Rat Model Of Type Research Articles

Potential of stem cell-derived exosomes to regenerate β islets through Pdx-1 dependent mechanism in a rat model of type 1 diabetes.

Type 1 diabetes, has been recognized as an autoimmune disease. Like other immunological conditions, regulation of immune response is a key strategy to control the autoimmunity in diabetic patients. Mesenchymal stem cells have been shown to have a distinct potential in modulating the immune reactions. However, treatment with stem cells is combined with concerns about safety issues. To overcome these concerns, in this study, we have utilized the regenerative potential of exosomes isolated from menstrual blood-derived mesenchymal stem cells to restore the β-cell mass and insulin production in type 1 diabetes. Exosomes are nanovesicles containing various cargos involved in cellular communications. Streptozotocin was used to induce islet destruction and diabetes in male Wistar rats. Then, exosomes were intravenously injected into animals at different time points and in a single or repeated therapeutic doses. After about 6 weeks, animals were euthanized and the pancreas was analyzed for the presence of the regenerated β islets as well as the insulin secretion. The non-fasting blood glucose and the serum insulin level were also monitored during the study. Our results represented that menstrual blood-derived mesenchymal stem cell-derived exosomes enhance the β-cell mass and insulin production in the pancreas of diabetic animals that received repeated doses of exosomes. Immunohistochemistry analysis also confirmed the presence of insulin in the islets of treated animals. Further investigations proposed that exosomes induce the islet regeneration through pancreatic and duodenal homeobox 1 pathway. The exosome tracking also revealed the homing of injected exosomes to the pancreas.

Pharmacological blockade of the P2X7 receptor reverses retinal damage in a rat model of type 1 diabetes.

Retinopathy is a leading cause of vision impairment in diabetes. Its pathogenesis involves inflammation, pathological angiogenesis, neuronal and glial dysfunction. The purinergic P2X7 receptor (P2X7R) has a leading role in inflammation and angiogenesis. Potent and selective P2X7R blockers have been synthesized and tested in Phase I/II clinical studies. We hypothesize that P2X7R blockade will ameliorate diabetes-related pathological retinal changes. Streptozotocin (STZ)-treated rats were intraperitoneally inoculated with either of two small molecule P2X7R receptor inhibitors, A740003 and AZ10606120, and after blood glucose levels increased to above 400mg/dL, retinae were analyzed for P2X7R expression, vascular permeability, VEGF, and IL-6 expression. STZ administration caused a near fourfold increase in blood glucose, a large increase in retinal microvasculature permeability, as well as in retinal P2X7R, VEGF, and IL-6 expression. P2X7R blockade fully reversed retinal vascular permeability increase, VEGF accumulation, and IL-6 expression, with no effect on blood glucose. P2X7R blockade might be promising strategy for the treatment of microvascular changes observed in the early phases of diabetic retinopathy.

Sex Differences in the Progression of Type 2 Diabetic Nephropathy

Diabetic nephropathy (DN) is the leading cause of chronic renal disease. To explore the age‐related progression and sexual dimorphisms in the development of DN, we used a rat model of type 2 diabetic nephropathy (T2DN). The T2DN rat was previously created by introgression of the mitochondria and some passenger loci from the Fawn Hooded Hypertensive rat into the background of the Goto‐Kakizaki (GK; type 2 diabetic) rat. Type 2 diabetes in T2DN rats is accompanied by renal histologic abnormalities that are characteristic of DN, similar to clinical observations in human patients. The experimental groups were Wistar (non‐diabetic controls), GK, or T2DN rats at the early stages of DN (12 weeks old) or the late stages of the disease (>40 weeks of age). At the early stage of DN, male T2DN and GK rats showed significant increases in blood glucose (374 ± 96 and 329 ± 45 vs. 280 ± 24 mg/dL in Wistar, respectively) and kidneys to body weight ratio (10.05 ± 1.19 and 9.39 ± 0.78 vs. 7.31 ± 1.13 mg/g, respectively). In the late stage of the disease progression, T2DN rats had a significant increase in renal damage compared with GK and Wistar rats, indicated by progressive albuminuria, diuresis, a high prevalence of medullary protein cats, and glomerular lesions. Besides a striking DN phenotype in the T2DN model, we found significant sex differences in the development and progression of the disease. The male weight was double that of females (414 ± 27 vs. 264 ± 19 g, respectively), which correlates with a significant difference in postprandial blood glucose levels (435 ± 50 vs. 353 ± 46 mg/dL, respectively). To further evaluate changes in type 2 diabetes between the sexes, we performed the glucose tolerance test (GTT) in fasting animals. The male GTT indicates significant impairment in the body's response to sugar load compared to the female (155 ± 18 vs. 118 ± 5 at control and 378 ± 19 vs. 183 ± 48 mg/dL after oral glucose gavage; male vs female respectively). Blood tests also show elevated levels of serum alkaline phosphatase (158 ± 32 U/L) and cholesterol in males, similar to the clinical observations in patients with diabetes mellitus. Analysis of the renal damage between the sexes reveals significant increases in protein cast formation and glomerular abnormalities indicated by a high percentage of damaged glomeruli in males (28% vs. 4% in females). Aged male T2DN rats also had increases in nephrin shedding in their urine, which correlates with the dramatic differences in albuminuria. In T2DN males, there was an inverse correlation in serum levels (2.5 ± 0.2 vs. 3.3 ± 0.1 g/dL) and urinary excretion of albumin (11.8 ± 5.7 vs. 0.98 ± 0.64 Alb/Cre ratio) in comparison to females of similar age. Here we report that T2DN rat develops renal and physiological lesions to those seen in patients with type 2 diabetes, and there is a dramatic sex difference in the progression of renal damage.Support or Funding InformationNHLBI R35 HL135749 and P01 HL116264AHA 17SDG33660149 and 18PRE34030127ADA 1‐15‐BS‐172This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Spatial and temporal studies of metabolic activity: contrasting biochemical kinetics in tissues and pathways during fasted and fed states.

The regulation of nutrient homeostasis, i.e., the ability to transition between fasted and fed states, is fundamental in maintaining health. Since food is typically consumed over limited (anabolic) periods, dietary components must be processed and stored to counterbalance the catabolic stress that occurs between meals. Herein, we contrast tissue- and pathway-specific metabolic activity in fasted and fed states. We demonstrate that knowledge of biochemical kinetics that is obtained from opposite ends of the energetic spectrum can allow mechanism-based differentiation of healthy and disease phenotypes. Rat models of type 1 and type 2 diabetes serve as case studies for probing spatial and temporal patterns of metabolic activity via [2H]water labeling. Experimental designs that capture integrative whole body metabolism, including meal-induced substrate partitioning, can support an array of research surrounding metabolic disease; the relative simplicity of the approach that is discussed here should enable routine applications in preclinical models.

The Role of Iron and Nerve Inflammation in Diabetes Mellitus Type 2-Induced Peripheral Neuropathy

Peripheral diabetic neuropathy (PDN) is one of the most common complications of diabetes mellitus. Previous studies showed an association between dietary iron load and inflammation in the development of PDN in a rat model of type 1 diabetes (T1D). Here we investigated the role of iron and neural inflammation in development of PDN in a animal model of obesity and type 2 diabetes (T2D). 3-month-old db/db mice were fed with a high, standard or low iron diet for 4 months. High iron chow lead to a significant increase in motor nerve conduction velocities compared to mice on standard and low iron chow. Direct beneficiary effects on lowering blood glucose and HbA1c concentrations were shown in the high iron treated diabetic mice. Numbers of pro-inflammatory M1 macrophages were reduced in nerve sections, and anti-inflammatory M2 macrophages were increased in db/db mice on high iron diet compared to other groups. These results confirm and extend our previous findings in STZ-diabetic rats by showing that dietary non-hem iron supplementation may partly prevent the development of PDN in opposition to iron restriction. The identification of these dietary iron effects on the metabolic and inflammatory mechanisms of PDN supports a role of dietary iron and leads us to suggest testing for iron levels in human diabetic patients.

Neuroprotective effects of PPARα in retinopathy of type 1 diabetes.

Diabetic retinopathy (DR) is a common neurovascular complication of type 1 diabetes. Current therapeutics target neovascularization characteristic of end-stage disease, but are associated with significant adverse effects. Targeting early events of DR such as neurodegeneration may lead to safer and more effective approaches to treatment. Two independent prospective clinical trials unexpectedly identified that the PPARα agonist fenofibrate had unprecedented therapeutic effects in DR, but gave little insight into the physiological and molecular mechanisms of action. The objective of the present study was to evaluate potential neuroprotective effects of PPARα in DR, and subsequently to identify the responsible mechanism of action. Here we reveal that activation of PPARα had a robust protective effect on retinal function as shown by Optokinetic tracking in a rat model of type 1 diabetes, and also decreased retinal cell death, as demonstrated by a DNA fragmentation ELISA. Further, PPARα ablation exacerbated diabetes-induced decline of visual function as demonstrated by ERG analysis. We further found that PPARα improved mitochondrial efficiency in DR, and decreased ROS production and cell death in cultured retinal neurons. Oxidative stress biomarkers were elevated in diabetic Pparα-/- mice, suggesting increased oxidative stress. Mitochondrially mediated apoptosis and oxidative stress secondary to mitochondrial dysfunction contribute to neurodegeneration in DR. Taken together, these findings identify a robust neuroprotective effect for PPARα in DR, which may be due to improved mitochondrial function and subsequent alleviation of energetic deficits, oxidative stress and mitochondrially mediated apoptosis.

Hypoglycemic and Hypolipidemic Effects of Phellinus Linteus Mycelial Extract from Solid-State Culture in A Rat Model of Type 2 Diabetes.

Hypoglycemic and hypolipidemic effects of P. linteus have been observed in numerous studies, but the underlying molecular mechanisms are unclear. In this study, we prepared P. linteus extract (PLE) from mycelia of solid-state culture, and evaluated its hypoglycemic and hypolipidemic effects in rat models of high-fat diet (HFD)-induced and low-dose streptozotocin (STZ)-induced type 2 diabetes. PLE treatment effectively reduced blood glucose levels, and improved insulin resistance and lipid and lipoprotein profiles. The hypoglycemic effect of PLE was based on inhibition of key hepatic gluconeogenesis enzymes (FBPase, G6Pase) expression and hepatic glycogen degradation, and consequent reduction of hepatic glucose production. PLE also: (i) enhanced expression of CPT1A and ACOX1 (key proteins involved in fatty acid β-oxidation) and low-density lipoprotein receptor (LDLR) in liver, thus promoting clearance of triglycerides and LDL-C; (ii) inhibited expression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in liver, thus reducing cholesterol production; (iii) displayed strong hepatoprotective and renal protective effects. Our findings indicate that PLE has strong potential functional food application in adjuvant treatment of type 2 diabetes with dyslipidemia.

Commercially available non-nutritive sweeteners modulate the antioxidant status of type 2 diabetic rats.

Non-nutritive sweeteners (NNS) are increasingly being used by diabetics, but little is known about their effects on antioxidant status. We investigated the effects of ad libitum consumption of commercially available NNS (aspartame, saccharin, sucralose, and cyclamate-based sweeteners) on antioxidative markers in a rat model of type 2 diabetes (T2D). NNS consumption reduced (p<0.05) T2D-induced lipid peroxidation and boosted serum, hepatic, renal, cardiac, and pancreatic glutathione (GSH) levels. Catalase, glutathione reductase, superoxide dismutase, and glutathione peroxidase activity was increased in the serum and most organs upon diabetes induction, perhaps due to adaptative antioxidant response to the diabetes-induced lipid peroxidation. NNS showed varying effects on serum and tissue antioxidant enzymes of animals. An antioxidant capacity scores sheet of NNS, suggest that aspartame-based NNS may not exert antioxidant effects in diabetics, while saccharin-based NNS may be a potent antioxidative sweetener as seen in the animal model of T2D. PRACTICAL APPLICATIONS: The use of NNS is becoming more popular, especially for diabetic individuals. While there are several commercial NNS available in the market, little is known about how they affect the antioxidant status of consumers. We therefore investigated how some commercially available NNS affect the antioxidant status of diabetic rats. Observed data revealed varying effects of NNS on serum and different organs, which suggest that some NNS may be better than others for diabetic oxidative stress and thus may be recommended for consumers. However, this finding is subject to additional corroborative clinical studies.

Obesity and inactivity, not hyperglycemia, cause exercise intolerance in individuals with type 2 diabetes: Solving the obesity and inactivity versus hyperglycemia causality dilemma

Obesity, a sedentary lifestyle and type 2 diabetes are intricately linked conditions contributing to reduced exercise tolerance, significant morbidity, and premature deaths. It is unknown whether the reported exercise intolerance associated with type 2 diabetes is a direct result of the hyperglycemia, the impact of a relatively sedentary lifestyle, or increased adiposity. We hypothesize that obesity and inactivity, not hyperglycemia, cause exercise intolerance in individuals with type 2 diabetes. An analysis of the literature and results from the Goto-Kakizaki (GK) rat model of type 2 diabetes strongly support this hypothesis. GK rats were not sedentary or obese when compared with Wistar control rats and did not have exercise intolerance. Specifically, despite being hyperglycemic, GK rats demonstrated a longer treadmill run time to exhaustion (150.6 ± 9.0 vs. 77.2 ± 12.9 min), further distance run (1506 ± 90 vs. 772 ± 129 m), more work performed per gram muscle (44.0 ± 2.8 vs. 21.9 ± 3.8 kg*m/g) and a small increase in total vertical work performed when accounting for body mass (116.8 ± 6.3 versus 98.9 ± 15.2 kg*m). These results document preserved exercise tolerance in the non-obese, non-sedentary GK rat supporting the hypothesis that the reported exercise intolerance in models of type 2 diabetes is dependent on obesity and inactivity. Solving the obesity and inactivity versus hyperglycemia causality dilemma is important in understanding the development of type 2 diabetes and implications for future pharmacological and life style interventions.

Nelumbo nucifera leaves extract attenuate the pathological progression of diabetic nephropathy in high-fat diet-fed and streptozotocin-induced diabetic rats

Diabetic nephropathy is not only a common and severe microvascular complication of diabetes mellitus but also the leading cause of renal failure. Lotus (Nelumbo nucifera) possesses antioxidative and anticancer properties. The present study aimed to investigate the antidiabetic and renoprotective effects of N. nucifera leaf extract (NLE) in a rat model of type 2 diabetic mellitus. Male Sprague–Dawley rats with type 2 diabetes induced by a high-fat diet (HFD)/streptozotocin (STZ) were treated with NLE at dosages of 0.5% and 1% (w/w) daily for 6 weeks. At the end of the experimental period, body weight, serum glucose levels, insulin levels, and kidney function were assessed. Furthermore, antioxidant enzyme and lipid peroxide levels were determined in the kidney, and histopathological examination was performed using hematoxylin and eosin staining, periodic acid Schiff staining, and Masson trichrome staining. To shed light on the molecular mechanism underlying the functioning of NLE, mouse glomerular mesangial cells (MES-13) treated with high glucose (HG, 25 mM glucose) were chosen as a model for an examination of the signal transduction pathway of NLE. The results revealed that NLE improved diabetic kidney injury by reducing blood glucose, serum creatinine, and blood urea nitrogen levels and enhanced antioxidant enzyme activities in kidney tissue. Treatment with NLE significantly reduced the malondialdehyde and 8-hydroxy-2-deoxyguanosine levels and increased serum insulin levels; expression of renal superoxide dismutase, catalase, and glutathione peroxidase activities; and glutathione content. Histological studies have also demonstrated that NLE treatment inhibited the dilation of Bowman's capsule, which confirmed its renoprotective action in diabetes. In addition, treatment with NLE and its major component quercetin 3-glucuronide attenuated 25 mM HG-induced suppressed nuclear factor erythroid 2-related factor 2 and antioxidant enzyme expression in MES-13 cells. Collectively, these findings indicate that NLE may have antidiabetic and renoprotective effects against HFD/STZ-induced diabetes, at least in part, through antioxidative pathways.

Overexpression of renal proapoptotic factors is attenuated subsequent to endurance exercise in Type I diabetes: An immunohistochemistry study

Background: Upregulation of Apoptotic markers (p53 and active caspase-3) is reported in diabetic nephropathy. Exercise training is reported to exert renoprotective effects in diabetes. This study correlated the effects of endurance exercise training on the renal expression of p53 and active caspase-3 in a rat model of Type 1 diabetes. Materials and methods: Thirty healthy Sprague-Dawley rats were randomly divided into the following three groups: sedentary control (SC), sedentary diabetic (SD) rats, and exercised diabetic (ED) rats. The drug alloxan was administered to SD and ED groups of rats in order to induce diabetes mellitus. Expression of p53 and active caspase-3 in the renal tissue from each of the three different groups was investigated by immunohistochemistry. Increased blood levels compared to control group of rats validated the onset of diabetes in rats from SD and ED groups. Results: Significantly (P

A deletion in the Ctns gene causes renal tubular dysfunction and cystine accumulation in LEA/Tohm rats

The Long-Evans Agouti (LEA/Tohm) rat has recently been established as a new rat model of type 2 diabetes. The onset of diabetes mellitus was observed only in male LEA/Tohm rats; however, urinary glucose appeared before the onset of diabetes. To clarify the genetic basis of urinary glucose, we performed genetic linkage analysis using (BN × LEA) F2 intercross progeny. A recessively acting locus responsible for urinary glucose excretion (ugl) was mapped to a 7.9 Mb region of chromosome 10, which contains the cystinosin (Ctns) gene. The Ctns gene encodes the cystine transporter, which transports cystine out of the lysosome and is responsible for nephropathic cystinosis in humans. Sequence analysis identified a 13-bp deletion in the Ctns gene, leading to a truncated and loss-of-function protein, which cause cystine accumulation in various tissues. We also developed a novel congenic rat strain harboring the Ctnsugl mutation on the F344 genetic background. Phenotypic analysis of F344-Ctnsugl rats indicated that the incidence of urinary glucose was 100% in both males and females at around 40 weeks of age, and marked cystine accumulation was observed in the tissues, as well as remarkable renal lesions and cystine crystals in the lysosomes of the renal cortex. Furthermore, treatment with cysteamine depleted the cystine contents in F344-Ctnsugl rat embryonic fibroblasts. These results indicated that the F344-Ctnsugl rat provides a novel rat model of cystinosis, which allows not only a better understanding of the pathogenesis and pathophysiology of cystinosis but will also contribute to the development of new therapies.

Characterization of the Goto-Kakizaki (GK) Rat Model of Type 2 Diabetes.

The Goto-Kakizaki (GK) rat is a model of type 2 diabetes mellitus, produced originally by selective inbreeding for a hyperglycemic trait. These rats are characterized as having insulin resistance and an insulin secretory defect. Pancreatic islets from these mice show abnormal morphology in the distribution of glucagon-secreting α cells and insulin-secreting β cells, which may affect paracrine functions involved in the secretory response. This chapter describes the characterization of GK rat islets using immunofluorescence microscopy and Western blot analyses to demonstrate the effects on islet architecture and how this translates to changes in expression of predominant islet proteins.

Left Ventricular Diastolic Dysfunction in a Rat Model of Diabetic Cardiomyopathy using ECG-gated 18F-FDG PET

In diabetic cardiomyopathy, left ventricular (LV) diastolic dysfunction is one of the earliest signs of cardiac involvement prior to the definitive development of heart failure (HF). We aimed to explore the LV diastolic function using electrocardiography (ECG)-gated 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging beyond the assessment of cardiac glucose utilization in a diabetic rat model. ECG-gated 18F-FDG PET imaging was performed in a rat model of type 2 diabetes (ZDF fa/fa) and ZL control rats at age of 13 weeks (n = 6, respectively). Under hyperinsulinemic-euglycemic clamp to enhance cardiac activity, 18F-FDG was administered and subsequently, list-mode imaging using a dedicated small animal PET system with ECG signal recording was performed. List-mode data were sorted and reconstructed into tomographic images of 16 frames per cardiac cycle. Left ventricular functional parameters (systolic: LV ejection fraction (EF), heart rate (HR) vs. diastolic: peak filling rate (PFR)) were obtained using an automatic ventricular edge detection software. No significant difference in systolic function could be obtained (ZL controls vs. ZDF rats: LVEF, 62.5 ± 4.2 vs. 59.4 ± 4.5%; HR: 331 ± 35 vs. 309 ± 24 bpm; n.s., respectively). On the contrary, ECG-gated PET imaging showed a mild but significant decrease of PFR in the diabetic rats (ZL controls vs. ZDF rats: 12.1 ± 0.8 vs. 10.2 ± 1 Enddiastolic Volume/sec, P < 0.01). Investigating a diabetic rat model, ECG-gated 18F-FDG PET imaging detected LV diastolic dysfunction while systolic function was still preserved. This might open avenues for an early detection of HF onset in high-risk type 2 diabetes before cardiac symptoms become apparent.

41 - Western diet promotes hyperacetylation of superoxide dismutase 2 and exacerbates vascular oxidative stress in a rat model of type 2 diabetes mellitus

Oxidative stress plays a key role in the onset of vascular complications, the most severe manifestation of type 2 diabetes mellitus (T2DM). However, current antioxidants have ineffectively treated T2DM vascular complications. Moreover, overconsumption of westernized diets increases the risk of developing vascular complications among the diabetic population. Preliminary data from our lab demonstrate that female rats challenged with Western diet (WD) for 5 months develop vascular complications and hypertension. We also found that aortas from diabetic rats exhibit high levels of acetylation. Based on these data, we hypothesized that WD will exacerbate vascular complications in T2DM rats via oxidative stress mechanisms associated with vascular hyperacetylation. Adult female Goto-Kakizaki (GK) rats, an non-obese model of T2DM, were randomized into a control group given standard chow (5% fat, 3.15% sucrose, 24.1% protein; n=6) and an experimental group given WD (21% fat, 34.1% sucrose, 20% protein, n=7). WD group exhibited increased body weight (338.0±10.14 vs. 267.0±2.017 g, p

Apelin‑13 ameliorates metabolic and cardiovascular disorders in a rat model of type 2 diabetes with a high‑fat diet.

Apelin has been reported to be associated with multiple physiological processes in the cardiovascular system. The aim of the present study was to investigate the effects of Apelin‑13 administration on cardiac function, hyperglycemia, insulin resistance (IR), dyslipidemia, endothelial function, inflammation and glucose metabolism in type 2 diabetic Goto‑Kakizaki (GK) rats, and compare the protective effects of Apelin‑13 with metformin or atorvastatin. In the present study, type 2 diabetes was induced in male Goto‑Kakizaki (GK) rats fed with high‑fat diet (HFD). Simultaneously, the rats were treated with metformin (350mg/kg/d, by gavage), atorvastatin (50mg/kg/d, by gavage) or Apelin‑13 (200µg/kg/d, intraperitoneal injection) once daily for 4 consecutive weeks. Hemodynamic parameters were examined by RM6240BD multi‑channel physiological signal monitoring. Fasting plasma glucose (FPG), fasting insulin (FINS), homeostasis model assessment for insulin resistance (HOMA‑IR), total cholesterol (TC), triglyceride (TG), high density lipoprotein‑cholesterol (HDL‑C), low density lipoprotein‑cholesterol (LDL‑C), endothelin‑1 (ET‑1), nitric oxide (NO), constitutive nitric oxide synthase (cNOS) activity, tumor necrosis factor‑α (TNF‑α), leptin and Apelin‑12 levels were measured. Western blotting was performed to determine the levels of Apelin‑12, glucose transporter 4 (GLUT4) and phosphorylated (p)‑5'adenosine monophosphate‑activated protein kinase (AMPK) α2. It was demonstrated that Apelin‑13 decreased heart rate, left ventricular end‑diastolic pressure, FPG, FINS, HOMA‑IR, TC, TG, LDL‑C, ET‑1, TNF‑α and leptin, whereas it increased the rise and fall of maximum rate of left ventricular pressure, HDL‑C, NO, cNOS activity and Apelin‑12 compared with the GK‑HFD group. In addition, GLUT4 and p‑AMPKα2 levels in myocardial tissues were elevated by administration of Apelin‑13. This protective effect of Apelin‑13 was comparable to that of metformin or atorvastatin. Overall, the present study demonstrated that administration ofApelin‑13 may be a promising therapeutic agent for the treatment of type 2 diabetes and metabolic syndrome.

Metformin attenuates increase of synaptic number in the rat spinal dorsal horn with painful diabetic neuropathy induced by type 2 diabetes: a stereological study.

In our previous study, we have shown that number of synapses in the L5 segment of spinal dorsal horn increased significantly in a rat model of painful diabetic neuropathy (PDN) induced by high-dose of streptozotocin (an animal model of type 1 diabetes). The aims of this study were: (1) to determine whether high fat diet/low dose streptozotocin-diabetes, a rat model for type 2 diabetes, related PDN was also associated with this synaptic plasticity, (2) to reveal the range of this synaptic plasticity change occurred (in the whole length of spinal dorsal horn or only in the L5 lumbar segment of spinal dorsal horn) and (3) to discover whether treatment with metformin had effect on this synaptic plasticity. Male adult Sprague-Dawley rats were randomly allocated into the control group (n = 7), the PDN group (n = 6) and the PDN treated with metformin (PDN + M) group (n = 7), respectively. 28days after medication, synaptic and neuronal numbers in the whole length of spinal dorsal horn or in 1mm length of the L5 segment of spinal dorsal horn were estimated by the optical disector (a stereological technique). Compared to the control group and the PDN + M group, number of synapses in the L5 segment of spinal dorsal horn increased significantly in the PDN group (P < 0.05). There was no significant change between the control group and the PDN + M group in terms of the parameters in the L5 segment of the spinal dorsal horn (P > 0.05). Parameters of the whole length of spinal dorsal horn showed no significant changes (P > 0.05). Our results suggest that high fat diet/low dose streptozotocin diabetes related PDN is also associated with a numerical increase of synapses in the L5 segment of spinal dorsal horn but not in the whole length of spinal dorsal horn. Furthermore, the analgesic effect of metformin against PDN is related to its inhibition of numerical increase of synaptic number in the rat spinal dorsal horn.

Antioxidant and anti-diabetic effects of Auricularia auricular polysaccharides and their degradation by artificial gastrointestinal digestion - Bioactivity of Auricularia auricular polysaccharides and their hydrolysates.

Auricularia auricular polysaccharides (AAPs) derived from the dried fruit body of A. auricular are valuable compounds with many bioactivities. This research aimed to investigate the antioxidant and anti- diabetic activities of these polysaccharides and their artificial gastrointestinal fluid hydrolysates (AAPHs). Artificially simulated gastrointestinal fluid was used to obtain polysaccharide-de- rived fragments, and a rat model of type 2 diabetes mellitus (T2DM) using a high-fat diet and low-dose streptozotocin (STZ) was established to assess their antioxidant and anti-diabetic effects. It was found that AAPs and AAPHs were both heteropolysaccharides and were comprised of arab- inose, xylose, mannose, 2-deoxy-glucose, glucose and glucosamine, but at different mole ratios. AAPHs was purified by Sephadex G-100 chromatography to produce three fractions, namely, AAPHs1, AAPHs2, and AAPHs3. The molecular weights of these three fractions were 320, 169, and 62 kDa respectively. Both AAPs and AAPHs exhibited the evident ability to enhance the activities of antioxidant enzymes and the level of GSH, while increasing the content of liver glycogen and plasma C-peptide compared with the diabetic model group (p < 0.05). Furthermore, AAPHs could cause a marked improvement in glucose-stimulated GLP-1 secretion from 0 min to 30 min (p < 0.05). The possible mechanism was that AAPHs could partly restore the STZ-induced impairment of GLP-1 secretion, and inhibit the oxidative stress pathway, and thereby alleviate the progression of diabetes. This data demonstrated that the molecular mole ratio and molecular weight had a definite effect on antioxi- dant and anti-diabetic activities.

Myocardial Protective Effects of Nicorandil on Rats with Type 2 Diabetic Cardiomyopathy.

BackgroundDiabetic cardiomyopathy (DCM) is a common but underestimated cause of heart failure in patients with diabetes. This study investigated the myocardial-protective effects of nicorandil (Nic) on rats with DCM.Material/MethodsA total of forty-seven 180–220 g male Wistar rats were randomly divided into 4 groups: a control group (control, n=8), a DCM group (DCM, n=13), a nicorandil-pretreated DCM group (Nic1, n=13), and a nicorandil-treated DCM group (Nic2, n=13). A rat model of type 2 diabetes was induced by high-fat and high-sugar diet and intraperitoneal injection of streptozotocin (STZ). Nicorandil (3 mg/kg/d) was orally administrated to rats in the Nic1 group starting at week 4. Nicorandil (3 mg/kg/d) was orally administrated only after the induction of diabetes in the Nic2 group. The serum lipoids, plasma glucose, insulin levels, heart weight index, serum creatine kinase (CK), lactate dehydrogenase (LDH) levels, superoxide dismutase (SOD) activity, and malondialdehyde (MDA) were analyzed in all groups.ResultsThe DCM group showed increased heart weight index, serum LDH, CK, and MDA content and decreased serum SOD activity, as compared with the control group (P<0.05). The DCM-induced increases in heart weight index, serum LDH, CK, and MDA content and decrease in serum SOD activity were attenuated in both Nic1 and Nic2 groups (P<0.05). However, there was no significant difference between Nic1 and Nic2 groups (P>0.05).ConclusionsNicorandil has protective effects on cardiac hypertrophy in DCM rats through increased SOD activity and decreased MDA content. Therefore, nicorandil may be a therapeutic method for diabetic patients with DCM.

Preparation of the controlled acid hydrolysates from pumpkin polysaccharides and their antioxidant and antidiabetic evaluation

Pumpkin polysaccharides (PPe) have various biological activities. This research was to optimize the acid hydrolysis process of PPe with OH scavenging ability based on central composite design (CCD), and to explore the antioxidant and antidiabetic activities of the acid hydrolysates (PPe-H). A rat model of type 2 diabetes mellitus (T2DM) using high-fat diet and low-dose streptozotocin were established to assess the bioactivities. Both PPe and PPe-H could distinctly reduce fasting blood glucose level, prevent the weight loss in T2DM rats, and exhibited the remarkable ability to enhance the activities of the antioxidant enzymes (CAT and GR, p < 0.01, p < 0.01) and the level of GSH (p < 0.05, p < 0.01). Besides, PPe-H could significantly decrease the level of MDA (p < 0.05). Furthermore, PPe-H could cause an evident improvement to glucose stimulated GLP-1 secretion from 0 min to 30 min (p < 0.05). PPe and PPe-H were both the heteropolysaccharide and composed of rhamnose, arabinose, glucose and galactose, their molecular weight were 104.27 kDa and 37.58 kDa, respectively. The potential antidiabetic mechanism of PPe-H might be related to stimulating the secretion of endogenous GLP-1, decreasing oxidative damages, and then slowing down the process of diabetes.