Diabetic Goto-Kakizaki Rats Research Articles

Pentamethylquercetin ameliorates fibrosis in diabetic Goto-Kakizaki rat kidneys and mesangial cells with suppression of TGF-β/Smads signaling

Pentamethylquercetin (PMQ) has been shown to possess glucose-lowering properties, but its effect on renal fibrosis in diabetes is still unclear. This study was designed to investigate the effect of PMQ on renal fibrosis and the underlying mechanisms in spontaneous type II diabetic Goto-Kakizaki rats and mesangial cells in high glucose. We found that in Goto-Kakizaki rats, PMQ treatment attenuated glomerular volume, glycogen deposition, renal collagen and fibronectin accumulation, in addition to amelioration of diabetic symptoms, including reduction of urine volume and urine glucose levels. In mesangial cells, PMQ remarkably inhibited the cell proliferation and total collagen accumulation, and suppressed cell hypertrophy. Further experiments showed that PMQ treatment down-regulated the expression of TGF-β1, up-regulated Smad7 and inhibited Smad2/3 activation in vivo and vitro. Our results demonstrated that PMQ ameliorated renal fibrosis in diabetes, which may be associated with suppressed TGF-β/Smads signaling.

Alterations in hepatic metabolism of sulfur amino acids in non-obese type-2 diabetic Goto-Kakizaki rats

Elevated plasma homocysteine has been identified as a risk factor for cardiovascular disease and non-alcoholic liver disease, which are major complications of diabetes. Hence, hepatic homocysteine metabolism has become a major focus of diabetes research. However, little information is available regarding plasma homocysteine levels in non-obese diabetic animals. Therefore, we investigated the hepatic metabolism of sulfur-amino acids in non-obese type-2 diabetic Goto-Kakizaki rats. The experiments were performed using 9-week-old Goto-Kakizaki rats and age-matched Wistar rats. The major finding of this study is that homocysteine levels in the liver and plasma are maintained by a balance between the up-regulation of betaine homocysteine methyltransferase and the inhibition of cystathionine β-synthase in non-obese type-2 diabetic rats. Hepatic levels of cysteine and its metabolites, such as hypotaurine, taurine, and glutathione, were increased despite inhibition of the transsulfuration of homocysteine to cysteine. The elevated hepatic taurine and glutathione levels may be attributed to the up-regulation of cysteine dioxygenase expression and increased cysteine availability for glutathione synthesis. Inhibition of hepatic methionine adenosyltransferase activity in Goto-Kakizaki rats was associated with a decrease in hepatic S-adenosylmethionine, which serves as an allosteric activator of cystathionine β-synthase. The non-obese type-2 diabetic condition results in profound changes in hepatic sulfur-amino acid metabolism and raises the possibility that sulfur-amino acid metabolism may be regulated by obesity- as well as diabetes-associated factors. Further study to elucidate the pathological significance of sulfur-amino acid metabolism in chronic liver disease in type-2 diabetic animals is underway in this laboratory.

Association of Rev-erbα in adipose tissues with Type 2 diabetes mellitus amelioration after gastric bypass surgery in Goto-Kakizaki rats

We estimated the key molecules related to Type 2 diabetes mellitus (T2DM) in adipose, liver, and muscle tissues, from nonobese diabetic Goto-Kakizaki (GK) rats and their Wistar controls, by computationally analyzing the expression profiles in open source data. With the aid of information from previous reports, Rev-erbα in adipose tissue emerged as one of the most plausible candidates. Here, in animal models, including GK rats surgically treated to ameliorate T2DM, we examined the association of Rev-erbα in adipose tissue with T2DM progression. After analyses of the Rev-erbα mRNA expression in the adipose tissue of our animal models, we compared the Rev-erbα protein expression levels in the adipose, liver, and muscle tissues of GK and Wistar controls at the ages of 1 mo (M), 3M, and 6M. The Rev-erbα protein levels in adipose tissue showed a distinctive pattern, with the negative correlation of an increasing trend in GK rats, and a decreasing trend in Wistar rats during aging, from those in liver and muscle tissues. Moreover, dysregulation of the circadian Rev-erbα expression in the adipose tissue of 6-mo-old GK rats was also observed. In particular, we ameliorated T2DM in GK rats by gastric bypass surgery, and revealed that T2DM amelioration in diabetic GK rats was associated with improved circadian Rev-erbα expression, in a comparison between the surgically treated and untreated GK rats. The roles of Rev-erbα in adipose tissue were further investigated by observations of Rev-erbα-related molecules, with reference to previous reports.

Methylglyoxal chronic administration promotes diabetes-like cardiac ischaemia disease in Wistar normal rats

Background and aimsThe influence of lifestyle is well documented, especially the diet regime, in the development of type 2 diabetes (T2D) and associated cardiovascular diseases. Diabetic patients have increased risk of suffering cardiac ischemia and impaired response to such accidents. Methylglyoxal (MG) circulates at high concentration in diabetics' blood and is linked to the development of diabetes chronic complications. We propose that besides promoting the cardiovascular disease, MG may also negatively regulate the endogenous cardioprotection pathways after ischemia. Methods and resultsWe performed a comparative study between three animal groups: normal Wistar (W), type 2 diabetic non-obese Goto-Kakizaki (GK) and normal rats submitted to MG chronic administration (3months) with gradually enhanced concentration, up to 75 mg/Kg (WMG). Hearts were submitted to different experimental conditions: control, ischemia and ischemia-reperfusion. Levels of oxidative stress markers, advanced glycation end-products (AGEs) and their receptors (RAGEs) were evaluated. The serine/threonine protein kinase Akt (Akt), crucial for cardiomyocytes recovery after ischemia, and apoptosis markers were also assessed.Levels of MG, systemic and cardiac oxidative stress markers, AGEs and RAGEs were similar in GK and WMG groups. Akt protein was negatively regulated by MG, leading to impaired apoptotic markers. ConclusionChronic MG administration to normal rodents mimicked most diabetic alterations, being associated with the development of cardiovascular disease and the impairment of survival pathways. Our results demonstrate the negative effect of MG rich diet in healthy animals and suggest the potential of methylglyoxal as a therapeutic target in diabetes.

Effects of exercise training on excitation–contraction coupling and related mRNA expression in hearts of Goto-Kakizaki type 2 diabetic rats

Although, several novel forms of intervention aiming at newly identified therapeutic targets are currently being developed for diabetes mellitus (DM), it is well established that physical exercise continues to be one of the most valuable forms of non-pharmacological therapy. The aim of the study was to investigate the effects of exercise training on excitation-contraction coupling and related gene expression in the Goto-Kakizaki (GK) type 2 diabetic rat heart and whether exercise is able to reverse diabetes-induced changes in excitation-contraction coupling and gene expression. Experiments were performed in GK and control rats aged 10-11 months following 2-3 months of treadmill exercise training. Shortening, [Ca(2+)]i and L-type Ca(2+) current were measured in ventricular myocytes with video edge detection, fluorescence photometry and whole cell patch clamp techniques, respectively. Expression of mRNA was assessed in ventricular muscle with real-time RT-PCR. Amplitude of shortening, Ca(2+) transients and L-type Ca(2+) current were not significantly altered in ventricular myocytes from GK sedentary compared to control sedentary rats or by exercise training. Expression of mRNA encoding Tpm2, Gja4, Atp1b1, Cacna1g, Cacnb2, Hcn2, Kcna3 and Kcne1 were up-regulated and Gja1, Kcnj2 and Kcnk3 were down-regulated in hearts of sedentary GK rats compared to sedentary controls. Gja1, Cav3 and Kcnk3 were up-regulated and Hcn2 was down-regulated in hearts of exercise trained GK compared to sedentary GK controls. Ventricular myocyte shortening and Ca(2+) transport were generally well preserved despite alterations in the profile of expression of mRNA encoding a variety of cardiac muscle proteins in the adult exercise trained GK diabetic rat heart.

Cerebro‐Vasculoprotective Effects of Azilsartan Medoxomil in Diabetes

We have shown that glycemic control prevents diabetes‐mediated remodeling of the cerebrovasculature. However, whether the remodeling can be reversed is unknown. Given that angiotensin II Type 1 receptor blockers (ARBs) reverse pathological vascular remodeling and function independent of changes in blood pressure in other vascular beds, we hypothesized that azilsartan medoxomil, a new ARB, reverses cerebrovascular remodeling in diabetes independent of blood pressure.MethodsControl Wistar and diabetic Goto‐Kakizaki rats (n=20/group), were treated with vehicle (water) or Azilsartan medoxomil (3 mg/kg/day) from 18 to 22 weeks of age. Blood glucose and blood pressure was monitored and middle cerebral artery structure and function was evaluated using pressurized arteriography.ResultsBlood glucose was higher in the GK compared to Wistar rats. Azilsartan treatment lowered blood glucose. There was no difference in blood pressure among the groups. Diabetic animals exhibited lower myogenic tone, increased wall thickness, and cross sectional area compared to controls which were corrected by azilsartan treatment.ConclusionAzilsartan medoxomil restores diabetes‐induced cerebrovascular remodeling independent of blood pressure. This effect may be partially mediated by improvement of blood glucose. Disclosure The project is supported by Takeda Pharmaceuticals North America Inc.

Dietary supplementation with a low dose of (−)‐ epigallocatechin‐3‐gallate reduces pro‐inflammatory response in peripheral leukocytes of non‐obese type 2 diabetic GK rat

(−)‐epigallocatechin‐3‐gallate (EGCG), which is found largely in green tea, is known to eliminate reactive oxygen species and associated oxidant stress in vitro and in cells. However, in vivo mechanisms underlying the effects of EGCG on amelioration of metabolic disorders are not fully understood. In this study, we examined whether dietary supplementation of EGCG reduces inflammatory response in peripheral leukocytes of non‐obese type‐ 2 diabetes animal model, Goto‐Kakizaki (GK) rats. GK rats at nine weeks of age were fed a control high‐fat diet (45 energy% from lard and corn oil) or the high‐fat diet containing 0.1%, 0.2% or 0.5% EGCG (w/w) for 25 weeks. Significantly reduced mRNA level of genes related to inflammatory response (IFN‐ E, IL‐1 fÒ, IL‐18 and CD11s) were found in rats fed the diet containing 0.1% EGCG, but not in those fed diets containing 0.2% or more EGCG as compared with control. These results suggest that supplementation of a low dose of EGCG in GK rats reduces expression of genes involved in inflammation in peripheral leukocytes.

449 Bladder and erectile dysfunctions in the type 2 Diabetic goto-kakizaki rat

449 Bladder and erectile dysfunctions in the type 2 Diabetic goto-kakizaki rat

Multimodal Highlighting of Structural Abnormalities in Diabetic Rat and Human Corneas.

This study aimed to highlight structural corneal changes in a model of type 2 diabetes, using in vivo corneal confocal microscopy (CCM). The abnormalities were also characterized by transmission electron microscopy (TEM) and second harmonic generation (SHG) microscopy in rat and human corneas. Goto-Kakizaki (GK) rats were observed at age 12 weeks (n = 3) and 1 year (n = 6), and compared to age-matched controls. After in vivo CCM examination, TEM and SHG microscopy were used to characterize the ultrastructure and the three-dimensional organization of the abnormalities. Human corneas from diabetic (n = 3) and nondiabetic (n = 3) patients were also included in the study. In the basal epithelium of GK rats, CCM revealed focal hyper-reflective areas, and histology showed proliferative cells with irregular basement membrane. In the anterior stroma, extracellular matrix modifications were detected by CCM and confirmed in histology. In the Descemet's membrane periphery of all the diabetic corneas, hyper-reflective deposits were highlighted using CCM and characterized as long-spacing collagen fibrils by TEM. SHG microscopy revealed these deposits with high contrast, allowing specific detection in diabetic human and rat corneas without preparation and characterization of their three-dimensional organization. Pathologic findings were observed early in the development of diabetes in GK rats. Similar abnormalities have been found in corneas from diabetic patients. This multidisciplinary study highlights diabetes-induced corneal abnormalities in an animal model, but also in diabetic donors. This could constitute a potential early marker for diagnosis of hyperglycemia-induced tissue changes.

Chronic effects of mild hyperglycaemia on left ventricle transcriptional profile and structural remodelling in the spontaneously type 2 diabetic Goto-Kakizaki rat

Heart failure in chronic type 2 diabetes mellitus is partly attributable to adverse structural remodelling of the left ventricle (LV), but the contribution of hyperglycaemia (HG) per se in remodelling processes is debated. In this study, we examined the molecular signature of LV remodelling in 18-month-old spontaneously diabetic male Goto-Kakizaki (GK) rats that represent a long-term mildly diabetic phenotype, using histological, immunoblotting and quantitative gene expression approaches. Relative to age-matched Wistar controls, mildly diabetic GK rats presented with LV hypertrophy, increased expression of natriuretic peptides and phosphorylation of pro-hypertrophic Akt. Fibrosis proliferation in the GK LV paralleled increased transcriptional and biologically active pro-fibrogenic transforming growth factor-β1 (TGFβ1) in the LV with upregulated mRNA abundance for key extracellular matrix (ECM) components such as fibronectin, collagen type(s) 1 and 3α and regulators including matrix metalloproteinases 2 and 9, and their tissue inhibitor (TIMP) 4, connexin 43 and α5-integrin. GK rats also presented with altered mRNA expression for cardiac sarcoplasmic reticulum Ca(2+)ATPase, Na(+)/Ca(2+) exchanger and the L-type Ca(2+) channels which may contribute to the altered Ca(2+) transient kinetics previously observed in this model at 18months of age (t test, p<0.05 vs. age-matched Wistar control for all parameters). The results indicate that chronic mild HG can produce the molecular and structural correlates of a hypertrophic myopathy. Diffuse ECM proliferation in this model is possibly a product of HG-induced TGFβ1 upregulation and altered transcriptional profile of the ECM.

Hydrogen Sulfide Treatment Promotes Glucose Uptake by Increasing Insulin Receptor Sensitivity and Ameliorates Kidney Lesions in Type 2 Diabetes

To examine if hydrogen sulfide (H2S) can promote glucose uptake and provide amelioration in type 2 diabetes. Treatment with sodium hydrosulfide (NaHS, an H2S donor) increased glucose uptake in both myotubes and adipocytes. The H2S gas solution showed similar effects. The NaHS effects were blocked by an siRNA-mediated knockdown of the insulin receptor (IR). NaHS also increased phosphorylation of the IR, PI3K, and Akt. In Goto-Kakizaki (GK) diabetic rats, chronic NaHS treatment (30 μmol·kg(-1)·day(-1)) decreased fasting blood glucose, increased insulin sensitivity, and increased glucose tolerance with increased phosphorylation of PI3K and Akt in muscles. Similar insulin-sensitizing effects of NaHS treatment were also observed in Wistar rats. Moreover, glucose uptake was reduced in the cells with siRNA-mediated knockdown of the H2S-generating enzyme cystathionine γ-lyase in the presence or absence of exogenous H2S. Moreover, chronic NaHS treatment reduced oxygen species and the number of crescentic glomeruli in the kidney of GK rats. This study provides the first piece of evidence for the insulin-sensitizing effect of NaHS/H2S in the both in vitro and in vivo models of insulin resistance. REBOUND TRACK: This work was rejected during a standard peer review and rescued by the Rebound Peer Review (Antoxid Redox Signal 16: 293-296, 2012) with the following serving as open reviewers: Jin-Song Bian, Samuel Dudley, Hideo Kimura, and Xian Wang.

Sustained Delivery of IL-1Ra from PF127-Gel Reduces Hyperglycemia in Diabetic GK-Rats

Interleukin-1beta (IL-1β) is a major cause for induction of various inflammatory mechanisms that are decisively involved to provoke pathogenesis of type 2 diabetes mellitus (T2DM). Interleukin-1 receptor antagonist (IL-1Ra) a naturally occurring anti-inflammatory antagonist of IL-1β has been recently approved for treatment of T2DM but due to its short half-life, higher doses and frequent dosing intervals are required. Pluronic F-127 (PF127) has previously shown to prolong the release of various proteinous drugs and their serum half-lives. Subsequently, in our previous work, we developed a new dosage form of IL-1Ra using PF127 and investigated its in-vitro and in-vivo effects. Here in present work, we have extended this approach using diabetic Goto-kakizaki (GK) rats. We administered IL-1Ra loaded in PF127 gel subcutaneously for one month into GK rats. IL-1Ra loaded in PF127 gel exhibited a sustained and prolonged hypoglycemic effects on treated animals. Intraperitoneal glucose tolerance test (IPGTT) results showed that IL-1Ra loaded in PF127 gel increased glucose tolerance along with increased insulin sensitivity and β-cell’s secretory function in treated rats. Moreover, significant reduction in pro-insulin/insulin ratio, lipid profiles and interleukin 6 (IL-6) were also observed. Immunohistochemical analysis showed slight macrophages infiltration in pancreatic islets. Histochemical analysis revealed no PF127-induced alteration in the normal physiology of skin and kidney of treated animals. Hence, we concluded that IL-1Ra loaded in PF127 gel has potential to exhibit broad spectrum anti-inflammatory effects alleviating the symptoms of T2DM.

Abstract TP256: Targets of Vascular Protection in Acute Ischemic Stroke Differ in Type 2 Diabetes

Background: Hemorrhagic transformation (HT) is an important complication of acute ischemic stroke particularly in diabetic patients receiving thrombolytic treatment with tissue plasminogen activator (tPA), the only approved drug for the treatment of AIS. The objective of the current study was to determine the effects of acute inhibition of the mediators of HT (i.e., NFkB, peroxynitrite, and matrix metalloproteinases) on vascular injury and functional outcome in a diabetic model of cerebral ischemia. Methods: Ischemia was induced by middle cerebral artery occlusion in control and type 2 diabetic Goto-Kakizaki rats. Treatment groups received a single dose of peroxynitrite decomposition catalyst FeTPPs, non-specific NFkB inhibitor curcumin, or broad-spectrum matrix metalloproteinase (MMP) inhibitor minocycline at reperfusion. Post-stroke infarct volume, edema, hemorrhage, neurological deficits, and MMP-9 activity were evaluated. Results: All therapies reduced MMP-9 and HT in diabetic groups. In addition, acute curcumin and minocycline therapy reduced edema in these animals. Improved neurological function was observed in varying degrees with treatment as indicated by beam-walk performance, modified Bederson scores and grip strength; however, infarct size was similar to untreated diabetic animals. In control animals, all treatments reduced MMP-9 activity yet bleeding was not improved. Neuroprotection was only conferred by curcumin and minocycline. Conclusion: Uncovering underlying mechanisms contributing to the success of acute therapy in diabetes will advance tailored stroke therapies. Table 1 . Summary of experimental stroke data. SE are shown in parentheses. a p&lt;0.05 vs. untreated control, b p&lt;0.05 vs. untreated, c p&lt;0.05 vs. untreated diabetes, d p&lt;0.001 vs. untreated control, e p&lt;0.01 vs. untreated control, * All values in this data set were below detection.

Type II diabetes increases mitochondrial DNA mutations in the left ventricle of the Goto-Kakizaki diabetic rat

Mitochondrial dysfunction has a significant role in the development of diabetic cardiomyopathy. Mitochondrial oxidant stress has been accepted as the singular cause of mitochondrial DNA (mtDNA) damage as an underlying cause of mitochondrial dysfunction. However, separate from a direct effect on mtDNA integrity, diabetic-induced increases in oxidant stress alter mitochondrial topoisomerase function to propagate mtDNA mutations as a contributor to mitochondrial dysfunction. Both glucose-challenged neonatal cardiomyocytes and the diabetic Goto-Kakizaki (GK) rat were studied. In both the GK left ventricle (LV) and in cardiomyocytes, chronically elevated glucose presentation induced a significant increase in mtDNA damage that was accompanied by decreased mitochondrial function. TTGE analysis revealed a number of base pair substitutions in the 3' end of COX3 from GK LV mtDNA that significantly altered the protein sequence. Mitochondrial topoisomerase DNA cleavage activity in isolated mitochondria was significantly increased in the GK LV compared with Wistar controls. Both hydroxycamptothecin, a topoisomerase type 1 inhibitor, and doxorubicin, a topoisomerase type 2 inhibitor, significantly exacerbated the DNA cleavage activity of isolated mitochondrial extracts indicating the presence of multiple functional topoisomerases in the mitochondria. Mitochondrial topoisomerase function was significantly altered in the presence of H2O2 suggesting that separate from a direct effect on mtDNA, oxidant stress mediated type II diabetes-induced alterations of mitochondrial topoisomerase function. These findings are significant in that the activation/inhibition state of the mitochondrial topoisomerases will have important consequences for mtDNA integrity and the well being of the diabetic myocardium.

Interleukin-1 receptor antagonist improves normoglycemia and insulin sensitivity in diabetic Goto-Kakizaki-rats

Type 2 diabetes mellitus has been considered as an auto-inflammatory syndrome. Interleukin-1 receptor antagonist (IL-1Ra) has attained considerable attention due to its broad spectrum anti-inflammatory therapeutic effects against various auto-immune diseases. The purpose of our study was to investigate its therapeutic effects of IL-1Ra on none-obese diabetic Goto-Kakizaki (GK) rats. We administered IL-1Ra subcutaneously for one month into GK rats. Insulin sensitivity and β-cell function was calculated by homeostatic model assessment (HOMA) and quantitative insulin sensitivity check index (QUICKI) models. IL-1Ra decreased the onset of hyperglycemia and did not impact the body weight and/or food intake. Insulin tolerance test (ITT) and intraperitoneal glucose tolerance test (IPGTT) results showed that IL-1Ra improved insulin sensitivity and glucose tolerance. The results of HOMA and QUICKI models revealed that IL-1Ra improved insulin sensitivity and β-cell function. Moreover, significant reduction of pro-insulin/insulin ratio and lipid profiles also exhibited significant therapeutic effects of IL-1Ra. Immunohistochemical analysis showed minimal macrophage infiltration in pancreatic islets demonstrating decreased intra-islet inflammation in IL-1Ra treated GK rats. The results of our present study revealed that IL-1Ra has broad spectrum therapeutic potentials but due to its short biological half-life (6–8h) high doses with frequent dosing intervals are required. Therefore, there is a need for the development of such dosage form that may prolong its half-life via extended release.

APG: an Active Protein-Gene Network Model to Quantify Regulatory Signals in Complex Biological Systems

Synergistic interactions among transcription factors (TFs) and their cofactors collectively determine gene expression in complex biological systems. In this work, we develop a novel graphical model, called Active Protein-Gene (APG) network model, to quantify regulatory signals of transcription in complex biomolecular networks through integrating both TF upstream-regulation and downstream-regulation high-throughput data. Firstly, we theoretically and computationally demonstrate the effectiveness of APG by comparing with the traditional strategy based only on TF downstream-regulation information. We then apply this model to study spontaneous type 2 diabetic Goto-Kakizaki (GK) and Wistar control rats. Our biological experiments validate the theoretical results. In particular, SP1 is found to be a hidden TF with changed regulatory activity, and the loss of SP1 activity contributes to the increased glucose production during diabetes development. APG model provides theoretical basis to quantitatively elucidate transcriptional regulation by modelling TF combinatorial interactions and exploiting multilevel high-throughput information.

Targets of vascular protection in acute ischemic stroke differ in type 2 diabetes

Hemorrhagic transformation is an important complication of acute ischemic stroke, particularly in diabetic patients receiving thrombolytic treatment with tissue plasminogen activator, the only approved drug for the treatment of acute ischemic stroke. The objective of the present study was to determine the effects of acute manipulation of potential targets for vascular protection [i.e., NF-κB, peroxynitrite, and matrix metalloproteinases (MMPs)] on vascular injury and functional outcome in a diabetic model of cerebral ischemia. Ischemia was induced by middle cerebral artery occlusion in control and type 2 diabetic Goto-Kakizaki rats. Treatment groups received a single dose of the peroxynitrite decomposition catalyst 5,10,15,20-tetrakis(4-sulfonatophenyl)prophyrinato iron (III), the nonspecific NF-κB inhibitor curcumin, or the broad-spectrum MMP inhibitor minocycline at reperfusion. Poststroke infarct volume, edema, hemorrhage, neurological deficits, and MMP-9 activity were evaluated. All acute treatments reduced MMP-9 and hemorrhagic transformation in diabetic groups. In addition, acute curcumin and minocycline therapy reduced edema in these animals. Improved neurological function was observed in varying degrees with treatment, as indicated by beam-walk performance, modified Bederson scores, and grip strength; however, infarct size was similar to untreated diabetic animals. In control animals, all treatments reduced MMP-9 activity, yet bleeding was not improved. Neuroprotection was only conferred by curcumin and minocycline. Uncovering the underlying mechanisms contributing to the success of acute therapy in diabetes will advance tailored stroke therapies.

Comparative Effect of Type 1 and Type 2 Diabetes Mellitus on Vascular Responses of Rat Thoracic Aorta to Potassium Ion Channel Openers

Background: Diabetes mellitus is associated with many cardiovascular dysfunction and impairment of potassium channel function. Aim: We compared the vascular reactivity in aorta from streptozotocin -induced and Goto-Kakizaki (GK) diabetic rat sto potassium channel openers. Methodology: Diabetes mellitus (DM) was induced in Sprague Dawley rats by intraperitoneal injection of streptozotocin (STZ) at 65 mg/kg body weight. After four weeks of DM, vascular reactivity of the aortic rings from STZ -induced Sprague Dawley and age-matched GK and control rats to phenylephrine, acetylcholine, levcromakalim and naringeninwas studied using standard organ bath procedure. Results:The phenylephrine-induced contraction was significantly (P<0.05) increased in

Brain-derived neurotrophic factor in VMH as the causal factor for and therapeutic tool to treat visceral adiposity and hyperleptinemia in type 2 diabetic Goto–Kakizaki rats

We previously reported that the type 2 diabetic Goto–Kakizaki (GK) rats at young adult ages (6–12 weeks) exhibited increased visceral fat mass and hyperleptinemia, due to hyperphagia caused primarily by neuropeptide Y (NPY) overexpression in the hypothalamic arcuate nucleus. Later, we found that GK rats continued to exhibit mesenteric fat accumulation and hyperleptinemia at least until 26 weeks of age, while hyperphagia and NPY overexpression ceased at 15 weeks of age. Therefore, we hypothesized that the long-lasting fat accumulation and hyperleptinemia are due to unidentified brain dysfunction other than NPY overexpression. In GK rats aged 26 weeks, glucose transporter-2 (GLUT2) mRNA expression in ventromedial hypothalamus (VMH) was markedly reduced in parallel with significant decreases in brain-derived neurotrophic factor (BDNF) mRNA level and BDNF-expressing cell numbers in the VMH. Pharmacologic inhibition of glucose utilization reduced BDNF mRNA expression in VMH in vivo and in vitro. The results suggested that impaired glucose utilization caused the reduction of BDNF. On the other hand, intracerebroventricular injection of BDNF for 6 days ameliorated hyperleptinemia in a long-lasting manner concurrently with feeding suppression in GK rats. Restricted feeding paired to BDNF-treated rats reduced plasma leptin level only transiently. BDNF treatment also reduced mesenteric fat mass in GK rats. These results reveal a novel action mode of BDNF to long-lastingly counteract visceral adiposity and hyperleptinemia in addition to and independently of its anorexigenic action. These results suggest that visceral fat accumulation and hyperleptinemia are at least partly due to the reduction of BDNF in VMH primarily caused by impaired glucose utilization in GK rats. The BDNF supplementation could provide an effective treatment of visceral obesity, hyperleptinemia and leptin resistance in type 2 diabetes.

Traditional Medicine in Management of Type 2 Diabetes Mellitus

The incidence of type 2 diabetes mellitus has now reached epidemic proportions. Although the disease manifests in the form of hyperglycemia, the cause could be varied ranging from disturbance in insulin secretion, insulin action, insulin resistance, glucose production and glucose uptake, interplay between different hormones, and various kind of stress. Due to such varied etiology, the management of diabetic condition poses a great medical challenge. No single agent has so far been unequivocally accepted as the antidiabetic drug. Alternative systems of medicine based on traditional wisdom have thrived through ages and are still practiced by a large population for the management of diabetes. A large number of plants have proved their efficacy in management of diabetes especially hyperglycemia. In many cases, scientific studies have validated the antidiabetic nature of plant-based medicines, and the bioactive principle has been isolated and characterized. It is important that more research is done to understand the mechanism(s) involved in the antidiabetic action of large number of plant-based medicines used as traditional therapy for the management of diabetic condition. The present special volume has brought together some interesting papers reporting the findings of the use of traditional medicines for the treatment of diabetes mellitus. S. I. Rizvi and N. Mishra provide a good review of the anti-diabetic potential and the bioactive compounds present in Ficus religiosa, Pterocarpus marsupium, Gymnema sylvestre, Allium sativum, Eugenia jambolana, Momordica charantia, and Trigonella foenum-graecum. All these plants are widely used in the Indian subcontinent for the management of diabetic condition. O. Eleazu et al. explore the chemical composition of cocoyam and unripe plantain flours and their potential in the dietary prevention of diabetic complications. D. Bailbe and colleagues evaluate the effects of Subetta (containing release-active dilutions of antibodies to beta-subunit of insulin receptor and antibodies to endothelial nitric oxide synthase) in Goto Kakizaki diabetic rats and demonstrate that 28-day administration improves glucose control to an extent similar to that of Rosiglitazone. H. Y. Jin et al. have tested the efficacy of DA-9801, a mixture of extracts from Dioscorea japonica and Dioscorea nipponica in the treatment of diabetic peripheral neuropathy in experimental diabetes. They have also presented a comparison of the effect of DA-9801 with lipoic acid. Statins are very widely used during dyslipidemia. Since type 2 diabetes is frequently associated with dyslipidemia, it is important to investigate the effect of statins on glucose homeostasis in diabetes. Wang et al. report that simvastatin may cause hyperglycemia and have an adverse effect on glucose homeostasis in diabetic rats. Syed Ibrahim Rizvi Elena Matteucci Pinar Atukeren