Streptozotocin-diabetic Rats Research Articles

Nigella Sativa Improve Redox Homeostasis in Heart and Aorta of Diabetic Rat

Background: Oxidative stress plays a pivotal role in the development of diabetes complications. The present study investigated the effects of Nigella Sativa hydroalcholic extract on oxidative stress injuries of heart and aorta in streptozotocin- induced diabetic rats. Methods: The animals were divided into six experimental groups; control, streptozotocin-diabetic, and diabetic rats treated with different doses of Nigella Sativa, 100, 200 and 400 mg/kg or metformin, 300 mg/kg, by daily gavage for 6 weeks. Malondialdehyde, total thiol levels and also the activities of Cu,Zn-superoxide dismutase and catalase in aortic and cardiac tissues were evaluated. Results: The malondialdehyde levels were decreased in all treated groups compared to diabetic group (p < 0.05 to p < 0.001). Thiol levels were increased in cardiac tissues of metformin and 100 mg/kg Nigella sativa groups compared to diabetic group (p < 0.05, p < 0.001). The activity of Cu,Zn-superoxide dismutase in aortic tissues of 100 and 200 mg/kg Nigella sativa groups was higher than control and diabetic groups (p < 0.001) and those of cardiac tissues in 200 and 400 mg/kg Nigella sativa groups were higher than diabetic and control group (p < 0.05). The activity of catalase in cardiac tissues of metformin, 100 and 400 mg/kg Nigella sativa groups was reduced compared to diabetic group (p < 0.01). Conclusion: The results showed that chronic administration of Nigella Sativa in streptozotocin-induced diabetic rats could decrease the oxidative stress in aortic and cardiac tissues. Keywords: Diabetes mellitus, Nigella Sativa, oxidative stress, heart, aorta.

Iodinated contrast media inhibit oxygen consumption in freshly isolated proximal tubular cells from elderly humans and diabetic rats: Influence of nitric oxide

Objectives Mechanisms underlying contrast medium (CM)-induced nephropathy remain elusive, but recent attention has been directed to oxygen availability. The purpose of this study was to evaluate the effect of the low-osmolar CM iopromide and the iso-osmolar CM iodixanol on oxygen consumption (QO2) in freshly isolated proximal tubular cells (PTC) from kidneys ablated from elderly humans undergoing nephrectomy for renal carcinomas and from normoglycemic or streptozotocin-diabetic rats.Materials PTC were isolated from human kidneys, or kidneys of normoglycemic or streptozotocin-diabetic rats. QO2 was measured with Clark-type microelectrodes in a gas-tight chamber with and without each CM (10 mg I/mL medium). L-NAME was used to inhibit nitric oxide (NO) production caused by nitric oxide synthase.Results Both CM reduced QO2 in human PTC (about –35%) which was prevented by L-NAME. PTC from normoglycemic rats were unaffected by iopromide, whereas iodixanol decreased QO2 (–34%). Both CM decreased QO2 in PTC from diabetic rats (–38% and –36%, respectively). L-NAME only prevented the effect of iopromide in the diabetic rat PTC.Conclusions These observations demonstrate that CM can induce NO release from isolated PTC in vitro, which affects QO2. Our results suggest that the induction of NO release and subsequent effect on the cellular oxygen metabolism are dependent on several factors, including CM type and pre-existing risk factors for the development of CM-induced nephropathy.

Heart mitochondrial dysfunction in diabetic rats

Diabetic cardiomyopathy, i.e. the ventricular dysfunction in the absence of hypertension or coronary arterial disease, is a common complication of diabetes mellitus that leads to a heightened risk of heart failure and death among diabetic patients. This contractile dysfunction could be associated to mitochondrial dysfunction, in which mitochondrial biogenesis could emerge as a compensatory mechanism triggered in response to hyperglycemia. It has been proposed that nitric oxide synthase activities with enhanced NO production are involved in this process. Alterations in the contractile response and lusitropic reserve were observed in streptozotocin diabetic rats after β-adrenergic stimuli. Additionally, tissue O2 consumption was declined. A condition of mitochondrial dysfunction with decreased mitochondrial state 3 O2 consumption, respiratory control ratio, mitochondrial respiratory complexes activities and ATP production were present in hearts of diabetic animals. We observed an increase in NO production by heart mitochondria and in cytochrome oxidase activity in heart homogenates. The latter suggests an increase of newly formed mitochondria. Thus, the impairment of mitochondrial function with increased mitochondrial biogenesis may precede the onset of diabetic cardiomyopathy. However, mitochondrial biogenesis does not necessarily imply that the resultant mitochondria are functional, which might explain the changes in cardiac energy metabolism occurring in hearts of diabetic rats.

ANTI-HYPERGLYCEMIC AND ANTIOXIDANT POTENTIAL OF WATER-ETHANOL EXTRACT OF MUSANGA CECROPIOIDES STEM BARK

The study investigated the effect of Musanga cecropioides (MC) water-ethanol stem bark extract on blood glucose level in both hyperglycemic loaded glucose rats and streptozotocin (STZ)-induced diabetic rats, and evaluated its antioxidant capacity. The Wistar rats were induced diabetes after fasting. Oral Glucose Tolerance Test (OGTT) was conducted on normoglycemic rats, and anti-hyperglycemic test on diabetic rats; five groups with five rats each were constituted. Group 1: negative control was treated with vehicle; Group 2, Group 3, and Group 4 were treated with increasing water-ethanol extract (200, 300 and 400 mg/kg b.w); Group 5 was the positive control, treated with glibenclamide. The antioxidant capacity of the extract was also evaluated by measuring the Ferric Reducing Antioxidant Power, Total Phenolic Content, Total Flavonoid Content, and radical scavenging activity of water-ethanol stem bark extract. In OGTT the water-ethanol extract of MC, at the dose of 300 mg/kg, significantly lowered the Area under Curve (AUC) induced by glucose. In STZ diabetic rats, the extract significantly lowered the AUC of blood glucose, at all doses. Glibenclamide was more efficient in both OGTT and anti-hyperglycemic test. The MC extract presented relevant antioxidant activity with IC50 = 6.23 mg/mL. Both the Total Phenolic Content and the Total Flavonoid Content increased in a dose-dependent manner. The correlation of DPPH % free radical scavenged and Total Flavonoid Content was positive and statistically significant. MC water-ethanol extract possesses a good antioxidant potential, and could be helpful to lower hyperglycemic state associated with diabetes.

Liver X Receptor Agonist TO901317 Prevents Diacylglycerols Accumulation in the Heart of Streptozotocin-Diabetic Rats

Background/Aims: Liver X receptors (LXRα and LXRβ) are ligand-activated transcription factors that regulate expression of genes involved in lipid and cholesterol metabolism. LXR expression has been identified in the heart, and enhanced LXR activity in the streptozotocin (STZ) diabetic myocardium was reported recently. The aim of this study was to investigate effect of in vivo LXR activation on myocardial lipid metabolism under conditions of STZ-induced diabetes. Methods: Wistar rats were randomly divided into three experimental groups: non-diabetic control, treated with STZ, and treated with STZ and LXR agonist - TO901317. Diabetes was induced by a single intraperitonal injection of STZ at a dose of 55 mg/kg. LXR agonist was administrated once daily in the morning by an oral gavage at a dose of 10 mg/kg/d during the last week of the experiment. After anesthesia samples of blood and the left ventricle were taken. Results: TO901317 administration increased expression of both LXR isoforms and its target genes: sterol response element binding protein 1c (SREBP-1c) and acetyl-coenzyme A carboxylase 1 (ACC1) in the heart of streptozotocin-diabetic rats. Treatment with LXR agonist had no effect on plasma lipids and glucose in the diabetic rats. Concomitantly, content of the examined lipid classes in the diabetic heart (nonesterified fatty acids, triacylglycerols, phospholipids, cholesterol esters, ceramide) was unchanged after treatment with TO901317. On the contrary, myocardial level of cholesterol and diacylglycerols (DAG) was decreased after LXR activation in diabetic rats, the change in DAG level was associated with downregulated expression of adipose triglyceride lipase (ATGL). Conclusion: Activation of LXRs by TO901317 protects cardiomyocytes against DAG accumulation and thus may reverse disturbances in lipid metabolism observed in streptozotocin-diabetic heart.

Antidiabetic, antihyperlipidaemic, and antioxidant activity of Syzygium densiflorum fruits in streptozotocin and nicotinamide-induced diabetic rats

Context Syzygium densiflorum Wall. ex Wight & Arn (Myrtaceae) has been traditionally used by local tribes of the Nilgiris, Tamil Nadu, India, for the treatment of diabetes, however, no definitive experimental studies are available.Objective This study investigates the antidiabetic, antihyperlipidaemic and antioxidant activities of ethanol extract of S. densiflorum (EFSD) fruits in streptozotocin (STZ) and nicotinamide (NA)-induced diabetic rats.Materials and methods Acute oral toxicity and oral glucose tolerance were assessed in normal rats. The antidiabetic, antihyperlipidaemic and antioxidant activities were investigated in STZ − NA-induced diabetic rats. Diabetic rats were orally administered with glibenclamide (10 mg/kg b.wt), EFSD (200, 400 and 800 mg/kg b.wt) for 28 d. Further, changes in the blood glucose level (BGL), biochemical parameters, antioxidants were observed and histology of pancreas was performed.Results No toxicity and lethality were observed. Results of the following parameters are represented by treated versus disease control (STZ + NA) groups. BGL (161.33 ± 22.8 versus 476.17 ± 56.58 mg/dl), glycosylated haemoglobin (5.285 ± 0.19 versus 8.05 ± 0.55%), urea (40.32 ± 1.96 versus 75.37 ± 2.91 mg/dl), uric acid (1.2 ± 0.07 versus 2.16 ± 0.05 mg/dl), total cholesterol (89.3 ± 5.14 versus 139.7 ± 5.95 mg/dl) and triglycerides (79.65 ± 2.52 versus 108.9 ± 3.61 mg/dl) were significantly decreased, whereas haemoglobin (11.75 ± 0.73 versus 7.95 ± 0.42 g/dl), high‐density lipoprotein cholesterol (14.2 ± 1.11 versus 6.97 ± 0.84 mg/dl), total protein (45%) and liver glycogen (87%) were significantly increased in EFSD-treated diabetic group. Significant changes were observed in the enzymatic and non-enzymatic antioxidants in EFSD-treated groups (p < 0.001). Histopathological examination showed the regeneration of β-cells in Islets of Langerhans.Conclusion This study confirms the antidiabetic, antihyperlipidaemic and antioxidant activities of S. densiflorum fruits.

Supplementation with L-Glutamine and L-Alanyl-L-Glutamine Changes Biochemical Parameters and Jejunum Morphophysiology in Type 1 Diabetic Wistar Rats.

We evaluated the effects of the supplementation with L-glutamine and glutamine dipeptide (GDP) on biochemical and morphophysiological parameters in streptozotocin-diabetic rats. For this purpose, thirty animals were distributed into six groups treated orally (gavage) during thirty days: non diabetic rats (Control) + saline, diabetic + saline; Control + L-glutamine (248 mg/kg), Diabetic + L-glutamine (248 mg/kg), Control + GDP (400 mg/kg), Diabetic + GDP (400 mg/kg). Diabetes was induced by an intravenous injection of streptozotocin (60 mg/kg) and confirmed by fasting glucose ≥ 200 mg/dL. Physiological parameters, i.e., body mass, food intake, blood glucose, water intake, urine and faeces were evaluated during supplementation. After the period of supplementation, the animals were euthanized. The blood was collected for biochemical assays (fructosamine, transaminases, lipid profile, total protein, urea, ammonia). Moreover, the jejunum was excised and stored for morphophysiological assays (intestinal enzyme activity, intestinal wall morphology, crypt proliferative index, number of serotoninergic cells from the mucosa, and vipergic neurons from the submucosal tunica). The physiological parameters, protein metabolism and intestinal enzyme activity did not change with the supplementation with L-glutamine or GDP. In diabetic animals, transaminases and fructosamine improved with L-glutamine and GDP supplementations, while the lipid profile improved with L-glutamine. Furthermore, both forms of supplementation promoted changes in jejunal tunicas and wall morphometry of control and diabetic groups, but only L-glutamine promoted maintenance of serotoninergic cells and vipergic neurons populations. On the other hand, control animals showed changes that may indicate negative effects of L-glutamine. Thus, the supplementation with L-glutamine was more efficient for maintaining intestinal morphophysiology and the supplementation with GDP was more efficient to the organism as a whole. Thus, we can conclude that local differences in absorption and metabolism could explain the differences between the supplementation with L-glutamine or GDP.

Effect of Birhi Vaiety of Date Palm Fruits, (Phoenix dactylifera L.) at the Tamr Stage on Serum Glucose Levels in Streptozotocin-Induced Diabetic Rats

&lt;p&gt;This study was carried out to investigate the effect of a dietary preparation of Birhi tamr (&lt;em&gt;Phoenix dactylifera&lt;/em&gt; L.) on serum glucose levels and body weight in normal, diabetic insulin-treated and diabetic insulin-untreated rats. Diabetes was partially induced by intraperitoneal injection of streptozotocin (32.25 mg/kg). Thirty six male Sprague-Dawley rats (239 ± 8.4 g) were divided into two normal, two diabetic insulin-treated and two diabetic insulin-untreated groups. Each group was fed a diet containing either 0% or 10% tamr for six weeks. Fasting serum glucose levels were determined by enzymatic-calorimetric method using a standard kit procedure.Feeding 10% tamr did not show significant differences (P &amp;gt; 0.05) in serum glucose levels in any of the normal and insulin-treated diabetic rats. Insulin-untreated diabetic rats fed 0% tamr or 10% tamr exhibited significantly (P &amp;lt; 0.05) higher serum glucose levels (496 ± 81.6, 315 ± 61.1 mg/dl respectively) compared to normal (147 ± 5.3, 156 ± 7.6 mg/dl respectively) and insulin-treated diabetic rats (227 ± 17.6, 268± 18.9 mg/dl respectively). Feeding 10% tamr to insulin-untreated rats induced significant (P &amp;lt; 0.05) reduction in this variable. The findings of the present study may provide support for the favourable effect of date palm fruits as tamr, on blood glucose in streptozotocin-diabetic rats. This effect cannot be simply explained on the basis of the macro-nutrient composition of tamr. However, due to the apparent effects of tamr on blood glucose in normal and insulin-treated and insulin-untreated diabetic rats, the possible presence of insulin-like substance in tamr may not be excluded. The mechanism of action of the blood glucose-lowering effect of tamr awaits further investigation.&lt;/p&gt;

Reestablishment of the hyperglycemia to the normal levels seems not to be essential to the anxiolytic-like effect induced by insulin.

Diabetes is a chronic metabolic disease accompanied by several comorbidities, including neuropsychiatric conditions. Since the hyperglycemia appears to be the primary factor involved in diabetic conditions, we examined the effect of insulin treatment in diabetic rats on behavioral responses related to anxiety and aversive memory extinction. For this, normoglycemic (NGL) or streptozotocin-diabetic (DBT) rats were submitted to the elevated T maze (ETM) and the contextual conditioned fear (CCF) tests. Therefore, animals were subjected to the prolonged treatment with insulin (6IU/day, s.c.) to investigate the effect of the treatment on distinct behaviors. When anxiety-like responses such as the inhibitory avoidance (IA) on the ETM and the time of freezing in the first session of the CCF test were evaluated, our data showed a more pronounced anxiogenic-like behavior in DBT animals when compared to NGL ones. In addition, an increased freezing time was observed in DBT animals exposed to the CCF test (sessions 2 and 3) when compared to the NGL group, suggestive of an impairment in the extinction of aversive memory. Insulin treatment induced an anxiolytic-like effect when IA and freezing time (session 1) was evaluated, but did not alter the impaired extinction of aversive memory (sessions 2 and 3). To better understand the involvement of a rigorous control of glycaemia, we also investigated the effect of a lower dose of insulin (3IU/day, s.c.), unable to reestablish the hyperglycemia to the normal levels, on the same behavioral parameters. Our data show that independent of the dose of insulin, the same effects were observed when animals were evaluated in the ETM and CCF tests. However, only the highest dose of insulin was able to reduce the hyperglycemia to the normal levels. To conclude, our data suggest that a severe glycemic control by insulin treatment seems to be important, but not essential in improving diabetes-induced anxiety.

Effect of omega-3 polyunsaturated fatty acid treatment over mechanical allodynia and depressive-like behavior associated with experimental diabetes

Neuropathic pain and depression are very common comorbidities in diabetic patients. As the pathophysiological mechanisms are very complex and multifactorial, current treatments are only symptomatic and often worsen the glucose control. Thus, the search for more effective treatments are extremely urgent. In this way, we aimed to investigate the effect of chronic treatment with fish oil (FO), a source of omega-3 polyunsaturated fatty acid, over the mechanical allodynia and in depressive-like behaviors in streptozotocin-diabetic rats. It was observed that the diabetic (DBT) animals, when compared to normoglycemic (NGL) animals, developed a significant mechanical allodynia since the second week after diabetes induction, peaking at fourth week which is completely prevented by FO treatment (0.5, 1 or 3g/kg). Moreover, DBT animals showed an increase of immobility frequency and a decrease of swimming and climbing frequencies in modified forced swimming test (MFST) since the second week after diabetes injection, lasting up at the 4th week. FO treatment (only at a dose of 3g/kg) significantly decreased the immobility frequency and increased the swimming frequency, but did not induce significant changes in the climbing frequency in DBT rats. Moreover, it was observed that DBT animals had significantly lower levels of BDNF in both hippocampus and pre frontal cortex when compared to NGL rats, which is completely prevented by FO treatment. In conclusion, our study demonstrates that FO treatment was able to prevent the mechanical allodynia and the depressive-like behaviors in DBT rats, which seems to be related to its capacity of BDNF level restoration.

Formation of Cholangiogenic Cysts Following Intrahepatic Islet Transplantation in Streptozotocin Diabetic Rats

Permanent hyperinsulinemia and the resulting overstimulation of the insulin receptor signaling pathway is suspected as a trigger of cancer genesis in the livers of type 2 diabetic patients. Liver tissue (LT) surrounding transplanted pancreatic islets (PI) can be permanently exposed to insulin in even higher concentrations than in type 2 diabetic patients. Therefore, this study examines the effect of PI transplantation (Tx) on LT in animals with streptozotocin (STZ)-induced diabetes mellitus. The suboptimal mass (400 or 1000) of isogeneic PI was transplanted into either the portal vein or under the kidney capsule of diabetic Brown Norway (BN) rats. Healthy BN rats treated with 400 isogeneic PI transplanted in the portal vein served as a control group. During the first 6 months after PI Tx, small and infrequent cystic lesions developed in animals with STZ diabetes, irrespective of the Tx site. In 10 months, frequent and complex cystic lesions appeared in these animals. In the control group, several small lesions were detected but not until 10 months after the PI Tx. In summary, STZ is the likely main inductor of hepatic cystic lesions, but the contribution of PI was not confirmed.

Neurorestorative effects of eugenol, a spice bioactive: Evidence in cell model and its efficacy as an intervention molecule to abrogate brain oxidative dysfunctions in the streptozotocin diabetic rat

Eugenol (EU), an active principle of cloves, is also widely distributed in various other plants (eg. basil, cinnamon, etc). While its antioxidant and anti-inflammatory properties are well established, biochemical insights related to its neuromodulatory potential in diabetic conditions are not clear. In the present study, initially we investigated its potential to modulate specific biochemical responses in SHSY5Y cells under experimentally -induced hyperglycemic condition. Co-exposure of cells with EU (5–10 μM) not only enhanced the cell viability, but significantly offset glucose -associated oxidative stress (as evidenced by diminished levels of reactive oxygen species and hydroperoxides). Further EU enhanced the reduced glutathione (GSH) levels and also ameliorated the levels of 3 – nitrotyrosine and expression of HSP70. We subsequently examined its efficacy to attenuate biochemical aberrations in brain regions of a streptozotocin (STZ) diabetic rat employing an intervention approach. Brain regions of EU treated (10 mg/kg bw/d, post 6 weeks of STZ) diabetic rats showed diminished levels of oxidative markers and protein carbonyls in both cytosolic and mitochondrial fractions. EU treatment caused enhanced activities of enzymic antioxidants and diminished both GSH and total thiols. Further, activities of complex I – III, succinate dehydrogenase and citrate synthase in brain regions were also significantly restored. Interestingly, EU treatment differentially attenuated the elevated activity of acetylcholinesterase and levels of calcium in brain regions. Collectively, based on the data obtained in in vitro and in vivo models, we hypothesize that EU may be employed as an adjuvant therapeutic molecule to alleviate complications under diabetic conditions.

Soluble Curcumin in the Prevention of Diabetic Retinopathy via Modulation of Anti-Oxidant Activity and Genetic Pathways – In Vivo Model

The aim of the present study was to investigate the protective effects of curcuminoids from regular curcumin Powder (95% curcuminoids), and UltraSOL™ Nutrient System with curcumin (CurcuWIN™ Turmeric Extract, 20% curcuminoids) in dry powder forms on retina and metabolic markers in streptozotocin-induced (STZ) diabetic rats. Male Wistar strain (WNIN) rats (2 months old; 213±14 g BW) were randomly assigned into 4 groups: control group (C), diabetic group (STZ-diabetic rats, D), STZ DM+ Soluble curcumin (SC, CurcuWIN™) and STZ DM +regular curcumin (RC). Daily food intake, weekly body weights, fasting glucose levels and HbA1C were assessed. Electroretinogram, immunohistochemistry and Immunofluorescence were performed in all treatment groups. At the end of 12 weeks, rats were euthanized and retinas harvested for histological and molecular analysis. In streptozotocin (STZ) diabetic rats (D) amplitude of oscillatory potentials (Ops) were reduced (334.2 µV) compared to normal control (C) animals. Curcumin resulted in significant changes in OP amplitudes suggested by sum of OPs, RC (445.7) and SC (455.3). Treatment with curcumin prevented gross morphological changes to a significant extent in diabetic retina. Treatment with RC and SC prevented loss of Rhodopsin (Rho) protein expression and nerve growth factor (NGF) protein expression in diabetic retina indicated by intense fluorescence. Treatment with RC and SC showed decreased protein expression in diabetic retina indicated by lower Hypoxia-inducible factor 1-alpha (HIF- 1-α) positive fluorescence indicating the prevention of hypoxia in the retinas. Treatment with RC did not affect the vascular endothelial growth factor (VEGF) over expression in diabetic retina but the SC reduced the VEGF expression. In STZDM the mRNA levels of Glial fibrillary acidic protein (GFAP), are up regulated drastically, while treatment with SC significantly prevented its increase but there is no significant effect of RC treatment. Therefore, soluble curcumin may have therapeutic potential in the treatment of diabetic retinopathy (DR) and appears to be more effective than regular curcumin.

Hypoglycemic effect of Citrullus colocynthis extracts

Citrullus colocynthis is a plant used as a traditional medicine for the treatment of diabetes mellitus in the Maghreb region and in the Middle East, and particularly in Tlemcen region–Algeria. In this study, we investigated the antihyperglycaemic effect of aqueous extracts, saponins, total alkaloids and glycosidic extracts of colocynth seeds (Citrullus colocynthis) administered intraperitoneally in normal Wistar rats and streptozotocin diabetic rats. The toxicity of these extracts was also evaluated using lethal dose 50 method (LD50).

Lupanine Improves Glucose Homeostasis by Influencing KATP Channels and Insulin Gene Expression.

The glucose-lowering effects of lupin seeds involve the combined action of several components. The present study investigates the influence of one of the main quinolizidine alkaloids, lupanine, on pancreatic beta cells and in an animal model of type-2 diabetes mellitus. In vitro studies were performed with insulin-secreting INS-1E cells or islets of C57BL/6 mice. In the in vivo experiments, hyperglycemia was induced in rats by injecting streptozotocin (65 mg/kg body weight). In the presence of 15 mmol/L glucose, insulin secretion was significantly elevated by 0.5 mmol/L lupanine, whereas the alkaloid did not stimulate insulin release with lower glucose concentrations. In islets treated with l-arginine, the potentiating effect of lupanine already occurred at 8 mmol/L glucose. Lupanine increased the expression of the Ins-1 gene. The potentiating effect on secretion was correlated to membrane depolarization and an increase in the frequency of Ca2+ action potentials. Determination of the current through ATP-dependent K+ channels (KATP channels) revealed that lupanine directly inhibited the channel. The effect was dose-dependent but, even with a high lupanine concentration of 1 mmol/L or after a prolonged exposure time (12 h), the KATP channel block was incomplete. Oral administration of lupanine did not induce hypoglycemia. By contrast, lupanine improved glycemic control in response to an oral glucose tolerance test in streptozotocin-diabetic rats. In summary, lupanine acts as a positive modulator of insulin release obviously without a risk for hypoglycemic episodes.

Metabolic Dysfunction Is Restricted to the Sciatic Nerve in Experimental Diabetic Neuropathy.

High glucose levels in the peripheral nervous system (PNS) have been implicated in the pathogenesis of diabetic neuropathy (DN). However, our understanding of the molecular mechanisms that cause the marked distal pathology is incomplete. We performed a comprehensive, system-wide analysis of the PNS of a rodent model of DN. We integrated proteomics and metabolomics from the sciatic nerve (SN), the lumbar 4/5 dorsal root ganglia (DRG), and the trigeminal ganglia (TG) of streptozotocin-diabetic and healthy control rats. Even though all tissues showed a dramatic increase in glucose and polyol pathway intermediates in diabetes, a striking upregulation of mitochondrial oxidative phosphorylation and perturbation of lipid metabolism was found in the distal SN that was not present in the corresponding cell bodies of the DRG or the cranial TG. This finding suggests that the most severe molecular consequences of diabetes in the nervous system present in the SN, the region most affected by neuropathy. Such spatial metabolic dysfunction suggests a failure of energy homeostasis and/or oxidative stress, specifically in the distal axon/Schwann cell-rich SN. These data provide a detailed molecular description of the distinct compartmental effects of diabetes on the PNS that could underlie the distal-proximal distribution of pathology.

Up-regulation of Hsp72 and keratin16 mediates wound healing in streptozotocin diabetic rats

BackgroundImpaired wound healing is a complication of diabetes and a serious problem in clinical practice. We previously found that whey protein (WP) was able to regulate wound healing normally in streptozotocin (STZ)-diabetic models. This subsequent study was designed to assess the effect of WP on heat shock protein-72 (Hsp72) and keratin16 (Krt16) expression during wound healing in diabetic rats.MethodsWP at a dosage of 100 mg/kg of body weight was orally administered daily to wounded normal and STZ-diabetic rats for 8 days.ResultsAt day 4, the WP-treated diabetic wound was significantly reduced compared to that in the corresponding control. Diabetic wounded rats developed severe inflammatory infiltration and moderate capillary dilatation and regeneration. Treated rats had mild necrotic formation, moderate infiltration, moderate to severe capillary dilatation and regeneration, in addition to moderate epidermal formation. Hsp72 and Krt16 densities showed low and dense activity in diabetic wounded and diabetic wounded treated groups, respectively. At day 8, WP-treatment of diabetic wounded animals revealed great amelioration with complete recovery and closure of the wound. Reactivity of Hsp72 and Krt16 was reversed, showing dense and low, or medium and low, activity in the diabetic wounded and diabetic wounded treated groups, respectively. Hsp72 expression in the pancreas was found to show dense reactivity with WP-treated diabetic wound rats.ConclusionThis data provides evidence for the potential impact of WP in the up-regulation of Hsp72 and Krt16 in T1D, resulting in an improved wound healing process in diabetic models.

Ameliorative effects of thymoquinone against eye lens changes in streptozotocin diabetic rats.

The possible protective effect of thymoquinone against eye lens changes in diabetic rats was investigated. Following diabetes induction by a single injection of streptozotocin (45 mg/kg, i.p.), thymoquinone was administered in three different doses (20, 40, and 80 mg/kg/day, p.o.) for 12 weeks. Thymoquinone significantly and dose-dependently attenuated the hypoinsulinemia and hyperglycemia in diabetic rats. Also, thymoquinone (particularly 40 and 80 mg/kg) significantly decreased the elevations of malondialdehyde, nitric oxide, tumor necrosis factor-α, glycated proteins, aldose reductase activity, sorbitol level, and caspase-3 activity in the lens tissues of diabetic rats. In addition, thymoquinone (particularly 40 and 80 mg/kg) significantly ameliorated the diabetes-induced reductions of glutathione peroxidase, superoxide dismutase, and catalase activities, and total and soluble protein contents in the lens tissues. It was concluded that thymoquinone significantly protected the lens tissue against changes induced by diabetes in rats through its antioxidant, anti-inflammatory, and antidiabetic effects.

Morphological Changes Caused by Streptozotocin-Induced Diabetes in the Healthy Gingiva of Rats.

Epidemiologic and clinical studies have indicated that diabetes is a risk factor for periodontal disease progression. The aim of the present study was to evaluate the morphological changes of gingiva in streptozotocin diabetic rats. 30 male Wistar rats that weighed 250-300 g were used in this study. The animals were randomly divided into 2 groups, one with streptozotocin-induced diabetes and another one with healthy (non-diabetic) animals. All rats were sacrificed after 21 days, and their maxillary first molars with surrounding tissues were observed morphological analyses. In this study, it was observed that the epithelial thickness was greater in the diabetes group, compared to the control group. The statistical comparison of the diabetes and control groups for the thickness of each of the layers of the epithelium demonstrated that the thickness of the keratinized (corneum), granular and basal layers had significantly increased in the diabetic animals. Furthermore, the diabetes group displayed a decrease in the height of the connective tissue papillae, which was found to be statistically insignificant. Another important finding detected in the diabetes group was the congestion of the gingival capillaries, which showed that blood circulation is impaired in diabetes cases. On the basis of the results obtained in this study, it was concluded that streptozotocin-induced diabetes may increase predisposition to periodontal disease by causing morphological changes in the periodontal tissues.

Potential effects of vildagliptin on biomarkers associated with prothrombosis in diabetes mellitus

Objective: Diabetes mellitus (DM) is one of the risks linked with susceptibility of thrombosis. We tried to inspect the effect of a novel oral antidiabetic agent, vildagliptin, in preventing prothrombosis associated with DM. Research design and methods: DM was produced by a dose of streptozotocin (STZ) or in albino wistar rats. Rats were treated orally with pioglitazone, standard treatment and vildagliptin alone and in combination for 3 weeks. Finally, the varied levels of coagulation biomarkers, including activated partial thromboplastin time (aPTT), prothrombin time (PT) and fibrinogen and inflammatory parameters, nitric oxide (NO), C-reactive protein (CRP) and TNF-α and lipid profile were estimated along with platelet count and total leukocyte count (TLC). In vitro fibrinolytic activity of both the drugs was also determined. Results: Vildagliptin significantly reduced cholesterol, triglycerides, TLC, CRP and TNF-α and increased aPTT and NO levels in STZ diabetic rats. However, pioglitazone was more successful in reducing fibrinogen and platelet count. Nevertheless, combination of the drugs was also effective than pioglitazone or vildagliptin alone in improvising hypercoagulation and inflammatory biomarkers. Conclusion: It is evident from the present study that vildagliptin has an influence on the biomarkers linked to the progression of thrombosis and may delay thrombogenesis linked to DM. Hence, vildagliptin alone and in combination might prove as an encouraging therapy for DM-linked thrombosis marked by inflammation and hypercoagulation.