Effects of cyclohexenonic long-chain fatty alcohol on diabetic rat trachea

In order to investigate the diabetes-associated neuropathy and prevent effects of cyclohexenonic long-chain fatty alcohol, a neurotrophic substance, in trachea, we studied its effect on streptozotocin-diabetic hyper-reactivity in the rat trachea. Diabetes was induced in 8-week-old male Sprague-Dawley rats by administering an intraperitoneal injection of streptozotocin (50 mg/kg). The rats were divided randomly into four groups and were maintained for four weeks: age-matched control rats, diabetic rats without treatment with cyclohexenonic long-chain fatty alcohol, and diabetic rats treated with cyclohexenonic long-chain fatty alcohol (2 and 8 mg/kg, i.p. every day). The serum glucose and insulin levels were determined, and the contractile responses of the trachea induced by carbachol and KCl were investigated. Treatment with cyclohexenonic long-chain fatty alcohol did not alter the rats' diabetic status, i.e., body weight, thickness of the trachea, serum glucose levels, and serum insulin levels, but significantly improved the diabetic-induced hyper-reactivity of the rat trachea in a dose-dependent manner. There was no significant difference in either the carbachol- or KCl-induced contractile forces between groups with or without mucosa in the functional studies. In histological examinations, thinning of cricoid cartilage, thickness of basal membrane, and degeneration, fragmentation of elastic fibers in the submucosal layer, and hypertrophy of smooth muscle bundle in the membranous wall of trachea were observed in the diabetic rat trachea, which were improved by treatment with cyclohexenonic long-chain fatty alcohol. Our data indicate that this drug can prevent hyper-reactivity in the diabetic trachea.     

Preventive effects of cyclohexenonic long-chain fatty alcohol on diabetic cystopathy in the rat

In this study, we investigated the preventive effect of n-hexacosanol on diabetes-induced bladder dysfunction in the rat. Diabetes was induced in 8-week-old male Sprague-Dawley rats by administering an injection of streptozotocin (50 mg/kg, i.p.). The rats were randomly divided into 4 groups (age-matched control rats, diabetic rats without treatment with n-hexacosanol, and diabetic rats treated with n-hexacosanol (2 and 8 mg/kg, i.p. every day)) and maintained for 4 weeks. The serum glucose and serum insulin levels were determined, and the functions of bladder were estimated by voiding behavior, cystometric, and functional studies to carbachol and KCl. Furthermore, we examined possible diabetic induced histological changes in these rats. Treatment with n-hexacosanol did not alter diabetic status including body mass, bladder mass, and serum glucose and serum insulin levels, but significantly improved the maximum contraction pressure of the detrusor and residual urine volume in cystometric studies and Emax values to carbachol in functional studies in a dose-dependent manner. Diabetes induced bladder smooth muscle hypertrophy, which tended to be ameliorated by treatment with n-hexacosanol in a dose-dependent manner. Treatment with n-hexacosanol did not alter the diabetic status, but significantly improved diabetic cystopathy in a dose-dependent manner.     

Contractile activity increases glucose uptake by muscle in severely diabetic rats

Muscle contractile activity is associated with an acceleration of glucose transport into muscle. It has been reported that the acceleration of glucose uptake by contractile activity in perfused rat muscles requires the presence of insulin in the perfusate. This claim was investigated using the perfused rat hindlimb preparation in the present study. Rats were made diabetic by injection of 125 mg/kg of streptozotocin and either studied 72 h later or maintained on insulin for 2 wk and then studied 3 days after cessation of insulin therapy. Only rats with plasma insulin levels too low to measure were used. The hindlimbs were washed out with 630 ml of medium over 75 min using a single flow-through washout before muscle stimulation. Despite the absence of insulin in the perfusion medium, stimulation of muscle contraction resulted in large increases in glucose uptake in both the diabetic and control rats. These findings do not support the claim that the stimulatory effect of muscle contraction on glucose uptake by perfused rat muscles requires the presence of insulin.     

Effect of exposure to diabetic and fasted plasma on glucose oxidation in rat aorta

Glucose metabolism is depressed in aortic intima-media of fasted and diabetic rats. The aim of this study was to elucidate the influence of diabetic and fasted plasma on glucose oxidation in rat aorta. Male Sprague-Dawley rats weighing about 200 g were used. Diabetes was induced by streptozotocin (65 mg/kg) and the rats were used after a diabetes duration of two weeks. Fasted rats were used after food deprivation for 3 days. Aortic intima-media was preincubated in plasma for 120 or 240 min. During a further incubation for 2 hours in Krebs-Henseleit bicarbonate buffer the oxidation of 14C-glucose to 14CO2 was measured. Preincubation of normal aorta in diabetic or fasted rat plasma and diabetic human plasma significantly depressed the subsequently determined glucose oxidation in comparison to aorta preincubated in normal plasma. Preincubation of aorta from diabetic or fasted rats in normal rat plasma enhanced the glucose oxidation compared with the glucose oxidation in aorta of diabetic or fasted rats after preincubation in the corresponding plasma. These results suggest that diabetic and fasted plasma contains factor(s) which in vitro depress glucose oxidation in vascular smooth muscle and, thus, may be of importance for the lowered glucose oxidation found in vascular smooth muscle preparations obtained from diabetic or fasted animals.     

Effects of taurine on the reactivity of aortas from diabetic rats

The effects of the semi-essential amino acid-like nutrient, taurine, on alterations in the reactivities of aortas from male rats with chronic streptozotocin-induced diabetes were examined under in vitro conditions. In the absence of taurine, the contractile responsiveness of endothelium-denuded aortic rings from diabetic rats to norepinephrine, but not KCl, was enhanced compared to controls. This effect of norepinephrine on the diabetic rat aorta appeared to be associated with increased release of intracellular calcium, influx of extracellular calcium and protein kinase C-mediated responses. Incubation of endothelium-denuded aortic rings with 10 mM, but not 5 mM, taurine for 2 h reduced the augmented contractile responses of the tissues from diabetic rats to norepinephrine close to control levels, and this was associated with inhibition of responses linked to the release and influx of calcium, and protein kinase C activation. Endothelium-dependent relaxation of aortas from diabetic rats to acetylcholine was depressed relative to controls. This effect of diabetes was ameliorated close to control levels by incubating the tissues with 10 mM, but not 5 mM, taurine for 2 h. Incubation of nondiabetic rat aortic rings with 45 mM glucose for 3 h caused enhancement of contraction of the vascular smooth muscle to phenylephrine and impairment of endothelium-mediated vasorelaxation to acetylcholine, as compared to control responses. Co-incubation of the tissues with 5-10 mM taurine concentration-dependently reduced the alterations in both contractile and relaxant responses caused by high glucose. Overall, the data suggest that taurine ameliorates or prevents vascular reactivity alterations in diabetes. Such an observation provides preliminary evidence for taurine's potential as a therapeutic agent for the prevention or amelioration of vascular disorders in diabetes.     

Clodronate changes neurobiological effects of pulsed magnetic field on diabetic rats with peripheral neuropathy

Several studies have reported that pulsed magnetic fields (PMFs) can be a choice of therapy for diabetic peripheral neuropathy. However, the exact underlying mechanism of PMF is still not known. The purpose of this study was, therefore, to investigate the effects of clodronate encapsulated with liposome, a specific agent depleting macrophage, on PMF-treated streptozotocin-induced type I diabetic rats with peripheral neuropathy. Effects of PMF, liposome-encapsulated clodronate (LEC) or their combined treatments were investigated in diabetic rats by measuring the thermal latencies, mechanical thresholds, whole blood glucose levels, serum insulin level, and body mass. In diabetic rats, PMF exhibited a decrease in the blood glucose levels but did not change the serum insulin level. Both mechanical thresholds and thermal latencies of diabetic rats enhanced throughout the PMF treatment. During the PMF treatment, the administration of LEC suppressed the PMF-induced decrease in blood glucose level, PMF-induced increase in mechanical threshold and thermal latencies in diabetic animals. In addition, PMF reduced the LEC-induced increase in insulin levels of diabetic rats. Findings demonstrated that although effects of both PMF alone and LEC alone on diabetic animals are mostly positive, LEC may remove the therapeutic efficacies of PMF in combined treatment.     

Gender differences in myosin heavy chain-beta and phosphorylated phospholamban in diabetic rat hearts

The objective of this study was to determine whether a gender difference exists in myosin heavy chain (MHC) isoform or sarcoplasmic reticulum protein levels in diabetic rat hearts. As is the case with normal rodent hearts, all four chambers of the control rat hearts expressed almost 100% MHC-alpha. In 6-wk diabetic rats, MHC-beta expression in ventricles of males was significantly greater (78 +/- 7%) than in females (50 +/- 5%). The cardiac sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2a) protein level was decreased and the phospholamban (PLB) protein level was increased in the left ventricle of diabetic rats, but there was no difference between male and female diabetic rats. The phosphorylated PLB level was decreased more in male than in female diabetic rats. Insulin treatment completely normalized blood glucose level, cardiac SERCA2a and PLB protein levels, and the decrease in MHC-beta levels in both male and female diabetic rats. Insulin treatment completely normalized serum insulin and almost completely normalized phosphorylation of PLB at serine 16 in male diabetic rats. Although insulin treatment completely normalized serum insulin levels in male diabetic rats, in females it only partially normalized serum insulin levels. Also, insulin treatment almost completely normalized phosphorylation of PLB at threonine 17 in female diabetic rats; however, the increase was significantly greater than that identified for insulin-treated male diabetic rats. We conclude that higher levels of MHC-beta and dephosphorylated PLB may contribute to more contractile dysfunction in male than in female diabetic rat hearts, and that phosphorylation of PLB at threonine 17 is more responsive to insulin in female diabetic rat hearts.     

Effects of streptozotocin-induced diabetes and insulin on calcium responsiveness of the rat vas deferens

In the present study, effects of streptozotocin-induced diabetes and insulin treatment on the reactivity of rat vas deferens to KCl and calmidazolium, a calmodulin antagonist, were evaluated and calmodulin levels in vas deferens tissue from diabetic and insulin-treated rats were determined. Diabetes was induced in rats by a single injection of streptozotocin. Five weeks after the induction of diabetes, one group of diabetic rats was injected with insulin for 3 weeks. After 8 weeks, vas deferens tissues on one side of diabetic and insulin-treated diabetic rats and their controls were mounted in organ bath to measure isometric tension, while the tissues on the other side of rats were homogenized to determine calmodulin levels by radioimmunoassay. Concentration-response curves to KCl were obtained in vas deferens tissues in the absence and presence of calmidazolium. The effects of KCl and calmidazolium on vas deferens isolated from 8-weeks diabetic rats were decreased. Calmodulin levels were also found to be decreased in vas deferens from diabetic rats. Decreased calmodulin levels in diabetic rat vas deferens were not corrected by insulin treatment. Only a partial correction following insulin treatment was observed in contractile effect of KCl on diabetic rat vas deferens, whereas insulin treatment increases the affinity of calmodulin in this muscle. Experimental diabetes causes an impairment in calcium/calmodulin-dependent contractile process of vas deferens, which is correctable partially following insulin therapy. The changes in the function of rat vas deferens due to streptozotocin diabetes seem to be related to impaired sexual functions in human diabetes.     

Rapid pacing-induced preconditioning is recaptured by farnesol treatment in hearts of cholesterol-fed rats: Role of polyprenyl derivatives and nitric oxide

Sodium selenate, administered intraperitoneally (i.p.), resulted in an improvement in glucose tolerance in treated diabetic rats. Fed rat plasma glucose levels were reduced by selenate treatment in streptozotocin diabetic rats. The lowest values of blood glucose were reached within 3 weeks of beginning the treatment. Food and fluid consumption was reduced in treated compared to untreated diabetic rats. Diabetic treated rats did not release insulin in response to a glucose challenge and insulin release in response to a challenge was markedly reduced in control treated rats. Assessment of heart function using a working heart apparatus showed that treated diabetic rats with improved blood glucose levels had normal heart function at 8 weeks of diabetes in contrast to hearts from non-treated diabetics. This study extends previous observations on the in vivo insulin-like effects of sodium selenate.     

Effect of chronic treatment with Bis(maltolato)oxovanadium (IV) in rat model of non-insulin-dependent-diabetes

Effect of chronic treatment with Bis(maltolato)oxovanadium (IV) (BMOV) was studied in streptozotocin (STZ)-induced neonatal non-insulin-dependent-diabetic (NIDDM) rats. Intraperitoneal injection of STZ (90 mg kg(-1)) in Wistar rat pups (day 2 old) produced mild hyperglycemia, impaired glucose tolerance and insulin resistance at the age of 3 months. Treatment with BMOV (0.23 mM kg(-1)) in drinking water for 6 weeks produced a significant decrease in elevated serum glucose levels without any significant change in serum insulin levels in diabetic rats. BMOV treatment significantly decreased integrated area under the glucose curve without any significant change in integrated area under the insulin curve indicating improved glucose tolerance. Treatment also significantly increased K(ITT) value of diabetic rats indicating increased insulin sensitivity. BMOV treatment significantly reduced hypercholesterolemia in diabetic rats. Treatment also significantly decreased serum triglyceride levels in both diabetic and non-diabetic rats. The data suggest that chronic BMOV treatment improves glucose and lipid homeostasis. These effects appear to be due to the insulin sensitizing action of vanadium.     

Anti-hyperglycemic activity of zinc plus cyclo (his-pro) in genetically diabetic Goto-Kakizaki and aged rats

We previously reported that treatment of streptozotocin-induced diabetic rats with zinc plus cyclo (his-pro) (CHP) decreased fed blood glucose levels and water intake. The present study was conducted to examine the dose-dependent, acute, and chronic treatment effects of CHP on oral glucose tolerance (OGT), fed blood glucose levels, water intake, and plasma insulin levels in young and aged Sprague-Dawley (S-D) rats, nondiabetic Wistar rats, and genetically diabetic Goto-Kakizaki (G-K) rats. Acute gastric gavage of 10 mg zinc plus 1.0 mg CHP/kg body weight significantly improved OGT in 4- and 13-month-old nondiabetic S-D rats and in 2-month-old diabetic G-K rats. Young S-D and G-K rats returned to pretreatment OGT values 1 week after acute gavage of zinc plus CHP (ZC), but improved OGT values persisted for at least 1 week after gavage in aged S-D rats. OGT values and fed blood glucose decreased to the greatest extent among other treatments when G-K rats were given free access to drinking water containing 1.0 to 1.5 mg CHP/L plus 10 mg zinc/L for 2 weeks. Although food and water intake showed a tendency to decrease, no statistically significant differences were observed in young G-K rats. Plasma insulin levels and blood glucose levels in both normal and diabetic G-K rats decreased with 2-week treatment with ZC. To test the direct effects of ZC on muscle tissue, we observed the effect of various doses of ZC on normal and G-K rat muscle slices. The optimal level of CHP alone for maximal muscle glucose uptake in muscle slices from normal rats was 10 microg/mL and 5.0 microg/mL in G-K rats, and ZC stimulated glucose uptake. However, no statistically significant difference was demonstrated between normal and G-K rat tissues in this study. These results indicate that oral intake of an optimal dose of ZC stimulates blood glucose metabolism, probably by stimulating muscle glucose utilization.     

Alterations of the plasma selenium concentrations and the activities of tissue peroxide metabolism enzymes in streptozotocin-induced diabetic rats

The activity of aortic glutathione peroxidase, a selenium-dependent enzyme, significantly decreased in rats 4 and 8 months after the injection of streptozotocin (STZ). Catalase activity was shown to occur at low levels in rat aorta and was not influenced by the diabetic state. Superoxide dismutase activity was less than detectable. The activity of selenium-dependent glutathione peroxidase in kidney, but not in lung and liver, increased in diabetic rats. Catalase and superoxide dismutase activities in the kidney were not altered. The plasma lipid peroxide value increased in diabetic rats. The selenium content in plasma of diabetic rats increased markedly while the increase in plasma glutathione peroxidase activities was insignificant. The observed abnormalities in plasma of STZ rats were improved by insulin treatment. The defects in glutathione peroxidase in the diabetic rat aorta were restored by insulin treatment. These results may suggest that the capacity of the antioxidative defense system in the aorta decreased in the diabetic state, and this may help clarify the mechanism of the pathogenesis of endothelial dysfunction associated with diabetes.     

Fatty acid metabolism is enhanced in type 2 diabetic hearts

The metabolic phenotype of hearts has been investigated using rodent models of type 2 diabetes which exhibit obesity and insulin resistance: db/db and ob/ob mice, and Zucker fatty and ZDF rats. In general, cardiac fatty acid (FA) utilization is enhanced in type 2 diabetic hearts, with increased rates of FA oxidation (db/db, ob/ob and ZDF models) and increased FA esterification into cellular triacylglycerols (db/db hearts). Hearts from db/db and ob/ob mice and ZDF rat hearts all have elevated levels of myocardial triacylglycerols, consistent with enhanced FA utilization. A number of mechanisms may be responsible for enhanced FA utilization in type 2 diabetic hearts: (i) increased FA uptake into cardiac myocytes and into mitochondria; (ii) altered mitochondrial function, with up-regulation of uncoupling proteins; and (iii) stimulation of peroxisome proliferator-activated receptor-alpha. Enhanced cardiac FA utilization in rodent type 2 diabetic models is associated with reduced cardiac contractile function, perhaps as a consequence of lipotoxicity and/or reduced cardiac efficiency. Similar results have been obtained with human type 2 diabetic hearts, suggesting that pharmacological interventions that can reduce cardiac FA utilization may have beneficial effects on contractile function.     

Plasma levels of nitrites, PGF1α and nitrotyrosine in LPS-treated rats: functional and histochemical implications in aorta

We investigated the effects of lipopolysaccharide (LPS) administration on plasma nitrite, nitrotyrosine and 6-keto prostaglandin F1alpha, (PGF1alpha) levels and the related resultant changes in function and histochemistry of aorta in rats. Plasma nitrite and PGF1alpha nitrotyrosine levels were analysed after 5 mg/kg intravenous LPS was administered to rats compared with those in non-treated rats. The distribution of nitrotyrosine in the aorta was studied immunohistochemically. The contractile responses of aortic rings to phenylephrine (PE) from both the LPS-treated and control rats were studied in the organ baths. There were increases in plasma nitrite, PGF1alpha, and nitrotyrosine concentrations of LPS-treated rats compared to non-treated rats. Immunoreactivity of nitrotyrosine residues were detected in the endothelial and smooth muscle cells in LPS-treated but not in control rat aorta. The contractile responses to PE of the LPS-treated rat aortic rings were significantly reduced as compared with those of control rat's. Incubation of the aortic rings from LPS-treated rats with cyclooxygenase inhibitor indomethacine or with a combination of indomethacine and nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) increased the contractile responses to the levels observed in control rats suggesting that both prostanoids and particularly nitric oxide (NO) are involved in the reduced contractile responses in LPS-treated rats. These results supported the view that LPS might cause an increment in both NO and PGI2 levels. This increase in the NO and PGI2 levels may be responsible from the reduction in responses of aorta to contractile agents in LPS-treated rats. Increased peroxynitrite formation in LPS-treated rats may lead to nitration of the tyrosil residues of the proteins in the aorta.     

Insulin-sparing effect of hydroxychloroquine in diabetic rats is concentration dependent.

To study the effect of hydroxychloroquine (HCQ) on glucose and insulin homeostasis, healthy rats were dosed with 160 mg x kg (-1) x day(-1) of HCQ orally, and streptozocin-induced diabetic rats received 80, 120, and 160 mg x kg(-1) x day(-1) of HCQ, while controls received normal saline. Ten days after treatment with HCQ, healthy animals were challenged intravenously with insulin or glucose, while diabetic rats were given only an i.v. injection of insulin. In healthy rats, the areas within and under the glucose concentration - time curve following insulin and glucose challenge were estimated. In diabetic animals, the areas under the curve for both the percent change in serum glucose from baseline (AUG) and the percent change in serum insulin from baseline (AUI) were used as pharmacodynamic end points. In healthy rats, HCQ did not influence fasting serum glucose concentrations or glycemic profiles following i.v. administration of glucose or insulin. In diabetic rats, AUG and AUI were increased dependent on blood HCQ concentrations. The normal homeostatic mechanisms responsible for insulin-glucose regulation may compensate for possible HCQ-induced reduction of insulin metabolism in healthy rats. The HCQ dose- or concentration-effect relationships for glucose and insulin were linear over the range of HCQ concentrations tested. It is concluded that HCQ significantly elevated insulin blood concentration resulting in reduced glucose levels in a concentration-dependent fashion in diabetic rats. HCQ may have therapeutic potential in the treatment of type I and type II diabetes.     

Effect of phorbol ester on contractile response of aorta from endotoxic rats

The influence of phorbol ester on the isometric contractile response of aorta from endotoxic rats was examined. In endotoxic rat aorta, the contractile responses to KCl and phorbol 12,13-dibutyrate (PDBu) were both remarkably diminished, compared to those in control rat aorta. Preincubation with PDBu augmented the aortic contractile response to KCl in both control and endotoxic rats. This augmentative effect of PDBu was significantly more pronounced in endotoxic rats than in controls. When the contractile response to 80 mM KCl reached a plateau after PDBu pretreatment, addition of 5 mM CaCl2 (final concentration) to the organ bath completely reversed the diminished contractile response of endotoxic rat aorta to the control level. These results suggest that the hyporesponsiveness of endotoxic rat aorta to KCl may be caused by decreases in both protein kinase C mediated response and calcium sensitivity of vascular smooth muscle cells.     

Reversibility of decreased insulin-stimulated glucose transport capacity in diabetic muscle with in vitro incubation. Insulin is not required

The mechanisms by which insulin deficiency affects muscle glucose transport were investigated. Epitrochlearis muscles from rats with streptozotocin-induced diabetes and from controls were incubated in vitro for 0.5-14 h. The incubation was shown not to impair muscle energy stores or tissue oxygenation. Diabetes decreased basal 3-O-methylglucose transport by 40% (p less than 0.01), and insulin-stimulated (20 milli-units/ml) glucose transport capacity by 70% (p less than 0.001). In vitro incubation gradually normalized insulin responsiveness (3.77 +/- 0.38 before versus 8.97 +/- 0.65 mumol X ml-1 X h-1 after 12 h of incubation). Basal glucose transport remained significantly reduced. The reversal of the insulin responsiveness did not require the presence of rat serum and, furthermore, took place even in the absence of insulin. In fact, insulin responsiveness was higher after incubation (14 h) with no insulin than with 100 microunits/ml insulin (9.85 +/- 0.59 versus 8.06 +/- 0.59 mumol X ml-1 X h-1, p less than 0.05). Glucose at 30 mM did not affect the normalization of the insulin-stimulated glucose transport capacity, whereas incubation in serum from diabetic rats resulted in a slightly (26%) blunted reversal (7.60 +/- 0.39 versus 8.89 +/- 0.45 mumol X ml-1 X h-1 with diabetic versus control serum for 14 h, p less than 0.05; before incubation the value was 3.87 +/- 0.40). Inhibition of protein synthesis by cycloheximide blocked the normalization by 80%. These results suggest the presence in diabetic serum of some labile factor that might inhibit the glucose transport system. The results indicate that the decreased insulin-stimulated glucose transport capacity, in the insulin-deficient diabetic muscle, is not a direct consequence of the lack of insulin or of high glucose concentrations.     

高糖高脂饮食联合注射STZ制备2型糖尿病大鼠缺血性心脏病模型

目的：制备2型糖尿病缺血性心脏病大鼠模型。方法：雄性Wistar大鼠20只,随机分为正常组和糖尿病模型组（n=10）。糖尿病模型组给予高糖高脂饮食饲喂4周后,一次性腹腔注射链脲佐菌素40mg/kg,制备糖尿病大鼠模型。每周常规监测血糖、血清胰岛素、体重的变化。糖尿病模型组与正常组大鼠,使用BL-41O生物机能试验系统,每周测定肢体2导联心电图。最后检测血清中的肌酸激酶和乳酸脱氢酶的含量。结果：高糖高脂饲料饲喂4周后胰岛素升高至4．05ng/ml,糖尿病模型组注射SIZ后空腹血糖迅速升高,达到17．9mmol/L。在第14周,糖尿病模型组出现S-T段抬高,并且与正常组比较,血清肌酸激酶（creatine kinase,CK）和乳酸脱氢酶（lactate dehydrogenase,LDH）均升高。结论：本实验成功建立的2型糖尿病缺血性心脏病大鼠模型,为研究糖尿病缺血性心脏病提供理想的动物模型。     

Effects of streptozotocin-induced hyperglycemia on agonist-stimulated phosphatidylinositol turnover in rat aorta

Altered vascular sensitivity and responsiveness has been previously described in various stages of experimental diabetes mellitus. Increases in membrane bound Ca2+ and intracellular calcium in diabetic aorta have been postulated to explain excitation-coupling dysfunction in diabetic vascular smooth muscle (VSM). Receptor-mediated phosphatidylinositol (PI) hydrolysis is known to activate VSM contraction; thus contractile changes in diabetic aorta could be functionally linked to abnormal PI turnover. To evaluate this possibility, parallel experiments were undertaken to study contractility and receptor-stimulated PI turnover with norepinephrine (NE), phenylephrine (PE), and serotonin (5-HT). At 7 and 28 days following injection of streptozotocin with production of the hyperglycemic state, aortas were harvested for contractile and PI turnover experiments. No differences in the contractile cumulative dose responses or receptor-mediated PI turnover were measured in the 7 day group. At 28 days, vascular supersensitivity and increased responsiveness were observed. PI hydrolysis in basal and agonist-stimulated aorta was, however, markedly decreased at 28 days. These findings suggest that mobilization and utilization of Ca2+ during contraction occur independently of receptor-stimulated PI hydrolysis in aorta from hyperglycemic rats. The duration of hyperglycemia also significantly effects contractility and PI turnover in rat aorta.     

Central visfatin potentiates glucose-stimulated insulin secretion and β-cell mass without increasing serum visfatin levels in diabetic rats

IntroductionOur previous study revealed that plasma visfatin levels were lower in pregnant women with gestational diabetes (GDM) than non-GDM independent of prepreganacy BMI. We examined whether central visfatin modulates energy and glucose homeostasis via altering insulin resistance, insulin secretion or islet morphometry in diabetic rats.MethodsPartial pancreatectomized, type 2 diabetic, rats were interacerbroventricularly infused with visfatin (100 ng/rat/day, Px-VIS), visfatin + visfatin antagonist, CHS-828 (100 μg/rat/day, Px-VIS-ANT), or saline (control, Px-Saline) via osmotic pump, respectively, for 4 weeks.ResultsCentral visfatin improved insulin signaling (pAkt → pFOXO-1) but not pSTAT3 in the hypothalamus. Central visfatin did not alter serum visfatin levels in diabetic rats whereas the levels were higher in non-diabetic rats than diabetic rats. Body weight at the 2nd week was lowered in the Px-VIS group due to decreased food intake in the first two weeks compared to the Px-Saline group and energy expenditure was not significantly different among the treatment groups of diabetic rats. Visfatin antagonist treatment nullified the central visfatin effect. Px-VIS increased whole body glucose disposal rates in euglycemic hyperinsulinemic clamp compared to Px-Saline and lowered hepatic glucose output, whereas Px-VIS-ANT blocked the visfatin effect on insulin resistance (P < 0.05). In hyperglycemic clamp study, the area under the curve of insulin in first and second phase were significantly higher in the Px-VIS group than the Px-Saline group without modifying insulin sensitivity at the hyperglycemic state, whereas the increase in serum insulin levels was blocked in the Px-VIS-ANT group. Central visfatin also increased β-cell mass by increasing β-cell proliferation.ConclusionsCentral visfatin improved glucose homeostasis by increasing insulin secretion and insulin sensitivity at euglycemia through the hypothalamus in diabetic rats. Therefore, visfatin is a positive modulator of glucose homeostasis by delivering the hypothalamic signals into the peripheries.