Streptozotocin Diabetic Group Research Articles

Antioxidant, antidiabetic, and anticholinesterase potential of Chenopodium murale L. extracts using in vitro and in vivo approaches

Abstract In this study, Chenopodium murale Linn. extracts have been evaluated for its in vitro antioxidant, enzyme inhibition, and in vivo neuropharmacological properties in streptozotocin (STZ)-induced memory impairment in rat model. First, the plant was subjected to extraction and fractionation, then quantitative phytochemical analysis was performed to estimate the major phytochemical groups in the extract where high amounts of phenolics and saponins were detected in crude and chloroform extract. The highest total phenolic contents, total flavonoid contents, and total tannin content were also recorded in crude extract and chloroform fraction. The in vitro antioxidant potential of chloroform fraction was high with IC50 value of 41.78 and 67.33 μg/mL against DPPH and ABTS radicals, respectively, followed by ethyl acetate fraction. The chloroform fraction (ChMu-Chf) also exhibited potent activity against glucosidase with IC50 of 89.72 ± 0.88 μg/mL followed by ethyl acetate extract (ChMu-Et; IC50 of 140.20 ± 0.98 μg/mL). ChMu-Chf again exhibited potent activity against acetylcholinesterase (AChE) with IC50 of 68.91 ± 0.87 μg/mL followed by ChMu-Et with IC50 of 78.57 ± 0.95 μg/mL. In vivo memory impairment was assessed using the novel object discrimination task, Y-maze, and passive avoidance task. Ex vivo antioxidant enzyme activities and oxidative stress markers like catalase, superoxide dismutase (SOD), malondialdehyde, and glutathione were quantified, and the AChE activity was also determined in the rat brain. No significant differences were observed amongst all the groups treated with crude, chloroform, and ethyl acetate in comparison with positive control donepezil group in connection to initial latency; whereas, the STZ diabetic group displayed a significant fall in recall and retention capability. The blood glucose level was more potently lowered by chloroform extract. The crude extract also increased the SOD level significantly in the brain of the treated rat by 8.01 ± 0.51 and 8.19 ± 0.39 units/mg at 100 and 200 mg/kg body weight (P < 0.01, n = 6), whereas the chloroform extract increased the SOD level to 9.41 ± 0.40 and 9.72 ± 0.51 units/mg, respectively, at 75 and 150 mg/kg body weight as compared to STZ group. The acetylcholine level was also elevated to greater extent by chloroform fraction that might contain a potential inhibitor of acetylcholinesterase. Treatment with C. murale ameliorated cognitive dysfunction in behavioral study, and provided significant defense from neuronal oxidative stress in the brain of the STZ-induced diabetic rats. Thus C. murale Linn. could be an inspiring plant resource that needs to be further investigated for isolation of potential compounds in pure form and their evaluation as a potent neuropharmacological drug.

Egg yolk oil accelerates wound healing in streptozotocin induced diabetic rats

ABSTRACT Impaired diabetic wound healing causes foot ulcers. We investigated egg yolk oil for skin wound healing in streptozotocin (STZ) induced diabetic rats. Rats were allocated into three groups of six. Group 1, nondiabetic control group, was treated topically with 2% fusidic acid ointment. Group 2, STZ diabetic control, was treated topically with 2% fusidic acid ointment. Group 3, STZ diabetic group, was treated topically with egg yolk oil. Three days after STZ injection, two full thickness excisional skin wounds were created on the back of each animal. Wound diameter was measured for 14 days and wound contraction was calculated. Re-epithelization time also was determined. Three rats from each group were sacrificed on experimental day 7 and the remaining rats on day 14. Wound samples were examined using hematoxylin and eosin, periodic acid-Schiff, Masson’s trichrome, Taenzer-Unna orcein and toluidine blue staining. Expression of endoglin (CD105), epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) were investigated using immunohistochemistry. Egg yolk oil increased the proliferation of epithelial cells and angiogenesis, and stimulated collagen deposition in the lesion area. Egg yolk oil increased CD105, EGF and VEGF expression in blood vessels, and EGF and VEGF expression in epidermis of the lesions. The predominant fatty acids in egg yolk oil are oleic, palmitic and linoleic, which likely were responsible for the beneficial effects of egg yolk oil on diabetic wound healing. Egg yolk oil appears to be a promising therapeutic agent for healing of diabetic wounds.

Structural Changes in the Urinary Bladder of Streptozotocin-Induced Diabetic Rats and the Possible Protective Role of Insulin

Introduction: Diabetes mellitus possesses severe adverse effects on the urinary bladder. Urinary bladder dysfunction is a common health problem affecting diabetic patients causing recurrent infections and urinary incontinence. Objective: To evaluate the histopathological changes in the tissue of urinary bladder in Streptozotocin (STZ) diabetic rats and the protective role of insulin. Methods: Thirty rats were classified into three groups: a control group which received no treatment (Group A), STZ diabetic group (Group B) and Insulin diabetic group (Group C). Animals were sacrificed after six weeks and urinary bladders were harvested and processed for light and electron microscopy. Results: Several histopathological changes were observed in the urinary bladder of the diabetic group including an increase in the thickness of the urothelium, epithelial cells with dark nuclei and large lenticular vesicles, and wide intercellular spaces with numerous collagen fibers. Treatment with insulin reduced the pathological changes induced by STZ. Conclusion: Diabetes mellitus caused significant pathological changes in the urinary bladder of experimental rats. For instance, treating diabetic animals with insulin prevented the development of damaging effects of diabetes on the urinary bladder.

Anti-inflammatory effects of C-peptide on kidney of type 1 diabetes mellitus animal model.

Type 1 diabetes mellitus (T1DM) is characterized by C-peptide deficiency and elevated levels of pro-inflammatory cytokines. The aim of this study was to investigate the role of C-peptide in renal and inflammatory complications in streptozotocin (STZ)-diabetic mice model of T1DM with kidney disease. The study was performed in 8-week old male C57BL/6 mice. Two streptozotocin-diabetic groups (a T1DM animal model), after 4weeks of diabetes, were treated with subcutaneous infusion of either vehicle (n = 12) or C-peptide (n = 11). Two non-diabetic groups (vehicle, n = 10; C-peptide, n = 9) were treated using the same protocol as described for the diabetic mice. The treatment with C-peptide in the diabetic group reduced the urinary levels of IL17 and TNFα, as well as IL4 and IL10 (p < 0.05). Contrary, the diabetic + C-peptide group presented higher IL10 gene expression in kidney. Besides, it displayed a reduction of TNFα gene expression. The data suggest that C-peptide may modulate pro- and anti-inflammatory signalling pathways, resulting in attenuation of kidney inflammation in T1DM animal model.

Effect of Lippia alba essential oil administration on obesity and T2DM markers in Wistar rats

Introduction: Lippia alba (Mill) N.E. Brown (Verbenaceae) is an aromatic plant from Central America, South America, and the Caribbean, it is traditionally used by the Colombian population to treat various diseases such as diabetes and hypertension. The purpose of this research was to evaluate the metabolic effects of Lippia alba essential oil (EO) oral administration on obesity and diabetes markers in Wistar rats. Methods: control and Streptozotocin (STZ) diabetes induced rats were used to evaluate the EO metabolic effects. Glucose and triglycerides were measured using commercial colorimetric kits, the animals’ weight was followed for 21 days treatment and TNF- and adiponectin concentration was determined with ELISA technique. Results: The consumption of EO shows body weight gain regulation, lower glucose and cholesterol levels in normal rats and lower TNF- in comparison with the Glibenclamide treated rats between the STZ diabetic groups. No toxic effects were founded. Conclusions: The EO exerts a benefical metabolic effect in rats, therefore it is interesting to be evaluate a future in human beings with T2DM or overweight.

Antioxidative Activities of Sanguisorba officinalis L. in Diabetic Rats

Background: Sanguisorba officinalis has been used in traditional Asian medicine owing to its beneficial effects on various diseases. The purpose of this study was to evaluate the effect of S. officinalis on the antioxidant system of Streptozotocin (STZ) and Alloxan (ALL) induced diabetic rats. Methods and Results: Triglyceride and Low-Density Lipoprotein (LDL)-cholesterol levels decreased in the STZ-induced diabetic groups treated with S. officinalis extract (SOE) compared to the corresponding levels in the control groups. Moreover, in the ALLinduced diabetic groups, SOE reduced triglyceride, LDL-cholesterol, and High-Density Lipoprotein (HDL)-cholesterol levels. Malondialdehyde (MDA) levels decreased significantly in the STZ and ALL-induced groups treated with SOE compared to the corresponding levels in the control group. Further, Glutathione (GSH) levels increased but did not reach statistical significance. The levels of Superoxide Dismutase (SOD) and Glutathione-S-Transferase (GST) showed a tendency to recover with SOE treatment in the STZ and ALL-induced diabetic groups. In addition, Catalase (CAT) levels in the SOE treatment group decreased significantly compared to those in the control group. Conclusions: These results suggest that SOE might be an effective agent in attenuating oxidative stress in diabetic patients by improving blood lipid profiles and inducing the anti-oxidative enzyme systems.

MP86-03 THE INFLUENCE OF MACA (LEPIDIUM MEYENII) ON THE GLUCOSE METABOLISM AND ERECTILE FUNCTION IN TYPE 1 DIABETIC RATS

You have accessJournal of UrologySexual Function/Dysfunction: Basic Research & Pathophysiology I1 Apr 2016MP86-03 THE INFLUENCE OF MACA (LEPIDIUM MEYENII) ON THE GLUCOSE METABOLISM AND ERECTILE FUNCTION IN TYPE 1 DIABETIC RATS Masaki Kimura, Amr Abdelhamed, Takahiro Noguchi, Takeshi Ashizawa, Hisashi Hirano, Hiroki Koyasu, Kazutaka Terai, Keisuke Saito, Hisamitsu Ide, Satoru Muto, Raizo Yamaguchi, and Shigeo Horie Masaki KimuraMasaki Kimura More articles by this author , Amr AbdelhamedAmr Abdelhamed More articles by this author , Takahiro NoguchiTakahiro Noguchi More articles by this author , Takeshi AshizawaTakeshi Ashizawa More articles by this author , Hisashi HiranoHisashi Hirano More articles by this author , Hiroki KoyasuHiroki Koyasu More articles by this author , Kazutaka TeraiKazutaka Terai More articles by this author , Keisuke SaitoKeisuke Saito More articles by this author , Hisamitsu IdeHisamitsu Ide More articles by this author , Satoru MutoSatoru Muto More articles by this author , Raizo YamaguchiRaizo Yamaguchi More articles by this author , and Shigeo HorieShigeo Horie More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2311AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Maca (Lepidium meyenii) is widely dispersed plant on high plateaus of the Andean mountain range in Peru. Maca is also known for its supportive effects on fertility and increase of libido. However, the influence of Maca on erectile dysfunction (ED) has not been fully investigated in diabetic rats. In the present study, we aim to investigate the influence of Maca on the Glucose metabolism and erectile function using streptozotocin (STZ)-induced type 1 diabetic rat. METHODS 40 adult male rats (8 weeks age) were divided into five groups, including control, STZ diabetic, STZ with Tadalafil, STZ with Maca, and STZ with Maca/Tadalafil. Diabetes was induced by a single intra-peritoneal injection of STZ in 0.1 citrate buffer (pH4.5) in a dose of 60mg/kg. Rats with blood glucose =200mg/dl were considered diabetic. STZ rats received daily Maca of 100mg/kg and/or Tadalafil of 1mg/kg for 8 weeks. Body weight and blood glucose level were measured at baseline and 8 weeks after treatment. Intracavernous pressure (ICP) measurements with cavernous nerve electrical stimulation were conducted after 8 weeks of treatment. We investigated the results of ICP/ mean arterial pressure (MAP) ratios for each rat. One way ANOVA test was used to test significance among the study groups. Each group contained 6 to 8 rats. RESULTS The body weight and blood glucose of STZ with Maca and STZ with Maca/Tadalafil groups were significantly decreased in comparison to STZ (P<0.001), and STZ with Tadalafil groups (P<0.001). In the STZ with Maca group, a significant increase in ICP/MAP was observed compared with STZ diabetic group (P<0.001). Similarly, In the STZ with Maca/Tadalafil group, a significant increase in ICP/MAP was observed compared with STZ diabetic group (P<0.001) and STZ with Tadalafil group (P=0.010). CONCLUSIONS Current data showed improvement of glucose metabolism and erectile function after 8 weeks of Maca treatment in STZ induced diabetic rats. Furthermore, synergetic effects of Maca along with PDE5 inhibitor administration were observed. Although more detailed mechanisms are needed to be elucidated, these findings suggest that Maca may exert beneficial effects for glucose tolerance and erectile dysfunction in diabetic patients. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e1107 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Masaki Kimura More articles by this author Amr Abdelhamed More articles by this author Takahiro Noguchi More articles by this author Takeshi Ashizawa More articles by this author Hisashi Hirano More articles by this author Hiroki Koyasu More articles by this author Kazutaka Terai More articles by this author Keisuke Saito More articles by this author Hisamitsu Ide More articles by this author Satoru Muto More articles by this author Raizo Yamaguchi More articles by this author Shigeo Horie More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Modulation of glucose metabolism by balanced deep-sea water ameliorates hyperglycemia and pancreatic function in streptozotocin-induced diabetic mice.

The aim of this study was to determine the effects of balanced deep-sea water (BDSW) on hyperglycemia and glucose intolerance in streptozotocin (STZ)-induced diabetic mice. BDSW was prepared by mixing DSW mineral extracts and desalinated water to yield a final hardness of 1000–4000 ppm. Male ICR mice were assigned to 6 groups; mice in each group were given tap water (normal and STZ diabetic groups) or STZ with BDSW of varying hardness (0, 1000, 2000, and 4000 ppm) for 4 weeks. The STZ with BDSW group exhibited lowered fasting plasma glucose levels than the STZ-induced diabetic group. Oral glucose tolerance tests showed that BDSW improves impaired glucose tolerance in STZ-induced diabetic mice. Histopathological evaluation of the pancreas showed that BDSW restores the morphology of the pancreatic islets of Langerhans and increases the secretion of insulin in STZ-induced diabetic mice. Quantitative real-time PCR assay revealed that the expression of hepatic genes involved in gluconeogenesis, glucose oxidation, and glycogenolysis was suppressed, while the expression of the genes involved in glucose uptake, β-oxidation, and glucose oxidation in muscle were increased in the STZ with BDSW group. BDSW stimulated PI3-K, AMPK, and mTOR pathway-mediated glucose uptake in C2C12 myotubes. BDSW increased AMPK phosphorylation in C2C12 myotubes and improved impaired AMPK phosphorylation in the muscles of STZ-induced diabetic mice. Taken together, these results suggest that BDSW is a potential anti-diabetic agent, owing to its ability to suppress hyperglycemia and improve glucose intolerance by modulating glucose metabolism, recovering pancreatic islets of Langerhans and increasing glucose uptake.

Role of hydrogen sulfide in the pain processing of non-diabetic and diabetic rats

Hydrogen sulfide (H2S) is a gasotransmitter endogenously generated from the metabolism of l-cysteine by action of two main enzymes called cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE). This gas has been involved in the pain processing and insulin resistance produced during diabetes development. However, there is no evidence about its participation in the peripheral neuropathy induced by this metabolic disorder. Experimental diabetes was induced by streptozotocin (50mg/kg, i.p.) in female Wistar rats. Streptozotocin injection increased formalin-evoked flinching in diabetic rats as compared to non-diabetic rats after 2weeks. Peripheral administration of NaHS (an exogenous donor of H2S) and l-cysteine (an endogenous donor of H2S) dose-dependently increased flinching behavior in diabetic and non-diabetic rats.Contrariwise, hydroxylamine (HA, a CBS inhibitor) and dl-propargylglycine (PPG, a CSE inhibitor) decreased formalin-induced nociceptive behavior in both experimental groups. In addition, an ineffective dose of HA and PPG partially prevented the l-cysteine-induced hyperalgesia in diabetic and non-diabetic rats. Interestingly, HA and PPG were three order of magnitude more potent in diabetic rats respect to non-diabetic rats, whereas NaHS was ten times more potent in the streptozotocin-diabetic group. Nine to 11weeks after diabetes induction, tactile allodynia was observed in the streptozotocin-injected rats. On this condition, subcutaneous administration of PPG or HA reduced tactile allodynia in diabetic rats. Paradoxically, H2S levels were decreased in nerve sciatic, dorsal root ganglion and spinal cord, but not paw nor blood plasma, during diabetes-associated peripheral neuropathy development. Collectively, results suggest that H2S synthesized by CBS and CSE participate in formalin-induced nociception in diabetic and non-diabetic rats, as well as; in tactile allodynia in streptozotocin-injected rats. In addition, data seems to indicate that diabetic rats are more sensible to H2S-induced hyperalgesia than normoglycemic rats.

Impaired heme oxygenase‐1 induction in the gastric antrum induces disruption of the interstitial cells of Cajal network in a rat model of streptozotocin‐induced diabetes

Streptozotocin (STZ) is known to induce type I diabetes and the loss of the interstitial cells of Cajal (ICC). However, the regulation of heme oxygenase-1 (HO-1) expression, which is reported to protect ICC, has not yet been elucidated in this model. The aim of this study was to investigate the alterations of HO-1 expression and clarify the mechanism of ICC loss in the stomach using the rat model of STZ-induced diabetes. Streptozotocin (65mgkg(-1) ) was intraperitoneally administered to 8-week-old female Wistar rats. Cobalt protoporphyrin (CoPP), an HO-1 inducer, was administered subcutaneously once a week after the STZ injection. The expressions of HO-1 and the receptor tyrosine kinase c-Kit (a marker for ICC) proteins were investigated by western blot analysis and immunofluorescence staining. Expression of c-Kit, particularly in the gastric antrum, was significantly decreased at 8weeks, not at 1week, compared to those of the control group. Significantly increased induction of HO-1 expression, especially in the gastric corpus but not in the antrum, was observed in the STZ group at 8weeks after the STZ injection relative to control. CoPP administration significantly up-regulated HO-1 expression in the STZ diabetic group and significantly restored the previously reduced ICC in the gastric antrum. Up-regulation of HO-1 expression in the STZ diabetic model was limited to the gastric corpus and impaired up-regulation of HO-1 expression in the gastric antrum likely induced the disruption of the ICC network.

Effect of streptozotocin induced diabetes on rat hippocampus

The present study was designed to evaluate the diabetes induced neuronal damage in the hippocampus of the rat brain. Diabetes mellitus is an endocrine metabolic disorder of impaired carbohydrate, fat and protein metabolisms characterized by chronic hyperglycemia. The neurological consequences of diabetes mellitus in the brain have gained attention most recently. Male albino rats of Wistar strain, aged 30 days were used. The rats were divided into (A) Normal Control (B) Vehicle Control (C) 15 days of Streptozotocin (STZ), (D) 30 days of STZ, (E) 45 days of STZ, (F) 60 days of STZ diabetic groups (n = 6 in each group). Blood glucose levels and body weight were measured before STZ injection, 2 days after STZ injection and on the day of sacrifice. At the end of the experimental period rats were scarified and brains were processed for cresyl violet staining and the number of survived neurons in the hippocampus was quantified. Microscopic examination of cresyl violet stained sections of diabetic rat hippocampus showed significant and reliable changes. There was a significant difference in the number of survived neurons especially in 30 days of STZ, 45 days of STZ and 60 days of STZ diabetic groups compared to normal control group. The results of our study indicated that diabetic complications can cause rapid damage to the neurons in the hippocampus (Fig. 12, Ref. 22).

Comparison of streptozotocin-induced diabetic and insulin resistant effects on spermatogenesis with proliferating cell nuclear antigen (PCNA) immunostaining of adult rat testis

Male reproductive function is one of the mammalian systems that are impaired by diabetes mellitus and on the average, it will affect many more men prior to and during their reproductive years. The present study aimed to compare proliferating cell nuclear antigen (PCNA) immunostaining effects at stage VII of the spermatogenic cycle in streptozotocin-induced and insulin resistant diabetic rat testis. Male adult Sprague-Dawley rats (120-140 g) were randomly divided into 3 groups. Group 1: control group; fed on normal rat pellets. Group 2: streptozotocin diabetic group; received a single dose IP injection of streptozotocin 45 mg/kg BW in Na+ citrate buffer pH 4.5. Group 3: insulin resistant diabetic group; fed ad libitum on a special diet containing 25% fructose W/W. Following hyperglycaemia confirmation, animals were perfused with 4% Paraformaldehyde (PFA). Testes were isolated, and fixed in 4% PFA overnight, embedded in paraffin, 5μm thick sections were made and mounted on poly-L-lysine coated slides. Immunohistochemical staining was carried out on the positively charged slides using the PCNA as primary antibody.The results of this study showed that diabetes mellitus induced by streptozotocin injection and chronic fructose consumption through insulin resistance significantly (P<0.05) reduced PCNA index, mean seminiferous tubular diameter and testicular diameter. It could also be inferred from the results that diabetes mellitus and insulin resistance may necessarily not impair differentiation of primordial germ cells (gonocytes) into Type A and Type B spermatogonia. J. Exp. Clin. Med., 2012; 29:209-214

Comparison between the effect of glibenclamide and captopril on experimentally induced diabetic nephropathy in rats

This study aimed to elucidate the role of glibenclamide in the prevention of diabetic nephropathy and to compare it with a reference drug captopril in rats. There were two main groups of rats. Control group (I) was subdivided into four subgroups which received distilled water, vehicle of streptozotocin, glibenclamide or captopril. The streptozotocin-diabetic Group (II) was subdivided into three subgroups: untreated, glibenclamide or captopril treated. Measurement of arterial blood pressure, serum glucose and creatinine levels, 24 h urinary protein and albumin/creatinine ratio, kidney weight and its histological examination were done after 1, 2, 4, 8, 12 and 16 weeks of treatment. In treated diabetic rats captopril reduced blood pressure significantly, while no significant change in the mean arterial blood pressure or blood glucose level was recorded with glibenclamide treatment. Glibenclamide and captopril-treated diabetic rats showed significant decrease in serum creatinine level, urine volume, urinary protein excretion, albumin:creatinine ratio and kidney:body weight ratio compared with the diabetic non-treated group. Histological examination of diabetic kidneys treated with either glibenclamide or captopril showed reduced glomerular hypertrophy, glomerulosclerosis, tubular degeneration and interstitial fibrosis compared with untreated diabetic rats. Glibenclamide attenuated some biochemical and histological changes produced by diabetic nephropathy, despite persistent hyperglycemia and hypertension.

The Effects of Combined Treatment of Antioxidants on the Liver Injury in STZ Diabetic Rats

The aim of this study was to examine whether an antioxidant combination of vitamin C, vitamin E, and sodium selenate (Se) has an effect on the liver of diabetic rats. Vitamin C, vitamin E, and Se were administered for 30 days to streptozotocin (STZ)-induced diabetic and control groups. In the STZ diabetic group, blood glucose levels, liver lipid peroxidation (LPO), and nonenzymatic glycosylation (NEG) levels increased, but blood and liver glutathione levels decreased. On the other hand, combined antioxidant treatment reversed these effects. In the diabetic group, some degenerative changes were observed by light and electron microscopic examinations, but the degenerative changes decreased in the diabetic group given antioxidant combination. Proliferating cell nuclear antigen (PCNA) immunohistochemistry showed that the number of proliferative hepatocytes increased significantly with antioxidant treatment. It was concluded that combined treatment with vitamin C, vitamin E, and Se has a curative effect against the hepatotoxicity produced by STZ-induced diabetes.

Effect of oral administration of diphenyl diselenide on antioxidant status, and activity of delta aminolevulinic acid dehydratase and isoforms of lactate dehydrogenase, in streptozotocin-induced diabetic rats

Male albino rats with diabetes induced by the administration of streptozotocin (STZ) (45 mg/kg, i.v.) were treated with oral administration of diphenyl diselenide (DPDS) pre-dissolved in soya bean oil. A significant reduction in blood glucose levels was observed in STZ-induced diabetic rats treated with DPDS compared with an untreated STZ diabetic group. The pharmacological effect of DPDS was accompanied by a marked reduction in the level of glycated proteins, and restoration of the observed decreased levels of vitamin C and reduced glutathione (GSH; in liver and kidney tissues) of STZ-treated rats. DPDS also caused a marked reduction in the high levels of thiobarbituric acid reactive substances (TBARS) observed in STZ-induced diabetic group. Finally, the inhibition of catalase, delta aminolevulinic acid dehydratase (eth-ALA-D) and isoforms of lactate dehydrogenase (LDH) accompanied by hyperglycemia were prevented by DPDS in all tissues examined. Hence, in comparison with our earlier report, the present findings suggests that, irrespective of the route of administration and the delivery vehicle, DPDS can be considered as an anti-diabetic agent due to its anti-hyperglycemic and antioxidant properties.

Diabetes-related changes in cAMP-dependent protein kinase activity and decrease in relaxation response in rat mesenteric artery

Using superior mesenteric artery rings isolated from age-matched controls and streptozotocin (STZ)-induced diabetic rats, we recently demonstrated that EDHF-type relaxation is impaired in STZ-induced diabetic rats, possibly due to a reduced action of cAMP via increased phosphodiesterase (PDE) activity (Matsumoto T, Kobayashi T, and Kamata K. Am J Physiol Heart Circ Physiol 285: H283-H291, 2003). Here, we investigated the activity and expression of cAMP-dependent protein kinase (PKA), an enzyme that is produced by a pleiotropic and plays key roles in the transduction of many external signals through the cAMP second messenger pathway and in cAMP-mediated vasorelaxation. The relaxation induced by cilostamide, a selective PDE3 inhibitor, was significantly weaker in superior mesenteric artery rings from STZ-induced diabetic rats than in those from age-matched controls. The relaxation responses to 8-bromo-cAMP (8Br-cAMP) and N6,O2-dibutyryl-adenosine-cAMP (db-cAMP), a cell-permeant cAMP analog, were also impaired in the STZ diabetic group. PKA activity in the db-cAMP-treated mesenteric artery was significantly lower in the STZ diabetic group. The expression levels of the mRNA and protein for PKA catalytic subunit Cat-alpha were significantly decreased in the STZ diabetic group, but those for PKA regulatory subunit isoform RII-beta were increased. We conclude that the abnormal vascular relaxation responsiveness seen in STZ-induced diabetic rats may be attributable not only to increased PDE activity but also to decreased PKA activity. Possibly, the decreased PKA activity may result from an imbalance between PKA catalytic and regulatory subunit expressions.

Distal tubule bicarbonate reabsorption in intact and remnant diabetic kidneys

In the diabetic patient, hyperkalemia and hyperchloremic metabolic acidosis has been attributed to one or more of the following factors associated with diabetic nephropathy: hypoaldosteronism, altered potassium homeostasis, or a distal tubular (DT) defect in hydrogen ion secretion. To evaluate maximal in vivo DT acidification in streptozotocin (STZ) diabetes, unidirectional bicarbonate reabsorption (JHCO3) was measured in DTs after acid loading and in surviving DT after 2/3 nephrectomy (Nx). Acid gavage induced hyperchloremic metabolic acidosis in four groups of rats: diabetic rats with hyperglycemia two (a) and (b) eight weeks after STZ injection, (c) diabetic rats with tight glucose control two weeks after STZ injection and insulin pump implantation; and (d) control nondiabetic rats. Another group of diabetic rats underwent (e) Nx one week after STZ injection; these rats were neither acid loaded nor pump implanted. In the acidotic rats, the plasma potassium concentration, the plasma and urine acid-base parameters in the three STZ diabetic groups was not different from control rats, whereas JHCO3 fluxes were brisk without important differences between groups. In Nx rats, although the plasma potassium concentration and acid-base status were normal, surviving JHCO3 fluxes were still brisk and not different from the acid-loaded rats. These in vivo measurements indicate there is no impairment in DT unidirectional bicarbonate reabsorption in the intact or remnant STZ diabetic kidney.

Dietary xylitol supplementation prevents osteoporotic changes in streptozotocin-diabetic rats

The effects of 10% and 20% dietary xylitol supplementation on the biomechanical properties, trabeculation, and mineral content of long bones were studied in streptozotocin-diabetic rats. Forty 3-month-old male Wistar rats were divided randomly into four groups of 10. Rats in three groups were administered a single injection of streptozotocin (50 mg/kg body weight) to induce type I diabetes, while animals in the fourth group were given a sham injection of physiological saline. The sham-injected group and one of the streptozotocin-diabetic groups were fed the basal diet, while the two diabetic groups were fed the same diet supplemented with 10% and 20% xylitol ( wt wt ). After 3 months, the rats were killed and the long bones were prepared for analysis. The 10% and 20% dietary xylitol supplementation significantly prevented the type I diabetes-induced decrease in the mechanical stress resistance of the tibia in the three-point bending test, the shear stress of the femur in the torsion test, and the stress resistance of the femoral neck in the loading test. No statistically significant differences were found between any groups in the values for strain or Young's modulus in the three-point bending test, or in the values for the shear modulus of elasticity in the torsion test. These findings indicate that dietary xylitol protects against the weakening of the bone strength properties of both cortical and trabecular bone without affecting the elastic-plastic properties. Supplementation with 10% and 20% dietary xylitol significantly prevented the type I diabetes—induced decrease of humeral ash weight and tibial density. Histomorphometric data for the secondary spongiosa of the proximal tibia showed that 10% and 20% dietary xylitol supplementation also significantly prevented the type I diabetes—induced loss of trabecular bone volume. In conclusion, dietary xylitol supplementation protects against the weakening of bone biomechanical properties in streptozotocin-diabetic rats. This is related to the preserved bone mineral content and preserved trabecular bone volume.

Variable effect of streptozotocin-diabetes on the growth of hamster pancreatic cancer (H2T) in the Syrian hamster and nude mouse

Background: Streptozotocin-diabetes prevents induction of pancreatic tumors in several animal models and inhibits the growth of established human pancreatic cancer implants in nude mice. However, it also promotes growth of the hamster pancreatic cancer cell line, H2T, in the Syrian hamster. To test the hypothesis that these contradictory effects are due to tumor host differences, the growth of the H2T cell line was examined in the streptozotocin-diabetic nude mouse. Methods: H2T cells were implanted subcutaneously into streptozotocin-diabetic nude mice ( n = 10) and untreated control mice ( n = 10). After 21 days, tumors were excised and weighed. Plasma insulin and somatostatin were determined by radioimmunoassay. Results: After 3 weeks, tumors in the control group weighed 118 mg and tumors in the diabetic group weighed 28 mg ( p < 0.001). Plasma insulin was significantly decreased in the streptozotocin-treated animals compared with control animals (insulin, 23 μ U/ml vs 31 μ U/ml; p < 0.001). In contrast, somatostatin was significantly elevated in the streptozotocin-diabetic group compared with the control group (somatostatin, 179 pg/ml versus 54 pg/ml, p <0.001). Competitive binding studies revealed specific cell surface receptors for insulin (K d, 15.5 nmol/L), and somatostatin (K d, 2.5 nmol/L) on the H2T cells. In an in vitro cell proliferation assay, cell division was promoted by insulin ( p < 0.01, maximum +11%) and inhibited by somatostatin ( p < 0.01, maximum –18%). Conclusions: The variable effect of streptozotocin-diabetes on pancreatic cancer growth is due to differences in the tumor host. The growth of pancreatic cancer, particularly in streptozotocin-diabetic nude mice, may be influenced by gut peptides in a receptor-dependent fashion.(Surgery 1998;123:315-20.)

GI Hormonal Changes in Diabetes Influence Pancreatic Cancer Growth

Streptozotocin diabetes prevents induction of pancreatic tumors in several animal models, suggesting a pivotal role for islet cell products in the pathogenesis of pancreatic cancer. To test the hypothesis that altered gastrointestinal peptide levels in streptozotocin diabetes influence tumor growth, human pancreatic cancer cells (MIA PaCa-2) were implanted subcutaneously into streptozotocin diabetic nude mice. After 3 weeks, tumors in the control group weighed 43 mg and tumors in the diabetic group weighed 12 mg ( P < 0.001). Plasma insulin and IGF-1 levels were significantly decreased in the streptozotocin-treated animals compared to those of control (insulin: 23 μU/ml vs 31 μU/ml, P < 0.001; IGF-1: 254 ng/ml vs 324 ng/ml, P < 0.001). In contrast, somatostatin and glucagon were significantly elevated in the streptozotocin diabetic group relative to control levels (somatostatin: 179 pg/ml vs 54 pg/ml, P < 0.001; glucagon: 290 pg/ml vs 134 pg/ml, P < 0.001). Competitive binding studies revealed specific cell surface receptors for insulin ( K d = 15.5 n M), IGF-1 ( K d = 30.0 n M), and somatostatin ( K d = 2.5 n M) on the MIA PaCa-2 cells. Receptors for glucagon were absent. In an in vitro cell proliferation assay, cell division was promoted by insulin ( P < 0.01, max + 11%) and IGF-1 ( P < 0.01, max +10%). Somatostatin inhibited cell division ( P < 0.01, max - 18%). No effect was seen with glucagon. The growth of pancreatic cancer, particularly in diabetes, may be influenced by gut peptides in a receptor-dependent fashion.