates could be related to the physiological changes of early diabetic neuropathy.     

Effect of chemical carcinogens and partial hepatectomy on "in vivo" (35S)methionine interaction with rat liver tRNA

The effect of carcinogens given by a single or multiple injections on the extent of (35S)methionine interaction with hepatic tRNA was studied in normal and partially hepatectomized rats. Either partial hepatectomy or administration of ethionine (100 or 330 mg/kg body weight) and dimethylnitrosamine (120 mg/kg body weight) by multiple i.p. injections inhibited the (35S)methionine-tRNA interaction, while administration of hepatocarcinogenic chemicals plus PH resulted rather in a stimulation. Methylnitrosourea enhanced the extent of interaction when administered in a single dose (100 mg per kg body weight) 18 h after partial hepatectomy.     

The Effects of stingless bee (Tetragonula biroi) honey on streptozotocin-induced diabetes mellitus in rats

Diabetes mellitus (DM) is a metabolic disease characterised by chronic hyperglycaemia with impaired carbohydrate, fat and protein metabolism caused by defects in insulin secretion or action. Based on our previous research, stingless bee honey (SLBH) from Tetragonula biroi and T. laeviceps can inhibit alpha-glucosidase activities. Therefore, the aim of the present study was to determine the effects of daily oral administration of SLBH on body weight (BW) and fasting blood glucose (FBG) levels of male rats with streptozotocin (STZ)-induced DM. Thirty-six male Sprague Dawley rats were divided into six groups of six rats each. One group of normal non-diabetic rats served as a positive control. The diabetic groups were intraperitoneally (i.p.) injected with STZ (50 mg/kg BW) for induction of DM and divided into five equal subgroups of six animals each: an untreated group as a negative control; a group treated with 0.6 mg/kg BW of glibenclamide as a positive control and three SLBN treatment groups that had daily oral administration of 0.5, 1.0 or 2.0 g/kg BW, respectively, for 35 days. The results showed that SLBH significantly reduced loss of BW in diabetic rats. FBG levels in diabetic rat blood, collected from the tail, were measured using Accu-Chek test strips. The FBG levels in diabetic rats that have oral administered intake with glibenclamide and SLBH were stable. There were no changes in serum FBG levels in SLBH-treated diabetic rats for 35 days. Pancreatic histopathology results from all groups showed no abnormalities or tissue damage in either diabetic or non-diabetic rats. The results of this study show that administration of SLBH reduced BW loss or improved BW of rats with STZ-induced DM. Meanwhile, the reduction in loss of BW that occurred in diabetic rats after 35 days of SLBH administration was the result of reduced formation of fats and proteins, which are broken down into energy. Further research is needed to determine the antidiabetic effects of honey from other stingless honeybee species.     

Biochemical effects of Nigella sativa L seeds in diabetic rats

Oral administration of ethanol extract of N. sativa seeds (300 mg/kg body weight/day) to streptozotocin induced diabetic rats for 30 days significantly reduced the elevated levels of blood glucose, lipids, plasma insulin and improved altered levels of lipid peroxidation products (TBARS and hydroperoxides) and antioxidant enzymes like catalase, superoxide dismutase, reduced glutathione and glutathione peroxidase in liver and kidney. The results confirm the antidiabetic activity of N. sativa seeds extract and suggest that because of its antioxidant effects its administration may be useful in controlling the diabetic complications in experimental diabetic rats.