Streptozotocin-diabetic Rats Research Articles

Phytochemical profiling of three Egyptian Phoenix dactylifera L. cultivars’ leaves with comparative positive impacts in controlling the streptozotocin diabetic rats

Background Date palm, Phoenix dactylifera L., is a tropical plant of the Arecaceae family. No sufficient studies have been directed to evaluate leaves’ phytochemistry and bioactivity. Objective The major aim of this study is to assess the phytochemical configuration and antidiabetic effect of palm leaf extracts cultivars. Materials and methods It included total phenolic and flavonoid contents determination, ultra-performance liquid chromatography coupled with mass analysis, and isolation of the main compounds while, the biological investigation targeted in vitro bioactivities and detailed in vivo antidiabetic activity. Animals were inducted with streptozotocin dose (40 mg/kg b.wt) and treated with different extracts dose (200 mg/kg b.wt). Results and conclusion Phenolic and flavonoid contents in three cultivars of Egyptian date palm leaves, Samani, Hayani, and Zaghloul were 545.652, 90.609, and 2231.304 mg GAE/g for phenolics, and 535.63, 118.00, and 2185.00 mg CE/g for flavonoids, respectively. Additionally, UPLC-QTOF-MS/MS elicited the recognition of 28, 27, and 40 phytoconstituents in three extracts, respectively. However, Zaghloul extract exhibited higher in vitro antioxidant activity compared with vitamin C. In vivo treatment with the extracts in contrast to glibenclamide as a standard drug for 4 weeks caused a significant glucose level decrease by 64.81, 65.61, 69.61, and 66.87%, respectively. The tested extracts showed significant in-vitro and in-vivo anti-diabetic activity and ameliorated the other accompanying diabetes parameters e.g. liver and kidney. Histopathological investigation showed that treatment with Zaghloul leaf extract has better results than reference drug and nearly similar effects for other leaf extracts.

Histological and Immunohistochemical Alterations of Spinal Cord and Sciatic Nerve in Streptozotocin-Diabetic Rats

Histological and Immunohistochemical Alterations of Spinal Cord and Sciatic Nerve in Streptozotocin-Diabetic Rats

L-Carnitine and Vitamin D attenuation of diabetic nephropathy in streptozotocin diabetic rats

L-Carnitine and Vitamin D attenuation of diabetic nephropathy in streptozotocin diabetic rats

Improvement of Serum Glucose and Lipid Factors by Some Polar and Non-Polar Extracts of Abelmoschus esculentus (L.) Moench and Eryngium caeruleum M. Bieb. in Streptozotocin-Diabetic Rats

Improvement of Serum Glucose and Lipid Factors by Some Polar and Non-Polar Extracts of Abelmoschus esculentus (L.) Moench and Eryngium caeruleum M. Bieb. in Streptozotocin-Diabetic Rats

Chrysophyllum albidum (African star apple) Fruit-Skin Attenuates Hyperglycemia-Mediated Oxidative Stress in Experimental Diabetic Rats

Diabetes mellitus, a chronic metabolic disturbance characterized by hyperglycemia has become a health problem affecting millions of people worldwide. Hyperglycemia mediated oxidative stress performs a key role in diabetic complications. The fruit-skin of Chrysophyllum albidum (African star apple) has been reported to have anti-hyperglycemic, hypolipidemic and in vitro antioxidant properties, but its effect on oxidative damage in diabetic animals has not been well investigated. This study investigated the effect of Chrysophyllum albidum fruit-skin (CAFS) in mitigating hyperglycemia induced oxidative stress in diabetic rats. Oxidative stress markers included superoxide dismutase (SOD) and catalase (CAT), lipidperoxidation status using malondialdehyde and non-enzymatic antioxidants in serum, hepatic and pancreatic tissues. Non-diabetic and streptozotocin-diabetic rats were compared after 4 weeks of treatment. The diabetic untreated group showed significant (p< 0.05) elevation of malondialdehyde and depression of non-enzymatic antioxidants levels, while suppressing SOD and CAT activities in serum, hepatic and pancreatic tissues when compared to normal rats. CAFS supplemented diet treatment ameliorated these metabolic disturbances and increased the activities of hepatic and pancreatic SOD from 0.28±0.25 to 0.61±0.13 Unit/mg protein and 0.08±0.01 to 0.15±0.01 Unit/mg protein respectively and CAT from 0.21±0.06 to 0.81±0.17 Unit/mg protein and 0.07±0.01 to 0.50±0.15 Unit/mg protein respectively. The findings suggest that CAFS treatment in diabetic rats exerts a protective effect via attenuation of oxidative stress mediated by hyperglycemia and improves the antioxidant status.

Abstract TMP117: Exposure to Single or Recurrent Hypoglycemia Increases Stroke Risk in Insulin-Treated Female Diabetic Rats

Stroke is a serious complication of diabetes. Intensive treatment of diabetes increases the risk of recurrent hypoglycemia (RH). Hypoglycemia exposure causes prothrombotic effects. Earlier, we demonstrated that exposure to single hypoglycemia (SH), 5-day RH (once every day), and twice-a-week RH for 6 weeks increases stroke risk in male insulin-treated diabetic (ITD) rats. In the present study, we determined the effect of SH and RH on stroke risk/thrombosis in female rats. Streptozotocin diabetic female rats were treated for hyperglycemia using insulin pellets (Figure A). Rats were randomly assigned to either hyperinsulinemic euglycemia (ITD+RH+Glucose, control) or hyperinsulinemic hypoglycemia (ITD+RH) groups (3 h duration) (Figure B). Separate groups tested the effect of SH, RH for 5 days, or RH for 6 weeks. Based on the results of the male studies, stroke risk after SH, 5-day RH, and 6-week RH were assessed on days 1, 7, and 3 post-last hypoglycemia, respectively. Groups were balanced (confirmed by Chi square test) in terms of the proportion of animals at different stages of the estrous cycle. To assess the risk of stroke, the carotid artery and jugular vein were linked with a shunt containing a suture, and the weight of the clot accumulated on the suture following 15 min of blood flow was quantified as a measure of stroke risk/thrombosis. The clot weight in the SH-exposed ITD group was significantly higher by 47% (22±3 mg, n=9, p<0.05) when compared to its respective control (15±1 mg, n=8). The clot weight determined 7 days after the 5-day ITD+RH group (18±1 mg, n=7) was significantly (p<0.05) higher than its control group (15±1 mg, n=9). The clot weight in the 6-week ITD+RH group was significantly higher by 47% (20±2 mg, n=9, p<0.01) when compared to its control (14±1 mg, n=7) (Figure C). Our results show that similar to male rats, SH and RH increase stroke risk in female ITD rats. We are currently evaluating the underlying mechanisms. Acknowledgment: NIH (NS122808).

Comparative Therapeutic Evaluation of Insuwin and Insuwin Forte Polyherbal Formulation on Streptozotocin and Nicotinamide Induced Diabetic Rats

Comparative Therapeutic Evaluation of Insuwin and Insuwin Forte Polyherbal Formulation on Streptozotocin and Nicotinamide Induced Diabetic Rats

Eremophila purpurascens: Anti-oxidant, Anti-hyperglycemic, and Hepatoprotective Potential of Its Polyphenolic Rich Leaf Extract and Its LC-ESI-MS/MS Chemical Characterization and Standardization.

The genus Eremophila, despite comprising more than 250 species, has scarce literature studies that could be traced concerning the chemical profile and bioactivity of Eremophila purpurascens. The current study targets the investigation of the in vitro and in vivo anti-oxidant, anti-hyperglycemic, and hepatoprotective potential of the polyphenol-rich leaf extract of E. purpurascens (EP). EP showed promising total anti-oxidant capacity with IC50 values of 106 and 114 μg/mL in 2,2'-azinobis [3-ethylbenzothiazoline-6-sulfonic acid]-diammonium salt (ABTS) and diphenyl-1-picrylhydrazyl (DPPH) assays, respectively, with total anti-oxidant capacities of 331, 245, and 1767 μmol/g in ABTS, DPPH, and ferric reducing anti-oxidant power assays, respectively. In HepG2 cells, pre-treated with CCl4, a dose of 100 μg/mL EP ameliorated the reduced superoxide dismutase and glutathione levels and total anti-oxidant capacity with values of 312.5 U/mL, 15.47 mg/dL, and 1.03 nmol/mL, respectively. In vitro anti-diabetic evaluation using 3T3-L1 adipocyte culture showed that at a dose of 30 μg/mL, the EP extract elicited a 6.3% decrease in the concentration of glucose (22.4 mmol/L), showing significant amelioration with regard to pioglitazone and insulin. EP also demonstrated elevated serum insulin by 77.78% with a marked reduction in fasting blood glucose level by 64.55% relative to the streptozotocin diabetic rats in vivo. EP also relieved the liver stress markers both in vitro in CCl4 and in vivo in tamoxifen (TAM) models. EP markedly decreased TAM toxicity, as demonstrated by the decline in the liver stress markers, ALT and AST, by 36.1 and 51.1%, respectively. It also relieved the oxidative stress triggered by TAM, as revealed by the reduction in the levels of TBARs and TNF-α by 21.4 and 40%, respectively. Liquid chromatography electrospray ionization mass spectrometry of EP revealed a total of twelve peaks belonging to phenylpropanoids, lignans, and phenolics, where verbascoside and pinoresinol-4-O-β-d-glucoside represented the most abundant secondary metabolites. The docking experiment showed that tri-O-galloyl-hexoside had the best fitting within the NADPH oxidase active sites with binding energy (ΔG = -81.12 kcal/mol). Thus, the plant can be of beneficial value in the control of hyperglycemia in diabetic patients, besides its prophylactic potential against hepatic complications.

Altered Chief Cell Morphology in the Gastric Gland of Streptozotocin-Diabetic Rats

Altered Chief Cell Morphology in the Gastric Gland of Streptozotocin-Diabetic Rats

Influence of Sterculia setigera Delile extract on oxidative stress enzyme activity and treatment of impaired glucose homeostasis in Streptozotocin-induced diabetic Wistar rats

BackgroundSterculia setigera Delile is a plant member of Sterculiacea family whose ethnobotanical investigation has revealed medicinal virtues. Traditional Chinese medicine (TCM) has several advantages as it includes a wide variety of plants, low cost, minimal toxic and side effects. More significantly, many bioactive compounds such as flavonoids, tannins and saponins are active constituents of traditional Chinese medicinal plants, which generally have no adverse effects. This study aimed to evaluate the influence of S. setigera Delile extract in impairing hyperglycemia and oxidative stress induced by streptozotocin in Wistar rats. MethodsThe intraperitoneal injection of streptozotocin (65 mg/kg) generated hyperglycemia in male Wistar rats. Diabetic animals were treated for 4 weeks with S. setigera extract. Insulin concentration and lipid profile biomarkers were evaluated. Oxidative stress biomarkers were assessed in pancreas and kidney. Histological sections of pancreas and kidney were made. ResultsAfter 4 weeks of treatment, the extract could decrease blood glucose levels by CI% (-92.3 to -39.94) compared to the diabetic control. Serum insulin, triglycerides and total cholesterol were improved towards their normal values. Pancreatic and renal cell architecture, were also improved in animals treated with the extract. ConclusionS. setigera extract could thus reverse hyperglycemia, dyslipidemia and oxidative stress in streptozotocin diabetic rats.

Inhibition of NF-κB ameliorates aberrant retinal glia activation and inflammatory responses in streptozotocin-induced diabetic rats.

To determine the anti-inflammatory effects of IMD-0354, a specific NF-κB blocker, on glial cells in rats with streptozotocin (STZ)-induced diabetic retinopathy (DR). The following four groups of rats were used: control, control + IMD-0354, STZ, and STZ + IMD-0354. After six weeks of STZ injection, diabetic rats and nondiabetic control rats received IMD-0354 (30 mg/kg) or an equal volume of 4% dimethyl sulfoxide (DMSO) in phosphate-buffered saline intraperitoneally for six consecutive weeks. The following four groups of primary rat retinal microglia and Müller cells were used: control (5 mM), control + IMD-0354, high glucose (20 mM), and high glucose + IMD-0354. The effects of IMD-0354 on nuclear factor-κB (NF-κB) activation, oxidative stress strength, expression of inflammatory cytokines and VEGF (vascular endothelial growth factor), activation of glial cells, and apoptosis of neuron cells were evaluated by immunohistochemistry, oxidative stress assays, western blot, enzyme linked immunosorbent assay (ELISA) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining respectively. Nuclear translocation of NF-κB was markedly increased in diabetic rat retina and high glucose treated glial cells. Systemic administration of IMD-0354 significantly inhibited NF-κB activation in both diabetic rat retina and high glucose treated glial cells, ameliorated oxidative injury, inflammatory responses, VEGF production and glial cell activation, and protected neurons from apoptosis. Our findings indicated that NF-κB activation is acritical step in the abnormal reactivity of glial cells in STZ-induced diabetic rats. Inhibition effect of IMD-0354 on NF-κB activation may represent a promising therapeutic strategy for DR via a variety of mechanisms, including inflammation reduction and glial cells regulation.

Diazoxide improves muscle function in association with improved dyslipidemia and decreased muscle oxidative stress in streptozotocin-induced diabetic rats.

Diabetes Mellitus is a chronic degenerative disease, and its main biochemical characteristic is hyperglycemia due to impaired insulin secretion, resistance to peripheral actions of insulin, or both. Hyperglycemia causes dyslipidemia and stimulates oxidative damage, leading to the main symptoms, such as fatigue and culminates in diabetic complications. Previous studies have shown that ATP-sensitive potassium channels counteract muscle fatigue and metabolic stress in healthy mouse models. To determine the effect of diazoxide on muscle strength development during diabetes, we tested the effect of diazoxide in streptozotocin-diabetic rats in muscle function, lipid profile and oxidative stress biomarkers. Wistar rats were divided into 4 groups of six animals each: (1) Control group, (2) diabetes group, (3) Control group + diazoxide, and (4) Diabetic + diazoxide (DB + DZX). 4 weeks after rats were sacrificed, soleus and extensor digitorum longus muscles (EDL) were extracted to prepare homogenates and serum was obtained for biochemical measurements. Oxidative damage was evaluated by the thiobarbituric acid method and the fluorescent for reactive oxygen species (ROS) probe 2,4-H2DCFDA, respectively. Diabetic rats with diazoxide administration showed an increase in the development of muscle strength in both muscles; in turn, the onset of fatigue was longer compared to the group of diabetic rats without treatment. Regarding the lipid profile, diazoxide decreased total cholesterol levels in the group of diabetic rats treated with diazoxide (x̅46.2mg/dL) compared to the untreated diabetic group (x̅=104.4mg/dL); secondly, diazoxide decreased triglyceride concentrations (x̅=105.3mg/dL) compared to the untreated diabetic rats (x̅=412.2mg/dL) as well as the levels of very low-density lipoproteins (x̅=20.4mg/dL vs. x̅=82.44mg/dL). Regarding the various markers of oxidative stress, the diabetic group treated with diazoxide was able to reduce the concentrations of TBARS and total reactive oxygen species as well as preserve the concentrations of reduced glutathione. Diazoxide administration in diabetic rats increases muscle strength development in EDL and soleus muscle, decreases fatigue, reduces cholesterol and triglyceride concentrations and improves oxidative stress parameters such as TBARS, ROS, and glutathione status.

Evaluation of Antidiabetic, Antioxidant and Anti-Hyperlipidemic Effects of Solanum indicum Fruit Extract in Streptozotocin-Induced Diabetic Rats.

Globally, diabetes mellitus is the most common cause of premature mortality after cardiovascular diseases and tobacco chewing. It is a heterogeneous metabolic disorder characterised by the faulty metabolism of carbohydrates, fats and proteins as a result of defects in insulin secretion or resistance. It was estimated that approximately 463 million of the adult population are suffering from diabetes mellitus, which may grow up to 700 million by 2045. Solanum indicum is distributed all over India and all of the tropical and subtropical regions of the world. The different parts of the plant such as the roots, leaves and fruits were used traditionally in the treatment of cough, asthma and rhinitis. However, the hypoglycaemic activity of the plant is not scientifically validated. The present study aimed to evaluate the antioxidant, antidiabetic and anti-hyperlipidaemic activity of methanolic fruit extract of Solanum indicum (SIE) in streptozotocin (STZ) induced diabetic rats. Experimentally, type II diabetes was induced in rats by an i.p. injection of STZ at a dose of 60 mg/kg. The effect of the fruit extract was evaluated at doses of 100 and 200 mg/kg body weight in STZ-induced diabetic rats for 30 days. The oral administration of fruit extract caused a significant (p < 0.05) reduction in the blood glucose level with a more prominent effect at 200 mg/kg. The fruit extract showed dose-dependent α-amylase and α-glycosidase inhibitory activity. It reduced the serum cholesterol and triglyceride levels remarkably in diabetic rats compared to normal. The extract showed the reduced activity of endogenous antioxidants, superoxide dismutase, glutathione peroxidase and catalase in the liver of STZ diabetic rats. The result confirmed that the fruit extract of Solanum indicum showed a dose-dependent blood glucose lowering effect and significantly reduced elevated blood cholesterol and triglycerides. It prevented oxidative stress associated with type II diabetes in STZ rats.

Fermented seeds of Pentaclethra macrophylla mitigate against memory deficit and restored altered enzymatic activity in the brain of streptozotocin-diabetic rats.

Memory deficit has been reported as one of the complications of diabetes. Fermented seeds of Pentaclethra Macrophylla (P. macrophylla) have been used in folklore for the management of metabolic diseases. The research aims to evaluate the impact of diets with the inclusion of the fermented seed of P. macrophylla on memory deficit in diabetic rats and its underlying mechanisms. Before the induction, the rats were subjected to training sessions. Thereafter, streptozotocin (50mg/kg body weight) was administered to the trained rats via intraperitoneal (i.p). 72hours after, the rats blood glucose level was checked, rats with blood glucose level greater than 250mg/dl were selected for the memory index evaluation study. The induced rats were randomly distributed into groups: Normal rats (group 1), untreated diabetic rat (Group 2), acarbose treated diabetic rats (group 3); diabetic rats placed on diet supplemented with fermented seed of P. macrophylla (10 & 20% inclusion) were allotted to group 4 & 5. Then, evaluation of memory retention capacity was performed on the day 14 of the experiment. Thereafter, experimental rats were sacrificed, tissue of interest (brain) was excised, homogenized and homogenates were used for biochemical analysis. The cholinergic, angiotensin-1-converting enzyme (ACE), arginase activity and biomarkers for oxidative stress were significantly altered in untreated diabetic rats when compared with non-diabetes rats. Also, the memory capacity of the diabetic rats was significantly reduced when compared with the non-diabetes rats. Meanwhile, diabetic rats placed on diet with fermented seeds of P. macrophylla (10 & 20% inclusion) exhibited significantly higher memory capacity, lower activity of cholinergic, ACE, arginase activity in relation to untreated diabetic rats while the antioxidant status of the brain was enhanced. Nevertheless, fermented seeds of P. macrophylla ameliorated memory deficit in STZ induced diabetes rats. This gave credence to P. macrophylla nutraceutical potential as claimed in folk medicine.

Study of hypoglycemic properties of «Glyphasonorm» tablets and «Glyphasolin» capsules on the streptozotocin-induced diabetic rat model

The risk of developing any complications of diabetes is significantly reduced by monitoring and correcting blood glucose levels and blood pressure, as well as by observing healthy lifestyle rules. Early detection and treatment of type 2 diabetes contribute to the prevention of disease progression and the development of complications.&#x0D; The aim is to study the hypoglycemic effect of «Glyphasonorm» tablets and «Glyphasolin» capsules in a rat model of streptozotocin-induced diabetes.&#x0D; Materials and methods. The studies were carried out on Wistar rats injected intraperitoneally with nicotinamide at a dose of 230 mg/kg 15 minutes before intravenous injection of streptozotocin at a dose of 65 mg/kg. The dynamics of body weight of rats, glucose and glycosylated haemoglobin levels under the impact of long-term administration of metformin, «Glyphasonorm» tablets and «Glyphasolin» capsules were investigated.&#x0D; Results and discussion. The studies on a streptozotocin-induced diabetic model have established that under the action of «Glyphasonorm» tablets and «Glyphasolin» capsules, the level of glycosylated haemoglobin, which decreased along with the level of glucose in the blood of animals, was significantly reduced in comparison with diabetic control. After 14 days of research, the "Glyphasolin" capsules showed more pronounced hypoglycemic activity (4.4 % and 8.0 % more) than the "Glyphasonorm" tablets and the reference drug metformin. The «Glyphasolin» capsules on the 12th day of the study showed a marked decrease in glycosylated haemoglobin in the blood of animals (3.1 % and 5.6 % more) than the «Glyphasonorm» tablets and metformin.&#x0D; Conclusions. In the experimental model of streptozotocin diabetes in rats, "Gliphasolin" capsules showed a more pronounced hypoglycemic effect, which was manifested by a decrease in the content of glycosylated haemoglobin in the blood and prevailed over the effect of the comparative drug metformin and "Gliphasonorm" tablets.&#x0D; «Glyphasolin» capsules and «Glyphasonorm» tablets based on bioflavonoid complex from bean show promise in the treatment of type 2 diabetes on the background of obesity and reducing the risk of micro- and macroangiopathy

Comparative Efficacy Study of N-Chromosome Royal Jelly Versus Semelil (ANGIPARS) on Wound Healing of Diabetic Rats

Objective: The healing effects of two different dilutions (5 &amp; 100%) of N-Chromosome Royal Jelly and ANGIPARS ointment were investigated and measured on experimental injuries in streptozotocin (STZ)- induced diabetic rats. This study investigated the healing effects of 2 different N Chromosome Royal Jelly dilutions on injuries of STZ-induced diabetic rats.&#x0D; Materials and Methods: For diabetes induction, male Wistar rats received STZ (55 mg/kg) intraperitoneally and plasma glucose level measurement after 72 hours demonstrated diabetes induction. Rats were randomly divided into 5 groups of 6 members and one square centimeter (cm2 ) wound was surgically induced in the dorsal region of each rat. The test groups were treated with ANGIPARS, undiluted royal jelly N chromosome, and royal jelly N chromosome 5% separately. The control groups were including non-diabetic and untreated diabetic rats.&#x0D; Results: The findings indicate a significant acceleration in wound healing of the diabetic rats treated by ANGIPARS ointment or royal jelly N chromosomes 5%. RJ also shortened the healing period of desquamated skin lesions. Thus, RJ possesses an anti-inflammatory action and is able to augment wound healing, but does not have an insulin-like action in streptozotocin-diabetic rats.&#x0D; Conclusion: Regarding the mentioned findings, royal jelly as a natural product may play an effective role in treating chronic wounds in mice, which makes it a proper candidate for use in human wound repair. Nonetheless, it seems that determination of the suitable dilution of this compound will result in better effects, thus more studies are recommended.

Effect of Trigonelline on Dendritic Morphology in the Hippocampus and Prefrontal Cortex in Streptozotocin-Induced Diabetic Rats

Introduction: Diabetes mellitus causes adverse changes in the neurological morphology of the hippocampus and prefrontal cortex of the brain by increasing oxidative stress. Trigonelline has antihyperglycemic effects and can inhibit oxidative stress. The aim of this study was to evaluate the protective effect of trigonelline on dendritic changes in hippocampal and prefrontal cortex neurons in diabetic rats.&#x0D; Methods: In this experimental study, 32 male Wistar rats in the weight range of 195-235 grams were randomly divided into 4 groups consisting of control, trigonelline-treated control, diabetic and trigonelline-treated diabetic. Oral trigonelline treatment at a dose of 50 mg/kg/day during 7 weeks was done. Diabetes induction was done by single dose injection of intraperitoneal streptozotocin at a dose of 60 mg/kg. Serum glucose and body weight were measured at the beginning and at weeks 4 and 8 after diabetes induction. For evaluation of hippocampal and prefrontal cortex neuronal dendrites, Golgi impregnation method was used. For statistical analysis, one-way ANOVA and Tukey post-tests in SPSS version 16 were used. P&lt;0.05 was considered as a significant level.&#x0D; Results: Serum glucose level in the diabetic group treated with trigonelline significantly has been reduced compared with the diabetic group (p&lt;0.01). The density of dendritic spines of prefrontal cortex and hippocampal neurons in the diabetic group significantly reduced compared to the control group (p&lt;0.01). Moreover, in the diabetic group treated with trigonelline, dendritic spine density significantly increased compared to the diabetic group (p&lt;0.05).&#x0D; Conclusion: Trigonelline is hypoglycemic and can prevent reduction of dendritic spines in the prefrontal cortex and the hippocampus of streptozotocin diabetic rats.

Guanfacine Normalizes the Overexpression of Presynaptic α-2A Adrenoceptor Signaling and Ameliorates Neuropathic Pain in a Chronic Animal Model of Type 1 Diabetes.

Background: Diabetes is associated with several complications, including neuropathic pain, which is difficult to manage with currently available drugs. Descending noradrenergic neurons possess antinociceptive activity; however, their involvement in diabetic neuropathic pain remains to be explored. Methods: To infer the regulatory role of this system, we examined as a function of diabetes, the expression and localization of alpha-2A adrenoceptors (α2-AR) in the dorsal root ganglia and key regions of the central nervous system, including pons and lumbar segment of the spinal cord using qRT-PCR, Western blotting, and immunofluorescence-based techniques. Results: The data revealed that presynaptic synaptosomal-associated protein-25 labeled α2-AR in the central and peripheral nervous system of streptozotocin diabetic rats was upregulated both at the mRNA and protein levels. Interestingly, the levels of postsynaptic density protein-95 labeled postsynaptic neuronal α2-AR remained unaltered as a function of diabetes. These biochemical abnormalities in the noradrenergic system of diabetic animals were associated with increased pain sensitivity as typified by the presence of thermal hyperalgesia and cold/mechanical allodynia. The pain-related behaviors were assessed using Hargreaves apparatus, cold-plate and dynamic plantar aesthesiometer. Chronically administered guanfacine, a selective α2-AR agonist, to diabetic animals downregulated the upregulation of neuronal presynaptic α2-AR and ameliorated the hyperalgesia and the cold/mechanical allodynia in these animals. Conclusion: Together, these findings demonstrate that guanfacine may function as a potent analgesic and highlight α2-AR, a key component of the descending neuronal autoinhibitory pathway, as a potential therapeutic target in the treatment of diabetic neuropathic pain.

Phenolic fraction concentrates supplementation ameliorates learning and memory impairments in chronically stressed streptozotocin-diabetic rats by reducing brain tumor necrosis factor-α

Introduction: The present work aims to assess if insulin combined with phenolic fraction concentrates (PFCs) prevents diabetes-related cognitive impairments by controlling neuroinflammation in streptozotocin-induced diabetic rats exposed to chronic mild stress (CMS). Methods: Directly after confirming the hyperglycemia, diabetic animals were treated with insulin combined with PFC and were exposed to 2 stressors/day for 12 weeks. Then, four cognitive tests were carried out to assess learning and memory performances. Finally, the rats were anesthetized, blood samples were collected for corticosterone and Tumor necrosis factor alpha (TNF-α) analysis, and the brain regions viz. striatum, hippocampus, and prefrontal-cortex of each hemisphere were dissected out for TNF-α analysis. Results: Both diabetes and stress could induce learning and memory impairments, which were more prominent in stressed diabetic animals, and significantly reversed by insulin treatment supplemented with PFC compared to the insulin monotherapy. Moreover, diabetic rats exposed to CMS displayed disturbances in glucose homeostasis as well as corticosterone secretion. These dysfunctions were linked to the significant increase of TNF-α in the blood as well as in the prefrontal cortex, hippocampus, and striatum. Insulin significantly ameliorated this inflammatory abnormality, while the supplemented treatment showed a significant effect, by stabilizing TNF-α to its normal levels in the hippocampus and in the blood when compared to insulin monotherapy. Conclusion: Insulin supplemented with PFC has a favorable effect over insulin alone on inflammatory aberrations linked with type 1 diabetes and stress in animals, confirming the preference of the combined treatment over insulin for the management of cognitive impairment in stressed diabetic subjects.

Recurrent hypoglycemia increases hepatic gluconeogenesis without affecting glycogen metabolism or systemic lipolysis in rat

IntroductionRecurrent hypoglycemia (RH) impairs secretion of counterregulatory hormones. Whether and how RH affects responses within metabolically important peripheral organs to counterregulatory hormones are poorly understood. ObjectiveTo study the effects of RH on metabolic pathways associated with glucose counterregulation within liver, white adipose tissue and skeletal muscle. MethodsUsing a widely adopted rodent model of 3-day recurrent hypoglycemia, we first checked expression of counterregulatory hormone G-protein coupled receptors (GPCRs), their inhibitory regulators and downstream enzymes catalyzing glycogen metabolism, gluconeogenesis and lipolysis by qPCR and western blot. Then, we examined epinephrine-induced phosphorylation of PKA substrates to validate adrenergic sensitivity in each organ. Next, we measured hepatic and skeletal glycogen content, degree of breakdown by epinephrine and abundance of phosphorylated glycogen phosphorylase under hypoglycemia and that of phosphorylated glycogen synthase during recovery to evaluate glycogen turnover. Further, we performed pyruvate and lactate tolerance tests to assess gluconeogenesis. Additionally, we measured circulating FFA and glycerol to check lipolysis. The abovementioned studies were repeated in streptozotocin-induced diabetic rat model. Finally, we conducted epinephrine tolerance test to investigate systemic glycemic excursions to counterregulatory hormones. Saline-injected rats served as controls. ResultsRH increased counterregulatory hormone GPCR signaling in liver and epidydimal white adipose tissue (eWAT), but not in skeletal muscle. For glycogen metabolism, RH did not affect total content or epinephrine-stimulated breakdown in liver and skeletal muscle. Although RH decreased expression of phosphorylated glycogen synthase 2, it did not affect hepatic glycogen biosynthesis during recovery from hypoglycemia or after fasting-refeeding. For gluconeogenesis, RH upregulated fructose 1,6-bisphosphatase 1 and monocarboxylic acid transporter 1 that imports lactate as precursor, resulting in a lower blood lactate profile during hypoglycemia. In agreement, RH elevated fasting blood glucose and caused higher glycemic excursions during pyruvate tolerance test. For lipolysis, RH did not affect circulating levels of FFA and glycerol after overnight fasting or upon epinephrine stimulation. Interestingly, RH upregulated the trophic fatty acid transporter FATP1 and glucose transporter GLUT4 to increase lipogenesis in eWAT. These aforementioned changes of gluconeogenesis, lipolysis and lipogenesis were validated in streptozotocin-diabetic rats. Finally, RH increased insulin sensitivity to accelerate glucose disposal, which was attributable to upregulated visceral adipose GLUT4. ConclusionsRH caused metabolic adaptations related to counterregulation within peripheral organs. Specifically, adrenergic signaling was enhanced in liver and visceral fat, but not in skeletal muscle. Glycogen metabolism remained unchanged. Hepatic gluconeogenesis was augmented. Systemic lipolysis was unaffected, but visceral lipogenesis was enhanced. Insulin sensitivity was increased. These findings provided insights into mechanisms underlying clinical problems associated with intensive insulin therapy, such as high gluconeogenic flux and body weight gain.