Streptozocin-induced Diabetes Mellitus Research Articles

L-Lysine Ameliorates Diabetic Nephropathy in Rats with Streptozotocin-Induced Diabetes Mellitus.

Introduction Diabetic nephropathy is one of the leading causes of end-stage renal disease worldwide. Uncontrolled hyperglycemia and subsequent production of glycation end-products activate the paths which lead to diabetic nephropathy. The aim of this study was to assess the effects of L-lysine on antioxidant capacity, biochemical factors, kidney function, HSP70 level, and the expression of the TGFβ, VEGF, and RAGE genes in rats with streptozocin-induced diabetes mellitus. Methods Thirty-two male Wistar rats were randomly allocated to four eight-rat groups, namely, a healthy group, a diabetic group treated with vehicle (DM + vehicle), a diabetic group treated with L-lysine (DM + Lys), and a healthy group treated with L-lysine (healthy + Lys). Rats in the DM + Lys and the healthy + Lys groups were treated with L-lysine 0.15%. The levels of fasting blood glucose, insulin, HbA1C, advanced glycation end-products (AGEs), lipid profile, serum creatinine, blood urea nitrogen, glomerular filtration rate, urine microalbumin, oxidative stress parameters, kidney histology and morphology, and TGFβ, VEGF, and RAGE gene expressions were assessed. Findings. An eight-week treatment with L-lysine significantly reduced the levels of fasting blood glucose, AGEs, kidney function parameters, oxidative stress parameters, lipid profile, and the TGFβ, VEGF, and RAGE gene expression and significantly increased the levels of serum insulin and tissue HSP70. Conclusion Treatment with L-lysine seems to slow down the progression of diabetic nephropathy.

Effect of green tea on pancreas of streptozocin induced diabetes mellitus in adult albino rats (Electron microscopic study)

Effect of green tea on pancreas of streptozocin induced diabetes mellitus in adult albino rats (Electron microscopic study)

Saxagliptin protects against diabetic nephropathy by inhibiting caspase 3/PARP-1-dependent nephrocyte apoptosis.

Saxagliptin (SAX) can protect against tissue damage caused by diabetic nephropathy. However, whether this compound can restore kidney function, and its specific mechanism of action remain unclear. The present study explored the therapeutic effects and mechanisms of SAX. Male Wistar rats (8 weeks old) were randomly divided into the following groups: A control group (n=10); a group with streptozocin-induced diabetes mellitus (DM) treated with saline (n=20); and a group with streptozocin-induced DM treated with SAX (n=20). Following 20 weeks of treatment, renal function and the extent of renal damage were assessed based on histological staining using hematoxylin and eosin, periodic acid-Schiff and Masson's trichrome staining. The experimental results indicated that Streptozocin induction of DM led to thicker basement membranes in mesangial cells and a more abundant extracellular matrix. These changes were ameliorated following treatment with SAX. The data demonstrated that renal tissue and renal cell apoptosis were ameliorated significantly following treatment with SAX. Furthermore, the expression levels of the apoptotic genes poly (ADP-ribose) polymerase-1 (PARP-1) and caspase 3 were significantly decreased following treatment with SAX. Therefore, SAX may reduce the extent of renal apoptosis and pathological outcomes in diabetic nephropathy by downregulating the expression of caspase 3 and PARP-1 in the death receptor pathway of apoptosis.

Mixture of leaf and flower extract of Prunus spinosa L. alleviates hyperglycemia and oxidative stress in streptozotocin-induced diabetic rats

Diabetes Mellitus is a global health problem that leads to various complications associated with hyperglycemia. In traditional medicine, herbal treatment is one of the alternative ways to cope with this type of disease. The aim of this study is to investigate the antidiabetic and hepato-pancreatic protective effects of the mixture of Prunus spinosa leaves and flowers (PSE) extract in streptozocin-induced diabetes mellitus. Seven random experimental groups of Wistar rats (n = 8) were created as followed; control, diabetic, PSE25, PSE50, insulin, metformin, and acarbose. α-amylase and α-glucosidase inhibitory activities of PSE were determined. Antioxidant enzymes activities and lipid peroxidation were analyzed in the liver tissue. Histopathological examination of liver and pancreas was also performed. α-amylase and α-glucosidase IC50 inhibition values of PSE were found more efficient, comparing to those of standard acarbose. While blood glucose levels severely increased in all diabetic groups, PSE25 and PSE50 treatments were effective in regulating blood glucose levels. Moreover, administration of PSE25 and PSE50 improved insulin levels compared to the diabetic group. Although increased oxidative stress in the diabetes seriously suppressed antioxidant activities, PSE25 and PSE50 supplementation significantly recuperated liver antioxidant capacity. Despite severe degenerative and necrotic changes in diabetes, these findings alleviated with PSE administrations. Moreover, PSE treatments remarkably recuperated β-cells. These results reveal that there may be an alternative way to control high blood glucose levels, which is one of the most important complications of diabetes. Furthermore, PSE can provide a protection against oxidative stress, liver and pancreatic damage by augmenting antioxidant capacity in diabetes.

Effect of Photomodulation Therapy on Development of Oxidative Stress in Blood Leukocytes of Rats with Streptozocin-Induced Diabetes Mellitus

Abstract—Oxidative stress is among the main causes of developing severe complications in diabetes mellitus (DM). Existing pharmaceuticals, although efficient in reducing the blood glucose level, infrequently demonstrate antioxidant properties. On the other hand, there are many reliable reports about a broad range of biological activity exhibited by photobiomodulation therapy (PBMT). Its potential sugar-lowering and antioxidant action makes this type of therapy a promising option for the treatment of DM and its complications. The effect of PBMT on the state of the antioxidant defense system in blood leukocytes was investigated in rats with streprozocin-induced DM. This study has shown that the PBMT increased superoxide dismutase (SOD) activity in rats with DM and normalized the content of oxidative stress markers (thiobarbituric acid (TBA)-active products, oxidatively modified proteins, and protein glycation end products).

Metformin inhibited Nod-like receptor protein 3 inflammasomes activation and suppressed diabetes-accelerated atherosclerosis in apoE−/− mice

AimsThe present study aimed to investigate the effect of metformin on diabetes-accelerated atherosclerosis and whether Nod-like receptor protein 3 (NLRP3) inflammasome is a target for metformin. Materials and methodsApoE−/− male mice were divided randomly into control, streptozocin-induced diabetes mellitus and metformin groups. Metabolic parameters, atherosclerotic lesion, activation of NLRP3 inflammasomes and related signaling pathways were detected. THP-1-differentiated macrophages were used in in vitro experiments. ResultsCompared with control mice, increased plasma lipids and proinflammatory interleukin-1β, aggravated macrophage infiltration into the atherosclerotic lesion, and accelerated development of atherosclerosis were observed in diabetic mice, which were associated with the activation of NLRP3 inflammasomes and dysregulation of thioredoxin-1 and thioredoxin-interacting protein. Treatment with metformin alleviated diabetes-induced metabolic disorders and atherosclerosis, as well as NLRP3 inflammasomes activation and dysregulation of thioredoxin-1/thioredoxin-interacting protein. In vitro experiments showed that high glucose induced the accumulation of reactive oxygen species and activated NLRP3 inflammasomes, which was significantly suppressed by treatment with metformin or antioxidant N-acetyl-L-cysteine. Moreover, Compound C, an inhibitor of adenosine 5′-monophosphate-activated protein kinase (AMPK), blocked the anti-inflammatory effect of metformin, indicating that metformin inhibited high glucose-induced NLRP3 inflammasomes activation through AMPK activation. Moreover, high glucose decreased thioredoxin-1 expression and increased thioredoxin-interacting protein expression, which was also reversed by metformin. ConclusionsMetformin inhibited NLRP3 inflammasomes activation and suppressed diabetes-accelerated atherosclerosis in apoE−/− mice, which at least partially through activation of AMPK and regulation of thioredoxin-1/thioredoxin-interacting protein.

CCR2 upregulation in DRG neurons plays a crucial role in gastric hyperalgesia associated with diabetic gastropathy.

BackgroundDiabetic gastropathy is a complex neuromuscular dysfunction of the stomach that commonly occurs in diabetes mellitus. Diabetic patients often present with upper gastrointestinal symptoms, such as epigastric discomfort or pain. The aim of this study was to assess gastric sensation in streptozocin-induced diabetes mellitus (DM) rats and to determine the contribution of C-C motif chemokine receptor 2 (CCR2) signaling to gastric hyperalgesia.ResultsDM rats showed signs of neuropathy (cutaneous mechanical hyperalgesia) from two weeks after streptozocin administration until the end of the experiment. Accelerated solid gastric emptying was observed at two weeks after streptozocin administration compared to the controls. Intense gastric hyperalgesia also developed in DM rats at two weeks after streptozocin administration, which was significantly reduced after intrathecal administration of the CCR2 antagonist INCB3344. Immunochemical analysis indicated that CCR2 expression was substantially upregulated in small and medium-sized dorsal root ganglia neurons of DM rats, although the protein level of monocyte chemoattractant protein-1, the preferred ligand for CCR2, was not significantly different between the control and DM groups.ConclusionsThese data suggest that CCR2 activation in nociceptive dorsal root ganglia neurons plays a role in the pathogenesis of gastric hyperalgesia associated with diabetic gastropathy and that CCR2 antagonist may be a promising treatment for therapeutic intervention.

Histological and Immunohistochemical Studies on the Effect of Streptozocin-Induced Diabetes Mellitus in Cerebellum of Adult Albino Rats

Histological and Immunohistochemical Studies on the Effect of Streptozocin-Induced Diabetes Mellitus in Cerebellum of Adult Albino Rats

Effect of Pedalium murex Dry Seed Extract on Testicular Dysfunction in Streptozocin Induced Diabetes Mellitus in Wistar Albino Rats

Introduction Diabetes mellitus is a common metabolic disorder, characterized by hyperglycemia. T2DMwhich contributes major share of total diabetic population occurs due to diminished insulin secretion or insulin resistance. There is an increasing trend of diabetic population encompassing 108 mill

Berberine protects against metformin-associated lactic acidosis in induced diabetes mellitus.

Objective(s):Causality of occurrence of metformin-associated lactic acidosis (MALA) is a clinical problem. Currently, there is no drug available to prevent MALA. The present study was conducted to evaluate the protective effect of Berberine (BBR) against MALA in induced diabetic rat model.Materials and Methods:A sample of 75 healthy male Wistar rats was randomly selected according to inclusion and exclusion criteria. 75 male Wistar rats were randomly divided into a control and 4 experimental groups. Streptozotocin (STZ) in citrate buffer (pH 4.5) at a dose of 45 mg/kg was injected for induction of diabetes mellitus and rats achieving fasting blood glucose >250 mg/dl were included. Blood samples were collected 18 hr after the last dose of metformin and berberine. Ethical approval was taken before the study was conducted. Staistix 10.0 (USA) software was used for data analysis.Results:Berberine decreased MALA. Metformin, metformin + BBR 50 mg/kg bwt, and metformin + BBR 100 mg/kg bwt showed serum lactate as 1.87±0.4 mmol/lL, 1.62 ± 0.44 mmol/l and 1.47± 0.45 mmol/l, respectively (P=0.0001). Insulin resistance and liver enzymes were improved in BBR treated rats.Conclusion:The present study reports berberine protects against MALA in streptozocin-induced diabetes mellitus.

Comparative Effects of Quail Eggs, Quail Eggs/Vit C and Glibenclamide on Streptozocin-induced Diabetes mellitus

In recent years, quail eggs have become a subject of interest because of its properties and medical benefits. In this study, the separate and combined effects of quail eggs and vitamin C on the blood glucose level and body weight of streptozotocin-induced diabetic rats were investigated. The 30 wistar rats were randomly assigned into five groups; Group I (control), Group II (diabetic rats without treatment), Group III (diabetic rats treated with raw quail eggs only), Group IV (diabetic rats treated with raw quail eggs and vitamin C) and Group V (diabetic rats treated with Glibenclamide 600 µg/kg body weight). Diabetes mellitus was induced in fasted rats with a single intraperitoneal injection of streptozotocin (50 mg/kg body weight). The induced rats were then treated with the Quail eggs, Quail eggs/vit C, and Glibenclamide. At the end of the 10 days of treatment, the group treated with quail eggs and vitamin C at 0.15 ml/kg and 200 mg/kg body weight per day, respectively showed a significant (p< 0.05) hypoglycaemic effect, as the mean blood glucose level in the group decreased with an increase in the mean body weight. The group treated with Glibenclamide showed similar and stronger effect of hypoglycaemia. The group treated with quail eggs alone did not show any significant hypoglycaemic effect. Consequently, the groups treated quail eggs/vit C and Glibenclamide lost significant body weight. Quail eggs alone, quail eggs combined with vit C and Glibenclamide have hypoglycaemic effect after 10 days of administration, and could therefore be used to manage diabetes mellitus. Glibenclamide is however more potent for this purpose than quail egg/vit C, which is also more potent than quail egg alone.

Beneficial effect of PEDF-transfected ADSCs on erectile dysfunction in a streptozotocin-diabetic rat model.

Diabetes mellitus (DM) is an important risk factor for erectile dysfunction. Adipose-derived stem cells (ADSCs) are essential for maintaining erectile function but their function is impaired during hyperglycemia. To evaluate the effects of pigment epithelium-derived factor (PEDF)-transfected ADSCs on the restoration of erectile function ADSCs and PEDF-transfected ADSCs were exposed to normal or high glucose levels for 72h and the effects on cell survival and protein expression were determined. For in vivo studies, rats with streptozocin-induced DM were intravenously injected with ADSCs or PEDF-transfected ADSCs. Two weeks later, the intracavernosal pressure (ICP) and mean arterial pressure (MAP) were measured to assess erectile function, and penile tissues were harvested for further evaluation. PEDF overexpression in ADSCs protected cells against hyperglycemia-induced apoptosis (as determined by a TUNEL assay), increasing the expression of neurotrophic factors and decreasing the expression of inflammatory cytokines and oxidative stress-related proteins (as determined by western blotting and ELISA). In DM rats, transplantation with PEDF-transfected ADSCs effectively restored erectile function, as determined by the ICP/MAP ratio, compared with untreated ADSCs. PEDF overexpression also resulted in higher survival rates and decreased apoptosis of ADSCs. Promotion of neurotrophic factor expression and suppression of inflammatory cytokines and oxidative stress-related proteins were also observed after transplantation of PEDF-transfected ADSCs. Thus, our results demonstrate that transplantation of ADSCs restored erectile function in a rat model of DM, attenuating the negative effects of hyperglycemia. These findings indicate the therapeutic potential of ADSCs for treating erectile dysfunction and the additional benefits of PEDF overexpression.

Smooth muscle cell transplantation improves bladder contractile function in streptozocin-induced diabetic rats

Background aimsDamage to smooth muscle has been the primary cause of dysfunction in diabetic bladders. Major changes in the filling phase of the bladder result in the loss of compliance and incomplete emptying in patients. MethodsCell-based therapies in the lower urinary tract have shown promising results. We argue that because diabetic bladder dysfunction is primarily a problem arising out of altered smooth muscle cells (SMCs), it would be an interesting approach to introduce healthy SMCs into the bladder wall. ResultsFurthering this hypothesis, in this experiment, we were successful in introducing syngeneic, healthy SMCs into diabetic bladders. We attempted a method wherein bladder function can be improved in streptozocin-induced diabetes mellitus. Ex vivo–cultured healthy SMCs were introduced into the diabetic bladders of syngeneic Sprague-Dawley rats during the hypercontractile phase after induction of diabetes. Cystometry, metabolic cage evaluation, organ bath studies and histological analyses were performed on the healthy control, the diabetic and the diabetic group transplanted with SMCs. ConclusionsDuring the 2-week follow-up period after transplantation, we noticed an increase in contractile response of the bladder correlating to a decrease in residual urine. Cell survival studies revealed a cell survival rate close to 1.5%.

Impaired tissue regeneration corresponds with altered expression of developmental genes that persists in the metabolic memory state of diabetic zebrafish

As previously reported by our laboratory, streptozocin-induced diabetes mellitus (DM) in adult zebrafish results in an impairment of tissue regeneration as monitored by caudal fin regeneration. Following streptozocin withdrawal, a recovery phase occurs to reestablish euglycemia, via pancreatic beta-cell regeneration. However, DM-associated impaired fin regeneration continues indefinitely in the metabolic memory (MM) state, allowing for subsequent molecular analysis of the underlying mechanisms of MM. This study focuses on elucidating the molecular basis that explains the DM-associated impaired fin regeneration and why it persists into the MM state with the aim of better understanding MM. Using a combination of microarray analysis and bioinformatics approaches, our study found that of the 14,900 transcripts analyzed, aberrant expression of 71 genes relating to tissue developmental and regeneration processes were identified in DM fish and the altered expression of these 71 genes persisted in MM fish. Key regulatory genes of major development and signal transduction pathways were identified among this group of 71. The aberrant expression of key regulatory genes in the DM state that persist into the MM state provides a plausible explanation on how hyperglycemia induced impaired fin regeneration in the adult zebrafish DM/MM model.

Зміни активності NO-синтаз та оксидативних процесів при активації 5-HT-рецепторів у шлунку та товстій кишці за умов стрептозотоциніндукованого цукрового діабету

We investigated the activity of NO-synthases, lipoperoxidation processes, antioxidant defense enzymes in the muscular layers of stomach and large intestine. The L-arginine concentration in blood plasma was also monitored under conditions of 2-weeks activation of 5-HT4 receptors by mosaprid in streptozocin-induced diabetes mellitus. We showed that the onset of diabetes mellitus is accompanied by a 2.4-2.8-fold increase in the activity of inducible NO-synthase and a 23-40% increase in the SOD activity. The nitric oxide content and TBA products in the muscular layers of stomach and large intestine were increased, whereas the motor-evacuational function of the stomach and large intestine decreased. Activation of 5-HT4 receptors by mosaprid under conditions of diabetes mellitus decreased the activity of inducible NO-synthase, the lipoperoxidation processes, nitrite anion content and TBA products in muscular layers of stomach and large intestine by 23%. At the same time, we observed an increase in the motor-evacuational function of stomach and large intestine without affecting the blood sugar level.

Blood Glucose Profiles in Diabetic Rodents Using Different Insulin Preparations

The aim of the present study was to evaluate several long-acting insulin preparations for their ability to normalize the blood glucose profile of rats and mice with streptozocin-induced diabetes mellitus. The single injection of a long-acting zinc insulin (CAS 8049-62-5) suspension or insulin glargine (CAS 160337-95-1) in both species induced a steep to moderate fall in blood glucose concentration. Blood glucose was then normalized for 2-3 h, until 3 h after insulin injection blood glucose concentration tended towards levels before insulin application. In contrast, implants produced with a mixture of human insulin and palmitic acid micro-crystals normalized blood glucose profile over 24 h in both species at least 30 days after implantation. Therefore, these implants with a sustained release of insulin are suitable to control the blood glucose in diabetic rats and mice.

Effect of streptozocin-induced diabetes mellitus on expression of methionine sulfoxide reductases and accumulation of their substrates in mouse lenses

To determine the influences of early-stage diabetes mellitus on methionine sulfoxide reductases (Msrs) expression in lenses, streptozocin (STZ)-induced diabetic mice as animal models were used in this study. The results showed that the contents of methionine sulfoxide (MetO), protein carbonyl (PC) and Malondialdehyde (MDA) in the lenses of STZ-induced diabetic mice after 14 days were significantly higher than that in the normal control, level of total sulfhydryl groups (TSH) was 60% of normal control, and mRNA expressing levels of the MsrA and MsrBs were significantly decreased compared with normal group, as was the expression of MsrB1 protein. These results suggest that STZ not only causes increased oxidative stress, but also suppresses Msr mRNA and MsrB1 protein expression during early-stage diabetes in mice. However, the mechanism remains to research.

Transcription Factors Krüppel-Like Factor 6 and Peroxisome Proliferator-Activated Receptor-γ Mediate High Glucose-Induced Thioredoxin-Interacting Protein

We demonstrated recently that thioredoxin-interacting protein (Txnip) and the transcription factor Krüppel-like factor 6 (KLF6) were up-regulated in both in vivo and in vitro models of diabetic nephropathy, thus promoting renal injury. Conversely, peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists have been shown to be renoprotective. Hence, this study was undertaken to determine whether Txnip expression is regulated by the transcription factors KLF6 and PPAR-gamma. By using siRNAs and overexpressing constructs, the role of KLF6 and PPAR-gamma in Txnip transcriptional regulation was determined in human kidney proximal tubule cells and in streptozocin-induced diabetes mellitus in Sprague-Dawley rats, in vitro and in vivo models of diabetic nephropathy, respectively. KLF6 overexpression increased Txnip expression and promoter activity, which was inhibited by concurrent exposure to PPAR-gamma agonists. In contrast, reduced expression of KLF6 by siRNA or exposure to PPAR-gamma agonists attenuated high glucose-induced Txnip expression and promoter activity. KLF6-Txnip promoter binding was decreased in KLF6-silenced cells, whereas PPAR-gamma agonists increased PPAR-gamma-Txnip promoter binding. Indeed, silencing of KLF6 increased PPAR-gamma expression, suggesting endogenous regulation of PPAR-gamma expression by KLF6. Moreover, renal KLF6 and Txnip expression increased in rats with diabetes mellitus and was inhibited by PPAR-gamma agonist treatment; however, KLF6 expression did not change in HK-2 cells exposed to PPAR-gamma agonists. Hence, Txnip expression and promoter activity are mediated via divergent effects of KLF6 and PPAR-gamma transcriptional regulation.

Testosterone treatment promotes tubular damage in experimental diabetes in prepubertal rats

Puberty unmasks or accelerates progressive kidney diseases, including diabetes mellitus (DM), perhaps through effects of sex steroids. To test the hypothesis that rising androgen levels at puberty permit diabetic kidney damage, we studied four groups of male rats with and without streptozocin-induced DM: adult onset (A), adult onset after castration (AC), juvenile onset (J), and juvenile onset with testosterone treatment (JT). Profibrotic markers were measured after 6 wk with blood glucose levels 300-450 mg/dl. JT permitted increased expression of mRNA for two isoforms of transforming growth factor-beta and connective tissue growth factor compared with J animals with DM; prior castration did not provide protection in adult-onset DM. JT also permitted greater tubular staining for alpha-smooth muscle actin and fibroblast-specific protein, two markers of cell damage and potential epithelial mesenchymal transition. Once again, castration was not protective for these effects of DM in the AC group. These data indicate that puberty permits detrimental effects in the tubulointerstitium in the diabetic kidney, an effect mimicked by testosterone treatment of juvenile animals and partially blunted by castration of adults, but damage does not correlate with testosterone levels, suggesting a less direct mechanism.

Pain Behavior and Response Properties of Spinal Dorsal Horn Neurons Following Experimental Diabetic Neuropathy in the Rat: Modulation by Nitecapone, a COMT Inhibitor with Antioxidant Properties

We attempted to characterize a spinal neuronal correlate of painful neuropathy induced by diabetes mellitus (DM). Pain behavior and response properties of spinal dorsal horn neurons were determined in rats with a streptozocin-induced DM. A catechol-O-methyltransferase inhibitor with potent antioxidant properties, nitecapone, was used in an attempt to attenuate neuropathic symptoms. Behaviorally DM induced mechanical hypersensitivity that was markedly attenuated by oral treatment with nitecapone. The antihyperalgesic effect of nitecapone was not reversed by naloxone, an opioid antagonist, or atipamezole, an α-2-adrenoceptor antagonist. Electrophysiological recordings performed in pentobarbitone-anesthetized animals revealed that the most distinct abnormality in response properties of spinal dorsal horn wide-dynamic range (WDR) neurons was the increase in their spontaneous activity observed in untreated but not in nitecapone-treated DM rats. Conditioning electrical stimulation and a lidocaine block of the rostroventromedial medulla (RVM) had a similar modulatory effect on evoked responses of spinal dorsal horn WDR neurons in all experimental groups. The response properties of spinal dorsal horn nociceptive-specific or low-threshold mechanoreceptive neurons were not markedly different between the experimental groups. The results indicate that increased spontaneous activity in spinal dorsal horn WDR neurons may be causally related to behaviorally observed mechanical hypersensitivity in DM. Attenuation of the increased spontaneous activity in WDR neurons may explain the antihyperalgesic effect by nitecapone, due to naloxone- and α-2-adrenoceptor-insensitive mechanisms. DM or nitecapone treatment did not produce significant changes in phasic or tonic descending pain regulation originating in the RVM.