Attenuation of hypertriglyceridemia-induced pressor effect in rats with fructose-induced insulin resistance

This study was designed to compare the pressor response to hypertriglyceridemia under basal glucose and insulin condition as well as the decay pattern of this lipid-induced pressor effect in normal (NRs) and fructose-induced insulin resistant rats (FIRs). The rats were on a fructose-enriched or a regular chow diet for 8 wks and then were further divided into two subgroups (n = 8/group) with lipofundin (a 20% triglyceride emulsion) or saline infusion during the following clamp study. The acute clamp experiment contained a 30-min basal period, followed by a 120-min test period and a 90-min off period. After the basal period, somatostatin (1.3 microg/kg/min) combined with regular insulin (0.6 mU/kg/min) and variable glucose infusion were given to keep insulin and glucose levels basal throughout the experiment. The baseline triglyceride levels were about 6 folds higher in FIRs than those in NRs. During the test period, the lipofundin infusion (1.2 ml/kg/hr) increased plasma triglyceride levels by 368 +/- 39 and 489 +/- 38 mg/dL from baseline in NRs and FIRs, respectively. The elevated triglyceride level was dropped promptly while the lipofundin infusion was discontinued in the following off period. FIRs have higher mean arterial blood pressure (MAP) levels than those in NRs. During the test period, the hypertriglyceridemia-induced press responses were markedly delayed and attenuated in FIRs compared with those in NRs. Accordingly, the value of deltaMAP/deltaTG served as an index of the hypertriglyceridemia-induced increase in BP was significantly lower in FIRs than in NRs. This hypertriglyceridemia-induced pressor effect was sustained to the end of study even after removal of the lipid infusion for 60 min in NRs and FIRs. In rats without lipofundin infusion, MAP and plasma triglyceride levels failed to change throughout the study. The present results suggest that the prolonged pressor response induced by acute hypertriglyceridemia is attenuated in rats with fructose-induced insulin resistance.     

Mechanisms of hepatic very low density lipoprotein overproduction in insulin resistance. Evidence for enhanced lipoprotein assembly, reduced intracellular ApoB degradation, and increased microsomal triglyceride transfer protein in a fructose-fed hamster model

A novel animal model of insulin resistance, the fructose-fed Syrian golden hamster, was employed to investigate the mechanisms mediating the overproduction of very low density lipoprotein (VLDL) in the insulin resistant state. Fructose feeding for a 2-week period induced significant hypertriglyceridemia and hyperinsulinemia, and the development of whole body insulin resistance was documented using the euglycemic-hyperinsulinemic clamp technique. In vivo Triton WR-1339 studies showed evidence of VLDL-apoB overproduction in the fructose-fed hamster. Fructose feeding induced a significant increase in cellular synthesis and secretion of total triglyceride (TG) as well as VLDL-TG by primary hamster hepatocytes. Increased TG secretion was accompanied by a 4.6-fold increase in VLDL-apoB secretion. Enhanced stability of nascent apoB in fructose-fed hepatocytes was evident in intact cells as well as in a permeabilized cell system. Analysis of newly formed lipoprotein particles in hepatic microsomes revealed significant differences in the pattern and density of lipoproteins, with hepatocytes derived from fructose-fed hamsters having higher levels of luminal lipoproteins at a density of VLDL versus controls. Immunoblot analysis of the intracellular mass of microsomal triglyceride transfer protein, a key enzyme involved in VLDL assembly, showed a striking 2.1-fold elevation in hepatocytes derived from fructose-fed versus control hamsters. Direct incubation of hamster hepatocytes with various concentrations of fructose failed to show any direct stimulation of its intracellular stability or extracellular secretion, further supporting the notion that the apoB overproduction in the fructose-fed hamster may be related to the fructose-induced insulin resistance in this animal model. In summary, hepatic VLDL-apoB overproduction in fructose-fed hamsters appears to result from increased intracellular stability of nascent apoB and an enhanced expression of MTP, which act to facilitate the assembly and secretion of apoB-containing lipoprotein particles.     

A high-fructose diet impairs Akt and PKCzeta phosphorylation and GLUT4 translocation in rat skeletal muscle.

The molecular mechanism of insulin resistance induced by high-fructose feeding is not fully understood. The present study investigated the role of downstream signaling molecules of phosphatidylinositol 3-kinase (PI3K) in the insulin-stimulated skeletal muscle of high-fructose-fed rats. Rats were divided into chow-fed and fructose-fed groups. The results of the euglycemic clamp study (insulin infusion rates: 6 mU/kg BW/min) showed a significant decrease in the glucose infusion rate (GIR) and the metabolic clearance rate of glucose (MCR) in fructose-fed rats compared with chow-fed rats. In skeletal muscle removed immediately after the clamp procedure, high-fructose feeding did not alter protein levels of protein kinase B (PKB/Akt), protein kinase C zeta (PKCzeta), or glucose transporter 4 (GLUT4). However, insulin-stimulated phosphorylation of Akt and PKCzeta and GLUT4 translocation to the plasma membrane were reduced. Our findings suggest that insulin resistance in fructose-fed rats is associated with impaired Akt and PKCzeta activation and GLUT4 translocation in skeletal muscle.     

FRUCTOSE PERFUSION IN RAT MESENTERIC ARTERIES IMPAIRS ENDOTHELIUM-DEPENDENT VASODILATION

We demonstrated that the fructose-induced hypertensive rat, representative of the principal metabolic abnormalities found in a majority of hypertensive patients, i.e. hypertriglyceridemia, hyperinsulinemia and insulin resistance (Syndrome X), is associated with an impaired response to endothelium-dependent vasodilators and that fructose may directly contribute to this impairment. Twelve male Wistar rats were divided into two groups, one given 10% fructose (n=6); the other no fructose (n=6) for 40 days in the drinking water. Systolic blood pressure was measured via the tail cuff method. Perfusion pressure responses to acetylcholine, were measured in the isolated perfused mesenteric vascular bed. Constrictor or dilator responses were measured as increases or decreases, respectively, of the perfusion pressure at a constant flow (4 ml/min). Fructose-fed rats had significantly higher blood pressure, insulin and triglyceride levels than control animals. In phenylephrine constricted beds, the endothelium-dependent dilatation to acetylcholine (0.001 to 1 μmol) was attenuated in the fructose-fed group compared to control animals. Whether this abnormality results from the syndromes (hyperinsulinemia, hypertension and hypertriglyceridemia) associated with the fructose-fed animal model is unknown. We therefore hypothesized that fructose can impair the endothelium-dependent vasodilator response. This was evaluated by perfusing mesenteric arteries from normal rats with control mannitol (40 mM) or fructose (40 mM). Endothelium-dependent dilation to acetylcholine was impaired in fructose-perfused mesenteric arteries. Indomethacin restored the vasodilator response to acetylcholine, suggesting that a cyclooxygenase derivative mediates the impaired response. Thus, we conclude that fructose can contribute to the impaired endothelium-dependent response in the fructose-induced hypertensive rat model. Published by Elsevier Science Inc.     

Endothelin-1 modulates angiotensin II in the development of hypertension in fructose-fed rats

Two of the most potent vasoconstrictors, endothelin-1 (ET-1) and angiotensin II (Ang II), are upregulated in fructose hypertensive rats. It is unknown whether an interrelationship exists between these peptides that may contribute to the development of fructose-induced hypertension. The objective of this study was to investigate the existence of an interaction between the endothelin and renin angiotensin systems that may play a role in the development of fructose-induced hypertension. High fructose feeding and treatment with either bosentan, a dual endothelin receptor antagonist, or with L-158,809, an angiotensin type 1 receptor antagonist, were initiated simultaneously in male Wistar rats. Systolic blood pressure, fasted plasma parameters, insulin sensitivity, plasma Ang II, and vascular ET-1-immunoreactivity were determined following 6 weeks of high fructose feeding. Rats fed with a high fructose diet exhibited insulin resistance, hyperinsulinemia, hypertriglyceridemia, hypertension, and elevated plasma Ang II. Treatment with either bosentan or L-158,809 significantly attenuated the rise in blood pressure with no effect on insulin levels or insulin sensitivity in fructose-fed rats. Bosentan treatment significantly reduced plasma Ang II levels, while L-158,809 treatment significantly increased vascular ET-1-immunoreactivity in fructose-fed rats. Thus, treatment with the endothelin receptor antagonist prevented the development of fructose-induced hypertension and decreased plasma Ang II levels. These data suggest that ET-1 contributes to the development of fructose-induced hypertension through modulation of Ang II levels.     

Neonatal chemical sympathectomy attenuates fructose-induced hypertriglyceridemia and hypertension in rats

Experiments were performed to determine the pathogenic contribution of the peripheral sympathetic nervous system to fructose-induced hypertriglyceridemia, hyperinsulinemia and hypertension in rats. Neonatal chemical sympathectomy was performed in neonatal Sprague-Dawley rats (1-week old) by administration of guanethidine (50 microg/g, i.p.) 5 times per week for consecutive 3 weeks and nerve-intact rats were served as controls. Both groups of rats were fed a fructose-enriched diet for 9 weeks. The systolic blood pressure (SBP) and body weight were measured weekly and arterial blood samples were taken weekly for determinations of plasma insulin, glucose and triglyceride levels. The results showed that fructose feeding for one week significantly increased SBP in intact rats and sympathectomized rats (116+/-1 to 119+/-1 mmHg and 116+/-1 to 120+/-1 mmHg, respectively). SBP further increased thereafter in both groups. However, the increased SBP levels were significantly higher in intact group than in sympathectomized group after 5 weeks of fructose feeding. Fructose feeding for one week concurrently produced hypertriglyceridemia that preceded the appearance of hyperinsulinemia in both groups. The elevated plasma triglyceride levels were significantly lower in sympathectomized rats than in intact rats after 3 weeks of fructose feeding, whereas the elevated plasma insulin concentrations were not different between groups throughout fructose feeding period. Plasma glucose concentrations of both groups were comparable and remained unchanged throughout the study. These data indicate that neonatal chemical sympathectomy attenuated, but did not prevent, fructose-induced elevations in blood pressure and plasma triglyceride levels, suggesting a partial dependency of fructose-induced hypertriglyceridemia and hypertension on the integrity of the peripheral sympathetic nervous system (SNS) in rats.     

The fructose-fed rat: a review on the mechanisms of fructose-induced insulin resistance and hypertension

The metabolic syndrome is an important public health concern that predisposes individuals to the development of cardiovascular disease and/or Type 2 diabetes. The fructose-fed rat is an animal model of acquired systolic hypertension that displays numerous features of the metabolic syndrome. This animal model is used to study the relationship between insulin resistance/compensatory hyperinsulinemia and the development of hypertension. Several mechanisms have been proposed to mediate the link between insulin resistance and hypertension. In this review, we have addressed the role of sympathetic nervous system overactivation, increased production of vasoconstrictors, such as endothelin-1 and angiotensin II, and prostanoids in the development of hypertension in fructose-fed rats. The roles of nitric oxide, impaired endothelium-dependent relaxation and sex hormones in the pathogenesis of the fructose-fed induced hypertensive rats have also been highlighted. More recently, increased formation of reactive oxygen species and elevated levels of uric acid have been reported to contribute to fructose-induced hypertension.     

Infusion of beta-endorphin improves insulin resistance in fructose-fed rats.

In an attempt to probe the effect of beta-endorphin on insulin resistance, we used Wistar rats that were fed fructose-rich chow to induce insulin resistance. Insulin action on glucose disposal rate (GDR) was measured using the hyperinsulinemic euglycemic clamp technique, in which glucose (variable), insulin (40 mU/kg/min), and beta-endorphin (6 ng/kg/min) or vehicle were initiated simultaneously and continued for 120 min. A marked reduction in insulin-stimulated GDR was observed in fructose-fed rats compared to normal control rats. Infusion of beta-endorphin reversed the value of GDR, which was inhibited by naloxone and naloxonazine each at doses sufficient to block opioid mu-receptors. Opioid mu-receptors may therefore be activated by beta-endorphin to improve insulin resistance. Next, soleus muscle was isolated to investigate the effect of beta-endorphin on insulin signals. Insulin resistance in rats induced by excess fructose was associated with the impaired insulin receptor (IR), tyrosine autophosphorylation, and insulin receptor substrate (IRS)-1 protein content in addition to the significant decrease in IRS-1 tyrosine phosphorylation in soleus muscle. This impaired glucose transportation was also due to signaling defects that included an attenuated p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3-kinase) and Akt serine phosphorylation. However, IR protein levels were not markedly changed in rats with insulin resistance. beta-endorphin infusion reversed the fructose-induced decrement in the insulin-signaling cascade with increased GDR. Apart from IR protein levels, infusion of beta-endorphin reversed the decrease in protein expression for the IRS-1, p85 regulatory subunit of PI3-kinase, and Akt serine phosphorylation in soleus muscle in fructose-fed rats. The decrease in insulin-stimulated protein expression of glucose transporter subtype 4 (GLUT 4) in fructose-fed rats returned to near-normal levels after beta-endorphin infusion. Infusion of beta-endorphin may improve insulin resistance by modulating the insulin-signaling pathway to reverse insulin responsiveness.     

Renal expression of arachidonic acid metabolizing enzymes and RhoA/Rho kinases in fructose insulin resistant hypertensive rats

Fructose feeding has been shown to induce insulin resistance and hypertension. Renal protein expression for the cytochrome P (CYP) 450 arachidonic acid metabolizing enzymes has been shown to be altered in other models of diet-induced hypertension. Of special interest is CYP4A, which produces the potent vasoconstrictor, 20-hydroxyeicosatetraenoic acid and CYP2C, which catalyzes the formation of the potent dilators epoxyeicosatrienoic acids as well as soluble epoxide hydrolase (sEH) which metabolizes the latter to dihydroxyeicosatrienoic acids. The RhoA/Rho kinase (ROCK) signaling pathway is downstream of arachidonic acid and is reported to mediate metabolic-cardio-renal dysfunctions in some experimental models of insulin resistance and diabetes. The aim of the present study was to determine the expression of CYP4A, CYP2C23, CYP2C11, sEH, RhoA, ROCK-1, ROCK-2, and phospho-Lin-11/Isl-1/Mec-3 kinase (LIMK) in kidneys of fructose-fed (F) rats. Male Wistar rats were fed a high fructose diet for 8 weeks. Body weight, systolic blood pressure, insulin sensitivity, and renal expression of the aforementioned proteins were assessed. No change was observed in the body weight of F rats; however, euglycemia and hyperinsulinemia implicating impaired glucose tolerance and significant elevation in systolic blood pressure were observed. Renal expression of CYP4A and CYP2C23 was significantly increased while that of CYP2C11 and sEH was not changed in F rats. Equal expression for RhoA in both control and F rats and an enhanced level of ROCK-1 and ROCK-2 constitutively activate 130 kDa cleavage fragments as well as phospho-LIMK. These data suggest that the kidneys could be actively participating in the pathogenesis of insulin resistance-induced hypertension through the arachidonic acid CYP 450-RhoA/Rho kinase pathway(s).     

Hyperinsulinemic rats are normotensive but sensitized to angiotensin II

The effect of insulin on blood pressure (BP) is debated, and an involvement of an activated renin-angiotensin aldosterone system (RAAS) has been suggested. We studied the effect of chronic insulin infusion on telemetry BP and assessed sympathetic activity and dependence of the RAAS. Female Sprague-Dawley rats received insulin (2 units/day, INS group, n = 12) or insulin combined with losartan (30 mg.kg(-1).day(-1), INS+LOS group, n = 10), the angiotensin II receptor antagonist, for 6 wk. Losartan-treated (LOS group, n = 10) and untreated rats served as controls (n = 11). We used telemetry to measure BP and heart rate (HR), and acute ganglion blockade and air-jet stress to investigate possible control of BP by the sympathetic nervous system. In addition, we used myograph technique to study vascular function ex vivo. The INS and INS+LOS groups developed euglycemic hyperinsulinemia. Insulin did not affect BP but increased HR (27 beats/min on average). Ganglion blockade reduced mean arterial pressure (MAP) similarly in all groups. Air-jet stress did not increase sympathetic reactivity but rather revealed possible blunting of the stress response in hyperinsulinemia. Chronic losartan markedly reduced 24-h-MAP in the INS+LOS group (-38 +/- 1 mmHg P < 0.001) compared with the LOS group (-18 +/- 1 mmHg, P 相似文献   

Selective alpha1-adrenoceptor blockade prevents fructose-induced hypertension

The purpose of this study was to investigate the effect of chronic treatment with prazosin, a selective α₁-adrenoceptor antagonist, on the development of hypertension in fructose-fed rats (FFR). High-fructose feeding and treatment with prazosin (1 mg/kg/day via drinking water) were initiated simultaneously in male Wistar rats. Systolic blood pressure, fasted plasma parameters, insulin sensitivity, plasma norepinephrine (NE), uric acid, and angiotensin II (Ang II) were determined following 9 weeks of treatment. FFR exhibited insulin resistance, hyperinsulinemia, hypertriglyceridemia, and hypertension, as well as elevations in plasma NE and Ang II levels. Treatment with prazosin prevented the rise in blood pressure without affecting insulin levels, insulin sensitivity, uric acid, or Ang II levels, while normalizing plasma NE levels in FFR. These data suggest that over-activation of the sympathetic nervous system, specifically α₁-adrenoceptors, contributes to the development of fructose-induced hypertension, however, this over-activation does not appear to an initial, precipitating event in FFR.     

Bezafibrate, an anti-hypertriglyceridemic drug, attenuates vascular hyperresponsiveness and elevated blood pressure in fructose-induced hypertensive rats

A high fructose diet induces hypertension, hyperinsulinemia - insulin resistance, and hypertriglyceridemia (syndrome X). In this study, we investigated the role of an abnormal lipid profile in mediating fructose-induced hypertension. We hypothesized that bezafibrate, a lipid-lowering drug, would reduce elevated blood pressure and inhibit increased vascular reactivity in fructose-fed rats. Male rats were placed on four different diets: group 1 was fed standard chow (n = 6); group 2 was fed 60% fructose (n = 5); group 3 was fed fructose plus bezafibrate (30 mg x kg(-1) x day(-1); drinking water; n = 5); and group 4 was fed standard chow plus bezafibrate (n = 6). In addition, the direct effects of very low density lipoprotein (VLDL) on vascular reactivity were examined. Bezafibrate treatment lowered blood pressure, free fatty acids, and triglycerides in the fructose-fed group, suggesting that lipid abnormalities play a role in the elevation of blood pressure in the fructose-induced hypertensive rat. Aortae from fructose-fed rats were hyperresponsive to the calcium channel agonist Bay K 8644, which was normalized with bezafibrate treatment. Incubation of aortae in a VLDL medium resulted in increased responsiveness to Bay K 8644, lending further support to lipid abnormalities altering vascular reactivity. An altered lipid profile evidenced by elevated triglycerides and free fatty acids is causally related to the development of high blood pressure and increased vascular reactivity in the fructose-induced hypertensive rat.     

Abnormalities in carbohydrate and lipid metabolisms in high-fructose dietfed insulin-resistant rats: amelioration by Catharanthus roseus treatments

High intake of dietary fructose has been shown to exert a number of adverse metabolic effects in humans and experimental animals. The present study was proposed to elucidate the effect of Catharanthus roseus (C. roseus) leaf powder treatment on alterations in carbohydrate and lipid metabolisms in rats fed with high-fructose diet. Male Wistar rats of body weight around 180 g were divided into four groups, two of these groups (groups C and C+CR) were fed with standard pellet diet and the other two groups (groups F and F+CR) were fed with high-fructose (66 %) diet. C. roseus leaf powder suspension in water (100 mg/kg body weight/day) was administered orally to group C+CR and group F+CR. At the end of a 60-day experimental period, biochemical parameters related to carbohydrate and lipid metabolisms were assayed. C. roseus treatment completely prevented the fructose-induced increased body weight, hyperglycemia, and hypertriglyceridemia. Hyperinsulinemia and insulin resistance observed in group F was significantly decreased with C. roseus treatment in group F+CR. The alterations observed in the activities of enzymes of carbohydrate and lipid metabolisms and contents of hepatic tissue lipids in group F rats were significantly restored to near normal values by C. roseus treatment in group F+CR. In conclusion, our study demonstrates that C. roseus treatment is effective in preventing fructose-induced insulin resistance and hypertriglyceridemia while attenuating the fructose-induced alterations in carbohydrate and lipid metabolisms. This study suggests that the plant can be used as an adjuvant for the prevention and/or management of insulin resistance and disorders related to it.     

Chronic ANG II infusion increases plasma triglyceride level by stimulating hepatic triglyceride production in rats

We recently observed that ANG II receptor blocker therapy improved the overproduction of triglyceride (TG) in fructose-fed rats and Zucker fatty rats with insulin resistance, which in turn suggests that ANG II may stimulate TG production. Accordingly, we investigated the effects of ANG II on TG production and the association with insulin resistance in normal rats. Male Wistar rats were continuously infused with ANG II (100 ng.min(-1).kg body wt(-1)) via an osmotic minipump for 14 days. ANG II infusion markedly elevated both the systolic and diastolic blood pressure. The plasma TG level increased twofold, but cholesterol was unchanged. ANG II infusion stimulated the TG secretion rate (TGSR) by twofold and increased the hepatic TG content by 31%. Lipogenesis determined by [2-(3)H]glycerol incorporation into hepatic TG was also significantly increased in ANG II-infused rats. The stimulatory effect of ANG II on TGSR was dose dependent and was not observed until 2 wk after the start of infusion. ANG II infusion significantly reduced insulin sensitivity index (SI) without affecting glucose effectiveness determined by Bergman's minimal model. The plasma TG level was positively correlated with TGSR (r = 0.88, P < 0.001) and inversely with SI (r = -0.80, P < 0.005). These results suggest that chronic ANG II infusion stimulates hepatic TG production, which is partly associated with simultaneous development of insulin resistance. Our results may suggest a new mechanism for the intimate association between hypertension and dyslipidemia.     

Effects of imidapril, an angiotensin-converting enzyme inhibitor, on insulin sensitivity and responsiveness in streptozotocin-induced diabetic rats.

We have studied the effect of imidapril, an angiotensin-converting enzyme inhibitor, on streptozotocin-induced diabetic rats. A sequential euglycemic hyperinsulinemic clamp procedure was used (insulin infusion rates: 3 and 30 mU/kg BW/min) in 30 diabetic rats. The rats were divided in 6 groups: a control group, a control group with N-monomethyl-L-arginine (L-NMMA, 1 mg/kg/min, a nitric oxide synthase inhibitor) infusion, a streptozotocin-induced diabetic group, a diabetic group with L-NMMA infusion, a diabetic group involving imidapril infusion (5 microg/kg/min), and a diabetic group involving simultaneous imidapril and L-NMMA infusion. Glucose concentrations were maintained around 140 mg/dl during the clamp studies. Plasma insulin levels during the 3 and 30 mU/kg BW/min insulin infusions were 30 and 400 microU/ml, respectively. Glucose infusion rates (GIR) in STZ-induced diabetic rats showed a significant decrease compared to controls. At both insulin infusion rates, imidapril-infused diabetic rats showed an increased GIR, compared with the saline infused ones. There was no significant difference in GIR between L-NMMA and saline infusion in diabetic rats. Simultaneous infusion of imidapril and L-NMMA did not significantly decrease GIR with low-dose insulin infusion, but the increase in GIR induced by imidapril with high-dose insulin infusion was impaired by 100 % by L-NMMA infusion in diabetic rats. These results suggest that imidapril may improve insulin action, in part, via nitric oxide.     

The effects of phentolamine on fructose-fed rats

Metabolic syndrome (MS) is a combination of medical disorders that increase the risk of developing cardiovascular disease and diabetes. MS is associated with obesity, increased blood pressure, hyperlipidemia, and hyperglycemia. This study was designed to investigate the pharmacological profile of phentolamine, a nonselective α adrenergic receptor antagonist, in the prevention of increased blood pressure in fructose-fed rats. Phentolamine prevented the fructose-induced increase in systolic blood pressure without affecting insulin sensitivity and major metabolic parameters. The levels of plasma noradrenaline and angiotensin II, 2 proposed contributors to the development of fructose-induced elevated blood pressure, were examined. Neither noradrenaline nor angiotensin II levels were affected by phentolamine treatment. Since overproduction of nitric oxide has been shown to lead to an elevation in peroxynitrite, the role of oxidative stress, a proposed mechanism of fructose-induced elevated blood pressure and insulin resistance, was examined by measuring plasma levels of total nitrate/nitrite. Plasma nitrate/nitrite was significantly elevated in all fructose-fed animals, regardless of treatment with phentolamine. Another proposed contributor toward fructose-induced MS is an elevation in uric acid levels. In this experiment, plasma levels of uric acid were found to be increased by dietary fructose and were unaffected by phentolamine treatment.     

罗格列酮联合胰岛素对糖尿病大鼠氧化应激及血脂水平的影响

摘要 目的：探讨罗格列酮（RSG）联合胰岛素（INS）对糖尿病大鼠的氧化应激和血脂水平的影响。方法：30只健康雄性Wistar大鼠,随机分为3组：健康对照组、DM模型组和RSG+INS组,每组10只。采用链脲佐菌素（STZ）造模法进行糖尿病大鼠模型诱导。此后以RSG （3 mg/kg/day）灌胃,INS （2.25 U/kg/day）皮下注射,均连续给药8周,对RSG+INS组大鼠进行干预治疗。每2周定期记录各组大鼠的体重和血糖值1次;药物干预治疗8周后,取各组大鼠血清,对血清总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白（LDL）、高密度脂蛋白（HDL）、糖化血红蛋白（HbA1c）和丙二醛（MDA）的含量以及超氧化物歧化酶（SOD）和谷胱甘肽（GSH）的活性进行检测;应用苏木素碱性复红苦昧酸（HBFP）染色分析心肌形态变化。结果：RSG联合INS组治疗糖尿病大鼠,导致血糖发生时间依赖性下降（均P<0.05）;药物干预处理8周后,RSG+INS组大鼠的血清TC、TG、LDL和HbA1c水平均显著低于DM模型组,而HDL显著高于DM模型组（均P<0.05）;与DM模型组相比,RSG+INS组大鼠的血清MDA含量显著下降,而SOD和GSH活性则显著升高（均P<0.05）;与DM模型组相比,RSG+INS组心肌缺血/氧程度减轻。结论：RSG联合INS可有效对抗糖尿病大鼠体内的氧化应激损伤,改善糖尿病大鼠的脂代谢异常情况,并对心肌组织有一定的保护作用。     

Taurine attenuates hypertension and improves insulin sensitivity in the fructose-fed rat, an animal model of insulin resistance

Fructose feeding induces moderate increases in blood pressure levels in normal rats, which is associated with hyperinsulinemia, insulin resistance, and impaired glucose tolerance. Increased vascular resistance, sodium retention, and sympathetic overactivity have been proposed to contribute to the blood pressure elevation in this model. Taurine, a sulphur-containing amino acid, has been reported to have antihypertensive and sympatholytic actions. In the present study, the effects of taurine on blood pressure, plasma levels of glucose and insulin, glucose tolerance, and renal function were studied in fructose-fed rats. Fructose-fed rats had higher blood pressure and elevated plasma levels of insulin and glucose. The plasma glucose levels were higher in fructose-fed rats than in controls at 15, 30, and 60 min after the oral glucose load. Treatment with 2% taurine in drinking water prevented the blood pressure elevation and attenuated the hyperinsulinemia in fructose-fed rats. The exaggerated glucose levels in response to the oral glucose load was also prevented by taurine administration. Thus, taurine supplementation could be beneficial in circumventing metabolic alterations in insulin resistance.     

Reduction of Fructose-induced Hypertriglyceridemia and Fatty Liver in Rats by 4-(4′-Chlorobenzyloxy)benzyl Nicotinate (KCD-232)

The effect of KCD-232, a new compound with a structure of 4-(4′-chlorobenzyloxy)benzyl nicotinate, on fructose-induced hypertriglyceridemia and fatty liver was studied in rats refed experimental diets for 3 days after having been starved for 2 days.

In younger or older rats refed 7% corn oil-containing diets, both the serum and liver triglyceride (TG) levels were higher in the fructose (F) group than in the glucose (G) group, and those of the F group were higher in the older rats than the younger rats. KCD-232 effectively inhibited fructose-induced hypertriglyceridemia and fatty liver in both the younger and older rats. In older rats refed 7% corn oil diets, an increase in hepatic fatty acid (FA) synthesis and decreases in the activities of hepatic TG lipase (HTGL) and adipose tissue lipoprotein lipase (LPL) were found in the F group, while the serum free FA level and hepatic FA oxidative activity of the F group were equal to those of the G group. KCD-232 strongly inhibited the fructose-enhanced FA synthesis, slightly repressed the fructose-suppressed HTGL activity and had no effect on LPL activity and FA oxidation.

These results suggest that fructose-induced hypertriglyceridemia and fatty liver are due to an enhanced hepatic FA synthesis and decreased hydrolytic activities required for TG clearance from the circulation system and that KCD-232 prevents them by inhibiting enhanced FA synthesis.     

Insulin infusion induces endothelin-1-dependent hypertension in rats

We previously showed that chronic insulin infusion induces insulin resistance, hyperendothelinemia, and hypertension in rats (C. C. Juan, V. S. Fang, C. F. Kwok, J. C. Perng, Y. C. Chou, and L. T. Ho. Metabolism 48: 465-471, 1999). Endothelin-1 (ET-1), a potent vasoconstrictor, is suggested to play an important role in maintaining vascular tone and regulating blood pressure, and insulin increases ET-1 production in vivo and in vitro. In the present study, BQ-610, a selective endothelin A receptor antagonist, was used to examine the role of ET-1 in insulin-induced hypertension in rats. BQ-610 (0.7 mg/ml; 0.5 ml/kg body wt) or normal saline was given intraperitoneally two times daily for 25 days to groups of rats infused with either saline or insulin (2 U/day via sc-implanted osmotic pumps), and changes in plasma levels of insulin, glucose, and ET-1 and the systolic blood pressure were measured over the experimental period, whereas changes in insulin sensitivity were examined at the end of the experimental period. Plasma insulin and ET-1 levels were measured by RIA, plasma glucose levels using a glucose analyzer, systolic blood pressure by the tail-cuff method, and insulin sensitivity by an oral glucose tolerance test. Our studies showed that insulin infusion caused sustained hyperinsulinemia in both saline- and BQ-610-injected rats over the infusion period. After pump implantation (2 wk), the systolic blood pressure was significantly higher in insulin-infused rats than in saline-infused rats in the saline-injected group (133 +/- 3.1 vs. 113 +/- 1.1 mmHg, P < 0.05) but not in the BQ-610-injected group (117 +/- 1.2 vs. 117 +/- 1.8 mmHg). Plasma ET-1 levels in both sets of insulin-infused rats were higher than in saline-infused controls (2.5 +/- 0.6 and 2.5 +/- 0.8 vs. 1.8 +/- 0.4 and 1.7 +/- 0.3 pmol/l, P < 0.05). Oral glucose tolerance tests showed that BQ-610 treatment did not prevent the insulin resistance caused by chronic insulin infusion. No significant changes were found in insulin sensitivity and blood pressure in saline-infused rats treated with BQ-610. In a separate experiment, insulin infusion induced the increase in arterial ET-1 content, hypertension, and subsequent plasma ET-1 elevation in rats. These results suggest that, in the insulin infusion rat model, ET-1 plays a mediating role in the development of hypertension, but not of insulin resistance.