Exendin-4 (Ex-4), an agonist of the glucagon-like peptide-1 receptor (GLP-1R), shares many of the actions of GLP-1 on pancreatic islets, the central nervous system (CNS), and the gastrointestinal tract that mediates glucose homeostasis and food intake.
The procedures described here were approved by the Institutional Animal Care and Use Committees at the University of Vigo and the University of Cincinnati. GLP-1-(7–36)-NH2, hexamethonium (HXM), guanethidine (GU), d-glucose, and pentobarbital sodium were all provided by Sigma-Aldrich (Alcobendas, Spain). Background: The oxidative stress is known to cause mutation-related disorders in diabetic patients. Antigenotoxic effects of a polyherbal drug septilin against the genotoxicity of cyclophosphamide in mice.
Insulin, a peptide hormone, is secreted by pancreatic ?-cells and is a key regulator in glucose homeostasis.
The HTRF Insulin assay can be used to measure rat, pig, mouse or human insulin in a variety of media, including cell supernatants and serum. Insulin standard curves obtained with the Sensitive Range protocol and performed using the designated final assay volumes and plate types.
INS-1E pancreatic ?-cells underwent starvation for 48 hours prior to stimulation with glucose and additional insulinotropic agents. In these studies rats were anesthetized and two catheters inserted, one used to obtain blood samples and the other used for the injection of glucose.
Mathieu J, Roussel M, Vallaghe J, Trinquet E, Charrier-Savournin F, Dalle S - INSERM U661, IGF, Montpellier, France.
GPR120 (FFAR4) is preferentially expressed in pancreatic delta cells and regulates somatostatin secretion from murine islets of Langerhans.
Stone VM1, Dhayal S, Brocklehurst KJ, Lenaghan C, Sorhede Winzell M, Hammar M, Xu X, Smith DM, Morgan NG.
Possible protective effect of membrane lipid rafts against interleukin-1?-mediated anti-proliferative effect in INS-1 cells. Molecular matchmaking between the popular weight-loss herb Hoodia gordonii and GPR119, a potential drug target for metabolic disorder. Wootten D, Savage EE, Valant C, May LT, Sloop KW, Ficorilli J, Showalter AD, Willard FS, Christopoulos A, Sexton PM. Gill D, Brocklehurst KJ, Brown HW, Smith DM - AstraZeneca Diabetes and Obesity Drug Discovery, Cheshire , UK. Chentouf M, Dubois G, Jahannaut C, Castex F, Lajoix AD, Gross R, Peraldi-Roux S - Centre de Pharmacologie et Innovation pour le Diabete, Faculte de Pharmacie, Montpellier, France. Youl E, Bardy G, Magous R, Cros G, Sejalon F, Virsolvy A, Richard S, Quignard JF, Gross R, Petit P, Bataille D, Oiry C - Centre de Pharmacologie et Innovation dans le Diabete (CPID), Montpellier, France.
Designed inhibitors of insulin-degrading enzyme regulate the catabolism and activity of insulin.
Leissring MA, Malito E, Hedouin S, Reinstatler L, Sahara T, Abdul-Hay SO, Choudhry S, Maharvi GM, Fauq AH, Huzarska M, May PS, Choi S, Logan TP, Turk BE, Cantley LC, Manolopoulou M, Tang WJ, Stein RL, Cuny GD, Selkoe DJ. Fu A, Ng AC, Depatie C, Wijesekara N, He Y, Wang GS, Bardeesy N, Scott FW, Touyz RM, Wheeler MB, Screaton RA. FRET (Fluorescence Resonance Energy Transfer) is based on the transfer of energy between two fluorophores – a donor and an acceptor – when in close proximity. Background: Herbal medicine is widely used in the treatment of diseases like diabetes mellitus. Tahereh Farkhondeh,Saeed Samarghandian Toxin Reviews. Manal Ismaiel,Hong Yang,Cui Min British Food Journal.
Heshmat Sepehri Moghaddam,Saeed Samarghandian,Tahereh Farkhondeh Toxicology Mechanisms and Methods. Because Ex-4 has a much longer plasma half-life than GLP-1, it is an effective drug for reducing blood glucose levels in patients with type 2 diabetes mellitus (T2DM). GLP-1 augments insulin secretion after meals in a glucose-dependent manner and is thought to be a key component of the “incretin effect” (7).
Lalbagh Main Gate, Hosur Road, Bangalore, India2 Department of Pharmacognosy, Al-Ameen College of Pharmacy, Opp. Failure to detect the anti-mutagenic effect of insulin in experimental type-2 diabetic rats.
Early and preventable changes of peripheral nerve structure and function in insulin-deficient diabetic rats.
Alterations in free radical tissue-defense mechanisms in streptozotocin-induced diabetes in rats. Experimental NIDDM: Development of new model in adult rats administered streptozotocin and nicotinamide. Chronic effect of insulin on monoamine oxidase and antioxidant enzyme activities in the rat brain stem. Generation of superoxide radical during autoxidation of hydroxylamine and an assay for superoxide dismutase. In vivo chromosome damaging effects of an inosine monophosphate dehydrogenase inhibitor: Ribavirin in mice. Induction of chromosome aberrations, micronucleus formation and sperm abnormalities in mouse following carbafuran exposure.
Incomplete development of human spermatozoa is associated with increased creatine phosphokinase concentration and abnormal head morphology. In vitro effect of gliclazide on DNA damage and repair in patients with type 2 diabetes mellitus (T2DM). Inhibitory effect of glimepiride on nicotinamide-streptozotocin induced nuclear damages and sperm abnormality in diabetic Wistar rats.
Protective role of glibenclamide against nicotinamide-streptozotocin induced nuclear damage in diabetic Wistar rats.
Failure to detect an anti-mutagenic effect of chloramphenicol in ultraviolet polar cap cells (early germ track) of drosophila. Lack of the anti-mutagenic effect of ascorbic acid on the genotoxicity of albendazole in mouse bone marrow cells.
Lack of modulatory effect of asparagus, tomato and grape juice on cyclophosphamide-induced genotoxicity in mice.
This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.AbstractReduced baroreflex sensitivity (BRS) is widely observed in diabetic human and animals. Insulin deficiency leads to insulin-dependent (type 1) diabetes, whereas resistance to insulin action is common in non-insulin-dependent diabetes (type 2), obesity, and endocrine dysfunctions. The assay is a sandwich immunoassay that uses two monoclonal antibodies, one labeled with Eu3+-Cryptate and one labeled with XL665, that recognize distinct epitopes. In these models, insulin secretion is monitored on pancreatic cell lines as well as in biological fluids.
Insulin concentrations in cell supernatants were determined using the HTRF Insulin assay following the Sensitive Range protocol. Molecular interactions between biomolecules can be assessed by coupling each partner with a fluorescent label and by detecting the level of energy transfer. We investigated the effects of guar gum in diabetic rats for the reduction of the risk of diabetes and cardiovascular disease.
Antihyperglycemic and antihyperlipidemic effects of guar gum on streptozotocin-induced diabetes in male rats. Evaluation of the hypoglycemic and hypolipidemic effects of an ethylacetate fraction of Artocarpus heterophyllus (jak) leaves in streptozotocin-induced diabetic rats. Contribution of receptor negative versus receptor defective mutations in the LDL-receptor gene to angiographically assessed coronary artery disease among young (25-49 years) versus middle-aged (50-64 years) men. Improvement of lipid profile in Type 2 (non-insulin-dependent) diabetes mellitus by insulin-like growth factor I. Cardiovascular autonomic neuropathy contributes to left ventricular diastolic dysfunction in subjects with Type 2 diabetes and impaired glucose tolerance undergoing coronary angiography.
The role of IGF-1 resistance in obesity and type 2 diabetes-mellitus-related insulin resistance and vascular disease. Managing highly insulin-resistant diabetes mellitus: Weight loss approaches and medical management.
Dietary fiber does not displace energy but is associated with decreased serum cholesterol concentrations in healthy children. Comparison of guar gum from different sources for the preparation of prolonged-release or colon-specific dosage forms. Production of galacto-manno-oligosaccharides from guar gum by beta-mannanase from Penicillium oxalicum SO.
Development of low-fat mayonnaise containing polysaccharide gums as functional ingredients. Persistence of acidosis in alloxan-induced diabetic rats treated with the juice of Asystasia gangetica leaves.
Assessment of lipid lowering effect of Sida rhomboidea: Roxb methanolic extract in experimentally induced hyperlipidemia. Glycaemic effects of traditional European plant treatments for diabetes, Studies in normal and Streptozotocin diabetic mice. Long term effects of dietary fiber on glucose tolerance and gastric empting in non-insulin dependent diabetic patients. Metabolic and nutritional effects of long term use of guar gum in the treatment of non-insulin-dependent diabetes of metabolic control. Addition of guar gum and soy protein increases the efficacy of the American Heart Association (AHA) step I cholesterol-lowering diet without reducing high density lipoprotein cholesterol levels in non-human primates.
Effects of dietary fibers on nonfasting plasma lipoprotein and apolipoprotein levels in rats.
Comparison of the effects of high- and low-methoxyl pectins on blood and faecal lipids in man. Role of dietary fiber from pulses and cereals as hypocholesterolemic and hypolipidemic agent. Mechanism and clinical effects of pioglitazone as a new agent for the treatment of Type-2 diabetes.
Siddiqui International Journal of Biological Macromolecules. Here, we report that acute administration of Ex-4, in relatively high doses, into either the peripheral circulation or the CNS, paradoxically increased blood glucose levels in rats. Because the endogenous GLP-1 signaling system promotes glucose homeostasis through a broad array of effects in addition to stimulation of insulin secretion (6a), there has been great interest in applying it to the treatment of diabetes. Ex-4 (0.1, 1, or 5 ?g) was given intracerebroventricularly (icv) in 5 ?l of saline to 24-h-fasted rats.
To study specifically the involvement of the parasympathetic branch of the autonomic nervous system (ANS), a cervical vagotomy was performed. Bone marrow micronucleus (MN) test and caudal epididymal sperm abnormalities were detected to find the somatic and germinal cell mutations, respectively. This can be evident from the presence of higher levels of DNA damaged products such as 8-hydroxy-2-deoxy guanosine (8-OHdG) in the blood of diabetic patients.
Rosiglitazone is one of the clinically used thiazolidinediones (TZD) known as PPARγ agonist. The HTRF® Insulin assay is a homogeneous assay for rapid and accurate measurement of insulin in rat, mouse, pig and human samples. Cisbio Bioassays' HTRF insulin assay has been validated using a number of experimental systems, including screening of insulinotropic molecules on pancreatic ?-cells under HTS conditions and monitoring of in vivo insulin and glucose production. Dietary pattern emphasizing foods high in complex carbohydrates and fiber are associated with low blood glucose and cholesterol levels.
This effect was independent of the insulinotropic and hypothalamic-pituitary-adrenal activating actions of Ex-4 and could be blocked by a GLP-1R antagonist. However, since GLP-1 has a very short half-life in the circulation due to rapid cleavage by the protease dipeptidyl peptidase IV (DPP IV) (19, 28), alternatives to the naturally occurring peptide have been sought. Trunk blood was collected 1 or 2 h later as indicated in prechilled tubes and immediately centrifuged (3,500 rcf for 5 min at 4°C), and the serum was stored at ?35°C prior to glucose determination. Under pentobarbital anesthesia, male SD rats (275–325 g) had both dorsal and ventral branches of the vagus nerve exposed at the cervical level and carefully severed. The antioxidant status was determined by estimating serum lipid peroxidation, catalase, superoxide dismutase and glutathione peroxidase levels.
Additionally, the klotho protein produced from choroid plexus in the central nervous system is regulated by PPARγ. The two detection reagents can be premixed and pre-plated, and the plates frozen for later use. As expected, the addition of insulinotropic agents stimulated increased insulin production compared to glucose alone. Induction of insulin was easily detected and correlated with glucose levels, using as little as 50µl blood samples. Comparable doses of GLP-1 did not induce hyperglycemia, even when protected from rapid metabolism by a dipeptidyl peptidase IV inhibitor. One of the primary strategies for using GLP-1 signaling in therapeutics has been the development of long-acting GLP-1 receptor (GLP-1R) agonists.
To avoid stress due to manipulation, rats were submitted to a sham-sampling procedure at least twice in the previous days before the experiment.
The correct placement of the cannula was confirmed by the staining of the third ventricle after postmortem injection of 10 ?l of Trypan blue.
Control sham-operated animals underwent the same surgical manipulations, except that the nerve branches were not severed.
The somatic cell nuclear damages can cause diseases such as cancer, heart ailments, neurological defects and aging, while germinal cell defect can result in infertility and inheritable disorders in newborns. This feature is possible due to the stability and robustness of HTRF reagents, and gives a practical advantage for screening.

Blood serum glucose, triglycerides, cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol levels, atherogenic index levels, body weights and food intake were monitored at 0, 7.14 and 28 days after induction of diabetes.
Acute hyperglycemia induced by Ex-4 was blocked by hexamethonium, guanethidine, and adrenal medullectomy, indicating that this effect was mediated by sympathetic nervous system (SNS) activation. Among these, exendin-4 (Ex-4), a reptilian peptide that has nearly 50% amino acid sequence homology with GLP-1 (10), has been developed into an effective drug to treat diabetic patients (8). We have found in previous studies that a similar pretreatment efficiently inhibits DPP IV activity (Aulinger BA and D'Alessio DA, unpublished data). The acute response to Ex-4 was tested as well in a cohort of conscious male Long-Evans rats.
Results: In spite of the fact that diabetes elevated blood lipids in all rats after 14 days, the guar gum diet significantly decreased the serum concentration of cholesterol, triacylglicerols and LDL-C and atherogenic index. Quantitative changes include increases in very-low-density lipoprotein (VLDL) as contrasted to normal due to an increase in the availability of glucose for VLDL synthesis and decrease in the lipoprotein lipase activity accompanied with a decrease of VLDL removal from peripheral circulation, increase in low-density lipoprotein cholesterol (LDL-C) levels and decrease in VLDL clearance. Tripathi Chinese Journal of Natural Medicines. The potency of Ex-4 to elevate blood glucose waned with chronic administration such that after 6 days the familiar actions of Ex-4 to improve glucose tolerance were evident. Ex-4 lacks the discrete peptide sequence required for cleavage by DPP IV but otherwise shares virtually all the effects of GLP-1, including stimulation of insulin secretion, inhibition of glucagon release, reduction of food intake, and inhibition of gastrointestinal motility (16, 24, 29, 30, 36). To study the involvement of the adrenal medulla, we studied the glucose responses to Ex-4 in medullectomized rats. Antioxidant exerts multiple effects to overcome the oxidative stress mediated damage on the nucleus, such as scavenging the free radical, increasing the host antioxidant enzyme levels and repairing the damaged nucleus. The most significant result in this study was the reduction of blood glucose in diabetic rats treated with the guar gum diet after 28 days versus non- and glibenclamide-treated rats. Qualitative changes include increased extent of triglycerides, LDL-C and high-density lipoprotein cholesterol (HDL-C), nonenzymatic glycation of LDL and nonenzymatic glycation of HDL thus increasing the probability of heart disease.
These findings indicate that, in rats, high doses of Ex-4 activate a SNS response that can overcome the expected benefits of this peptide on glucose metabolism and actually raise blood glucose. Each of these actions contribute to lower glycemia, and numerous studies in diabetic rodent models demonstrate that chronic administration of Ex-4 increases insulin secretion, reduces body weight, and improves glucose tolerance and chronic hyperglycemia (17, 35, 39, 42). The gum promoted a general improvement in the condition of the diabetic rats in body weight and food intake in comparison with nontreated rats. These results have important implications for the design and interpretation of studies using Ex-4 in rats. Although some of these actions are likely due to direct effects on end organs such as the pancreatic islet, several recent studies support neurally mediated effects of GLP-1 signaling to mediate blood glucose levels (23, 37). The cortex was finely cut with microsurgery scissors, and adrenal medulla was removed with fine forceps. Insulin therapy is reported to benefit the diabetic patients in reducing the complications associated with hyperglycemia. Cerebral infusion of recombinant klotho or oral administration of rosiglitazone reversed BRS in diabetic rats. Conclusion: The results of this research suggest that guar gum was significantly effective in comparison with glibenclamide in the treatment of hyperlipidemia and hyperglycemia in diabetes rats. Moreover, since there are many similarities in the response of the GLP-1R system across mammalian species, it is important to consider whether there is acute activation of the SNS by Ex-4 in humans.
Interestingly, GLP-1R signaling in the central nervous system (CNS) is known to increase arterial blood pressure and heart rate through autonomic responses (5), activate the hypothalamic-pituitary-adrenal axis (20), and promote visceral illness responses through midbrain and hindbrain pathways (21, 34).Because some of the CNS responses to Ex-4 activate glucose counterregulation, it is possible that this peptide's effects on glycemia are more complex than previously recognized. In conclusion, recovery of the decreased klotho in brain induced by rosiglitazone may restore the impaired BRS in diabetic rats. We report here a series of experiments demonstrating that acute administration of Ex-4 increases blood glucose levels in lean, nondiabetic rats.
Thus, rosiglitazone is useful to reverse the reduced BRS through increasing cerebral klotho in diabetic disorders.1.
This novel effect is abolished by pretreatment with the GLP-1R antagonist exendin-3-(9–39) (Ex-9), appears to be mediated by increased sympathetic activity, which temporarily overrides the insulinotropism of Ex-4, and wanes with repeated administration of Ex-4 over several days. At end of the experiment, the rats were euthanized and adrenal glands collected for histological assessment of the adrenal medullectomy.
IntroductionCardiovascular complications influence the prognosis of diabetic disorders and became the main reason for the high mortality of diabetic patients [1, 2].
These findings suggest that pharmacological activation of neural GLP-1R can override the typical actions of GLP-1 signaling to reduce blood glucose, at least in rats. A number of studies have reported that diabetes mellitus (DM) leads to impairment of the baroreflex control of heart rate (HR) in both diabetic patients and animals.
Hence, the present research is aimed evaluate the anti-mutagenic activity of insulin in diabetic Wistar rats, using bone marrow micronucleus (MN) and sperm abnormality tests. Impairment of the baroreflex sensitivity (BRS) underlying the diabetic state is closely related to life-threatening arrhythmias, heart failure, and sudden death [3, 4].To minimize the short-term fluctuations of blood pressure and maintain a homeostatic state, a negative feedback system called the baroreflex buffers these short-term changes such as an increased blood pressure which results in slower heart rate and vice versa [5].
Reduced BRS has been characterized in diabetic human [6, 7] and in diabetic rats induced by streptozotocin (STZ) as type 1-like diabetic model [8, 9].Many factors related to the baroreflex have been mentioned in the central nervous system. The higher baroreflex gain induced by angiotensin has been characterized in rats after an intracerebroventricular (ICV) injection. The experiments were conducted after obtaining prior approval from the Institutional Animal Ethics Committee.Induction of type-2 diabetesExperimental T2DM was developed in adult rats by administering streptozotocin (STZ) and nicotinamide (NA). ICV infusion of leptin ameliorated the variability of heart rate (HR) and the baroreflex sensitivity in STZ-induced diabetic rats [12]. El-Menyar, “Dysrhythmia and electrocardiographic changes in diabetes mellitus: pathophysiology and impact on the incidence of sudden cardiac death,” Journal of Cardiovascular Medicine, vol. Also, a single nucleotide polymorphism in human klotho gene has been mentioned to be associated with the development of hypertension in both Chinese Han [14, 15] and Caucasoid [16–19] subjects.
About 42% of the guar seed is endosperm, of which the predominant portion is mucilage or gum (guar gum).
As a soluble dietary fiber (SDF), guar gum is part of the total dietary fiber (TDF) fraction of the seed. The choroid plexus may produce cerebrospinal fluid (CSF) for neurons and the secreted klotho protein was observed in CSF [20].
Guar gum galactomannans form water-dispersible hydrocolloids, which thicken when dissolved in water, leading to their use as emulsifying, thickening or stabilizing agents for a wide range of processed foods. In clinics, agent of TZDs has been used to treat type 2 diabetic patients through correction of both hyperlipidemia and hyperglycemia [22, 23]. Also, TZDs ameliorate the renal injury in STZ-diabetic rats through the anti-inflammatory action [24] or increased PPARγ expression [25]. The renal protection in STZ-diabetic rats by TZDs produced without altering the blood glucose level [26]. Marrow suspension from femur and tibia bones prepared in 5% bovine serum albumin (BSA) was centrifuged at 1000 rpm for 8 min and the pellet was resuspended in a required quantity of BSA.
A drop of this suspension was taken on a clean glass slide and smear was prepared on glass slide and air-dried. The widely used TZDs, including pioglitazone, rosiglitazone, and troglitazone, were demonstrated to increase the expression of klotho, while rosiglitazone was most effective [21]. Thus, we employed rosiglitazone as the representative of TZDs in this study.The present study is designed to know whether rosiglitazone (TZD) ameliorates the impaired baroreflex sensitivity (BRS) in STZ-induced diabetic rats.
About 2000 PCEs and corresponding NCEs were scanned for the presence of MN using 100Χ oil immersion objective.
We also determined the mediation of klotho in this action because rosiglitazone is known to increase klotho [27]. In contrast, the insoluble fraction of TDF is required for normal lower intestinal function. One thousand sperms per animal were screened to find the different types of abnormality in one of the cauda epididymis. AnimalsThe male Wistar rats, weighing from 200 to 250 g, were obtained from the Animal Center of National Cheng Kung University Medical College. In guaran, about one-half of the D-mannopyranosyl main chain units contain a D galactopyranosyl side chain. Six types of abnormalities such as amorphous, hookless, banana shape, fused, double headed and double tailed were evaluated and finally represented as percentage total abnormality. The spermatozoa count was obtained by counting the number of sperm cells in the four WBC chambers using a Neubauer's slide. These actions tend to avoid constipation and reduce diverticulitis and prevalence of colon cancer.
The animal experiments were approved and conducted in accordance with local institutional guidelines for the care and use of laboratory animals in Chi-Mei Medical Center (number. Ursino, “Mathematical modeling of cardiovascular coupling: central autonomic commands and baroreflex control,” Autonomic Neuroscience, vol. The principle depends on the reaction between thiobarbituric acid with malondialdehyde, a secondary product of lipid peroxidation, at pH 4.
Therefore, the aim of the present study was to evaluate the effects of diets containing 0, 5, 10 and 20% guar gum on the lipidemic and glycimic metabolic control and also to determine the effects of these diets versus the effects of glibenclamide on the food intake, body weight and atherosclerosis index in diabetic rats. The reddish pink color developed was estimated at 532 nm, which indicates the extent of peroxidation. Louis, MO) and total cholesterol, triglyceride, HDL-C and LDL-C kits were purchased from Zistshimi (Tehran, Iran). At the end of treatment, animals were sacrificed, and the tissues were dissected, washed with saline, and weighed. Ltd., Haryana, India), and Cyamopsis tetragonaloba (guar plant) and guar were identified by the herbal medicinal specialist at Ferdowsi University.
Samples were then analyzed using the glucose kit reagents (AppliedBio assay kits; Hercules, CA, USA).
Gamba et al., “Time and frequency domain estimates of spontaneous baroreflex sensitivity provide early detection of autonomic dysfunction in diabetes mellitus,” Diabetologia, vol. During the oxidation, nitroblue tetrazolium (NBT) was reduced and nitrite was produced in the presence of ethylenediaminetetraacetic acid (EDTA), which could be detected colorimetrically at 560 nm.
The animals were housed according to the regulations of the welfare of experimented animals. Streptozotocin-treated rats received 5% glucose instead of water for 24 h after diabetes induction in order to reduce death due to hypoglycemic shock. The protein concentrations were determined using a Bio-Rad protein assay (Bio-Rad Laboratories, Inc., Hercules, CA, USA). Blood samples were taken from the tail vein 72 h after streptozotocin injection to measure the glucose levels with a portable glucometer.
The protein was transferred to expanded polyvinylidene difluoride membranes (Pierce, Rockford, IL, USA) with a Bio-Rad Trans-Blot system. Diabetes development was then checked every week by determination of glucose concentration in the blood.
During the experiment, blood glucose and lipid profile levels were verified four times at 0, 7, 14 and 28 days after the beginning of the treatment. Incubation with secondary antibodies and detection of the antigen-antibody complex were performed using an ECL kit (Amersham Biosciences, UK). During the treatment period, the rats were subjected to measure, body weight and food intake and also to collection of blood samples.
Administration of insulin produced no significant alteration in the sperm shape and sperm count defects in the diabetic rats.
Fritsch, “Baroreflex control of plasma norepinephrine and heart period in health subjects and diabetic patients,” Journal of Clinical Investigation, vol. Blood was collected from the retroorbital vein puncture using the microcapillary technique on days 0, 7, 14 and 28 from the day of being diabetic. However, none of the tested doses of insulin reversed significantly the diminished antioxidant profile in the diabetic animals [Table 3].
Intracerebroventricular (ICV) InjectionFollowing to the previous method [12], the well-anesthetized rats were immobilized in a stereotaxic frame to prepare for ICV injection. The serum obtained after centrifugation was used to estimate the blood glucose levels, triglyceride, total cholesterol, HDL and LDL-C.Biochemical analysisPlasma lipid parameters such as total cholesterol, triglyceride, glucose, HDL-cholesterol and LDL-C were determined by enzymatic colorimetric methods using commercial kits from Pars Azmoon (Tehran, Iran). The blood glucose estimation indicated that insulin exhibited a dose-dependent reduction in the NA-STZ-induced hyperglycemia. Briefly, blood samples were transferred directly into centrifuge tubes, allowed to clot at room temperature for 20 min and centrifuged for 20 min at 2000 rpm. NA-STZ-induced diabetic model in Wistar rats is commonly used since different levels of stable hyperglycemia can be produced, which are suitable for long-term studies. Arterial Pressure and Heart Rate RecordingThe rats were anesthetized with 2% isoflurane, and a catheter was inserted into the femoral artery for recording of blood pressure and heart rate. Further, this method of chemical diabetes is reported to mimic the clinical T2DM, especially in terms of insulin secretion in response to glucose load. The mechanism suggested for these responses is the partial protection offered by the NA against the STZ mediated oxidative damage to the pancreatic beta cells. After surgery, the animals were allowed 20 min to adapt the experimental conditions, such as sound and illumination.
Bone marrow MN test and sperm abnormalities test are commonly employed assays to determine the mutations in somatic and germinal cells, respectively. Blood glucose was determined by the GOD-POD method, [24] serum total cholesterol was determined by the CHOD-PAP method [21] and serum triglyceride concentration was determined by the GPO-PAP method. Salgado, “Power spectra of arterial pressure and heart rate in streptozotocin-induced diabetes in rats,” Journal of Hypertension, vol. MN in young erythrocytes arises primarily from chromosomal fragments or lagging chromosomes that are not incorporated into daughter nucleus at the time of cell division in the erythropoietic blast cells, and the changes in the incidences of MN are considered to reflect the chromosomal damage in somatic cells. Statistical AnalysisAll data are expressed as the mean ± standard error (SE) of each group. As expected, the main consistent of the guar gum appears as soluble fiber (75%), followed by insoluble fiber (7.6%).

Klotho Expression in the Medulla Oblongata of STZ-Diabetic RatsExpressions of the klotho protein in the medulla oblongata between Wistar rats and STZ-diabetic rats were compared using Western blotting analysis. These agents are reported to benefit the diabetic patients in reducing both hyperglycemia and also the mutagenic complications associated with enhanced oxidative stress.
Expression of klotho protein (130 kDa) in Wistar rats (Wistar) and STZ-diabetic rats (STZ) was identified using Western blotting analysis. No significant difference was detected between the glucose level of rats fed with 5%, 10% and 20% guar gum during the 28 days.
Cheng, “Impaired regulation function in cardiovascular neurons of nucleus tractus solitarii in streptozotocin-induced diabetic rats,” Neuroscience Letters, vol. The quantification is indicated as the means with the SE ( per group) in each column shown in the lower panel. It is noticeable that there was, in general, an increase in blood concentrations of the various components in the diabetic control compared with the normal rats. 1 = normal, 2 = diabetic + 0% guar gum, 3 = diabetic + 5% guar gum, 4 = diabetic + 10% guar gum, 5 = diabetic + 20% guar gum, 6 = diabetic + glibenclamide. Effect of TZD on the Expression of klotho in Medulla Oblongata of STZ RatsChanges of klotho expression in the medulla oblongata from STZ-diabetic rats were also identified using Western blots. The upper shows the klotho protein level (Klotho) or the corresponding β-actin (Actin) level as internal control in the medulla oblongata isolated from Wistar rats (Con) and STZ-diabetic rats receiving TZD (STZ + TZD) or not (STZ). Quantification of protein levels using klotho over β-actin to show the means with SE ( per group) in each column are indicated in the lower panel.
But, treatment with different doses of guar gum concentrations and glibenclamide elevated the reduced body weight so that there was no significant decrease in the body weight during the treatment period in rats fed the control diet [Table 2].
Diabetic controls and normal rats and the rats fed with glibenclamide showed significantly increased food intake after 28 days compared with the day of induction of diabetes. Zucker, “Central angiotensin (1–7) enhances baroreflex gain in conscious rabbits with heart failure,” Hypertension, vol. Chronic feeding diabetic rats with different concentrations of guar gum prevent the loss of body weight, polyphagia and polyuria. In this study, in spite of an increase of other lipidemic parameters induced by diabetes, the rats fed guar gum diets showed lower serum cholesterol, triglycerides and LDL-C concentrations compared with diabetic controls (rats fed 0% guar gum diet). DiscussionIn the present study, we demonstrate, for the first time, that the expression of klotho protein was significantly lower in the medulla oblongata of STZ-diabetic rats than normal Wistar rats.
The mechanisms involved in the circulating and tissue cholesterol reduction are not yet clearly established. The baroreflex gain in response to challenge with PE or SNP was also reduced in STZ-diabetic rats compared to normal rats. We infused recombinant klotho into the brain of this type 1-like diabetic animal to restore the baroreflex responses without correcting blood glucose. Soluble fibers are very viscous and can decrease food intake due essentially to its effects on the gastric emptying time. Additionally, the expression klotho was significantly reversed in diabetic rats receiving rosiglitazone (TZD). The increased viscosity of the gastric content produced by the hydrophilic character of some gums slows the gastric emptying rate, increasing the satiety and, consequently, reducing the food intake. The baroreflex responses triggered by PE or SNP were also increased in STZ-diabetic rats treated with rosiglitazone without changing blood glucose level.
Aizawa et al., “Mutation of the mouse klotho gene leads to a syndrome resembling ageing,” Nature, vol.
The klotho is documented to predominantly express in kidney and choroid plexus of the brain, although a slight expression of klotho has also been observed in the pituitary gland, placenta, skeletal muscle, colon, urinary bladder, pancreas, testis, ovary, and inner ear [13, 36]. After 28 days of guar gum treatment, gain in body weight was recognized in diabetic rats, and the results were comparable with that of the standard drug, glibenclamide. Thus, klotho protein is suggested as a humoral factor [38] and it is detectable in CSF [20]. The administration of 20% guar gum in the daily diet reduced the fasting blood glucose by 44.2% by the forth week. The glycemic control produced by guar gum in this study was significantly efficient in comparison with the effect produced by glibenclamide. Baroreflex dysfunction observed in diabetic subjects has important clinical implications, because the baroreflex included an important system that acts against wide oscillations in arterial pressure (AP). The results addressed in this paper on the effect of guar gum on blood serum glucose concentration agree with those of others who have also determined a reduction in the postprandial glycemia in diabetic individuals receiving fiber-like pectin in the diet. Additionally, clinical trials have shown an association between baroreflex dysfunctions [39, 40]. Studies using experimental animals have been conducted to investigate the mechanisms of cardiovascular reflex dysfunction in diabetes [41]. Yang et al., “Klotho gene polymorphism of rs3752472 is associated with the risk of urinary calculi in the population of Han nationality in Eastern China,” Gene, vol. It has been demonstrated that, in STZ-induced experimental diabetes, baroreflex control of circulation was impaired. On the other hand, it has been demonstrated that fiber needs to be well mixed with the food that is to be ingested to allow its maximum capability. In this study, we provide the first demonstration of a marked decrease of klotho in the medulla oblongata of STZ-diabetic rats. Wilson showed that guar gum reduced the cholesterol level without reducing HDL, [32] but our data for the first time showed that dietary fiber (guar gum) reduces triglycerides, LDL-C and cholesterol and also increases HDL-C in diabetic rats.
The present work for the first time showed the effectiveness of insoluble fiber (guar gum) in all aspect of atherosclerosis diseases. The pressor responses to PE were more marked in the STZ group than in the normal group, whereas the bradycardic reflex was reduced in the STZ group. Our data showed that guar gum not only decreases the lipid profile but also decreases the body weight, food intake and AI. Wang et al., “A potential regulatory single nucleotide polymorphism in the promoter of the Klotho gene may be associated with essential hypertension in the Chinese Han population,” Clinica Chimica Acta, vol. In our data, we also focused on comparing the effect of guar gum and glibenclamide, a first-line option for treating type 2 diabetes, on the lipid profile in diabetic rats. Our data showed that guar gum (20%) for long-period treatment induced a hypoglycemic effect.
In our knowledge, this is the first report showing that guar gum significantly induced hypoglycemic in diabetic rats versus those receiving the ordinary diabetic drug, glibenclamide.It is also potential that the activity of soluble polysaccharides in reducing postprandial hyperglycemia is due to its viscosity. The diets rich in soluble fiber accommodate an increase of intestinal content viscosity as these fibers are molecules that hold water and have the property of forming colloidal gels. The baseline heart rate values in STZ rats were alternatively lower than that in normal rats.
This decreases the association of food with the intestinal mucosa and the enzymatic digestion rate, consequently decreasing the intestinal absorption of monosaccharides and disaccharides.
It is may be the reason why there is no differences in bradycardiac peak between normal and STZ groups.
Additionally, the decreased baroreflex responses were restored by the recombinant klotho infused into the brains of STZ group by ICV injection. Although the body weight gain was not high, it could be considered important as the diabetes condition usually induces catabolic processes that lead to body weight reduction due to the accelerated catabolism of protein, carbohydrate and lipids. Thus, increase of cerebral klotho appears to be useful in the recovery of the lowered baroreflex sensitivity.Actually, STZ-diabetic rats treated with rosiglitazone result in an increase of klotho expression in the medulla oblongata (Figure 3).
Then, we evaluated the effect of rosiglitazone on baroreflex responses in STZ-diabetic rats.
In our study, the lower protein utilization by the rats in the control diabetic group could be a reflex of a high-reserve energy mobilization induced by the diabetes condition, leading to the significant weight loss observed. The basal MAP and HR in diabetic rats were both increased by rosiglitazone near to the values in normal rats. Huggins, “Lack of association of Klotho gene variants with valvular and vascular calcification in Caucasians: a candidate gene study of the Framingham Offspring Cohort,” Nephrology Dialysis Transplantation, vol. Other applied parameters for calculating the metabolic control on diabetics are triglycerides and cholesterol [33] in diabetic patients hypertriglyceridemia and low HDL-C levels are conventional. Additionally, the pressor responses to PE were reduced to normal rats in the STZ + TZD group; the bradycardic reflex and baroreflex gain were both restored in the STZ + TZD group. Similar changes were also noted in the SNP-challenged baroreflex gain in STZ-diabetic rats.
Thus, reduction of cholesterol, triglyceride and LDL-C levels by guar gum may develop valuable effects on streptozotocin-induced cardiovascular complications. Thus, treatment of rosiglitazone or TZD seems beneficial in the recovery of baroreflex sensitivity in STZ-diabetic rats without changing blood glucose.
However, other researchers articled an increase in blood triglycerides but a reduction in cholesterol by applying pectin. Taken together, we demonstrated that the higher the expression of klotho by rosiglitazone the more restored the baroreflex in STZ-diabetic rats.
However, the molecular mechanisms underlying the regulation of the baroreflex by klotho remain unclear and it needs more investigations in the future.
Several clinical researches have shown that guar gum absorption reduces the plasma cholesterol concentrations mainly due to a reduction of plasma LDL-C concentration, without affecting the HDL-C levels in normal, diabetic rats and in patients with hyperlipidemia. Rosiglitazone has been demonstrated to be able to cross the blood brain barrier and that it is not exported out of the brain [42].
It was able to significantly decrease the fasting blood glucose in comparison with diabetic controls, while the total cholesterol, triglyceride and LDL-C concentrations were diminished. The neuroprotective effects are introduced to be associated with PPARγ mediated suppression of the inflammatory pathway [47] or by increasing antioxidant-like activities [48].
Kato et al., “Association between KLOTHO gene and hand osteoarthritis in a female Caucasian population,” Osteoarthritis and Cartilage, vol.
Therefore, this may result in their potential ability to decrease macrovascular complications.
Taken together, there is no doubt that rosiglitazone can enter into central nervous system.5. ConclusionsWe found that klotho expression in the medulla oblongata was reduced in STZ-diabetic rats. This study confirmed the beneficial effects of guar gum intake in improving the condition of rats with experimentally induced diabetes. This is associated with the lower baroreflex response in STZ-diabetic rats because baroreflex was restored by the oral administration of rosiglitazone or treatment with the recombinant klotho through ICV infusion to higher cerebral klotho. All these results may show that the antihyperglycemic effect produced by guar gum at the high dose is higher than that produced by glibenclamide. They would also wish to thank the Javaneh Khorasan Company for making different concentrations of guar gum food for the rats.
Chiano et al., “Klotho gene polymorphisms associated with bone density of aged postmenopausal women,” Journal of Bone and Mineral Research, vol. Guan, “Peroxisome proliferator-activated receptor family and its relationship to renal complications of the metabolic syndrome,” Journal of the American Society of Nephrology, vol. Wolf, “Rosiglitazone increases PPARγ in renal tubular epithelial cells and protects against damage by hydrogen peroxide,” American Journal of Nephrology, vol. Cheng, “Rosiglitazone is effective to improve renal damage in type-1-like diabetic rats,” Hormone and Metabolic Research, 2013. Lund, “Alterations in the baroreceptor reflex control of heart rate in streptozotocin diabetic rats,” Journal of Molecular and Cellular Cardiology, vol. Chang, “Novel mechanism for plasma glucose-lowering action of metformin in streptozotocin-induced diabetic rats,” Diabetes, vol.
An, “Protective effect of rosiglitazone sodium on islet b̃-cell of stz induced diabetic rats through jnk pathway,” Journal of Sichuan University, vol. Sheehy et al., “Reduced plaque formation induced by rosiglitazone in an STZ-diabetes mouse model of atherosclerosis is associated with downregulation of adhesion molecules,” Atherosclerosis, vol. Aja et al., “C75, a fatty acid synthase inhibitor, reduces food intake via hypothalamic AMP-activated protein kinase,” Journal of Biological Chemistry, vol.
Campagnole-Santos, “Changes in the baroreflex control of heart rate produced by central infusion of selective angiotensin antagonists in hypertensive rats,” Hypertension, vol.
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Symptoms of hypoglycemia newborn ppt
Sugar levels for a diabetic coma occur
2-hour postprandial blood sugar normal range rover


  1. 22.10.2014 at 21:11:44

    Guidelines and was likely to be low gland, pancreas, and liver can blood glucose test.

    Author: sakira
  2. 22.10.2014 at 12:18:54

    Such, do not dramatically raise blood stomach the reading.

    Author: kroxa