The central serotonergic system mediates the analgesic effect of electroacupuncture on<Emphasis Type="Italic">Zusanli</Emphasis> (ST36) acupoints

Evidence in the past decade indicates that the mechanisms of anti-nociception of electroacupuncture (EAc) involve actions of neuropeptides (i.e., enkephalin and endorphin) and monoamines (i.e., serotonin and norepinephrine) in the central nervous system. Our present results using a subcutaneous injection of formalin to test pain sensation in mice provide further understanding of the involvement of serotonin in the actions of EAc-induced analgesia. Our observations show that (1) EAc at three different frequencies (2, 10 and 100 Hz) elicited an anti-nociceptive effect as determined by behavioral observations of reduced hindpaw licking; (2) exogenously intracerebroventricular administration of 5-hydroxy-tryptamine (5-HT) exhibited an analgesic effect, which partially mimicked the analgesic actions of EAc; (3) the anti-nociception of EAc at different frequencies was attenuated after reduced biosynthesis of serotonin by the administration of the tryptophan hydroxylase inhibitor,p-chlorophenylalanine, and (4) the 5-HT_1A and 5-HT₃ receptor antagonists, pindobind-5-HT_1A and LY-278584, respectively, blocked three different frequencies of EAc-induced analgesic effects, but the anti-nociceptive effect of 100 Hz EAc was potentiated by the 5-HT₂ receptor antagonist, ketanserin. These observations suggest that 5-HT_1A and 5-HT₃ receptors partially mediate the analgesic effects of EAc, but that the 5-HT₂ receptor is conversely involved in the nociceptive response.     

Effects of electroacupuncture Zusanli (ST36) on food intake and expression of POMC and TRPV1 through afferents-medulla pathway in obese prone rats

Objective: The purpose of this study was to determine the effects of electroacupuncture (EA) ST36 on food intake and body weight in obese prone (OP) rats compared to obese resistant (OR) strain on a high fat diet. The influences of EA on mRNA levels of pro-opiomelanocortin (POMC), transient receptor potential vanilloid type-1 (TRPV1), and neuronal nitric oxide synthase (nNOS) were also examined in the medulla regions and ST36 skin tissue. Methods: Advanced EA ST36 was conducted in two sessions of 20 min separated by an 80 min interval for 7 days. Food intake and body weight were recorded in conscious rats every day. Real time PCR was conducted in the micropunches of the medulla regions and skin tissues at the end of the treatment. Results: Food intake and body weight were significantly reduced by advanced EA ST36 in OP rats, but slightly decreased in OR strain and sham-EA rats. Advanced EA ST36 produced a marked increase in POMC mRNA level in the nucleus tractus solitarius (NTS) and hypoglossal nucleus (HN) regions. TRPV1 and nNOS mRNAs were simultaneously increased in the NTS/gracile nucleus regions and in the ST36 skin regions by the EA treatment in OP rats. Conclusions: We conclude that advanced EA ST36 produces an up-regulation of anorexigenic factor POMC production in the NTS/HN, which inhibits food intake and reduces body weight. EA-induced expression of TRPV1-nNOS in the ST36 and the NTS/gracile nucleus is involved in the signal transduction of EA stimuli via somatosensory afferents-medulla pathways.     

艾灸足三里对人体上腹部红外热像的影响：随机对照交叉实验

通过交叉对照实验观察艾灸足三里对人体上腹部红外热像的影响以研究经穴的特异性。受试者为健康男性学生,共31人,平均年龄（23．7±1．7）岁。对受试者左右两侧的足三里或对照非穴点进行直接温和艾灸15min,在艾灸前、艾灸后即刻以及艾灸后120min内每隔40min进行红外热像观察。研究发现在艾灸后即刻,足三里组与对照非穴点组的上腹中部与右侧的温度差改变量存在组间统计学差异,该现象与艾灸足三里对人体的保健作用之间的关系值得进一步研究。     

Effect of training intensity on insulin sensitivity as evaluated by insulin tolerance test

The purpose of this study was to evaluate the role of exercise intensity in the effect of physical training on insulin sensitivity. The insulin tolerance test (ITT) was applied to quantify insulin sensitivity. Eighteen healthy, young, untrained men and women participated in a 4-week, five times per week, 1-h per session bicycle-ergometer training program. Training consisted of 3-min bouts of cycling interspersed with 2 min at a lower exercise intensity. Intensities were 80 and 40% of pretraining maximal power output (W(max)) in the high-intensity (HI) and 40 and 20% W(max) in the low-intensity (LI) group. The insulin sensitivity index (IS(index)) was similar in the HI and LI group before the training intervention [mean (SD) -0.1898 (0.058) and -0.1892 (0.045), respectively]. After training, the IS(index) was -0.2358 (0.051) (P = 0.005 vs pretraining) in the HI group and -0.2050 (0.035) (P = 0. 099 against pretraining) in the LI group. We conclude that improvements in insulin sensitivity are more pronounced with high-intensity training, when exercise frequency and duration are kept similar. We further conclude that the ITT is suitable for use in intervention studies.     

Increased insulin sensitivity in soleus muscle from cold-exposed rats: reversal by an adenosine-receptor agonist

The effect of 0.5, 2, 7 and 14 days cold exposure at 4 degrees C on insulin sensitivity was investigated in the stripped soleus muscle preparation incubated in vitro. Cold-exposure for 2 or 7 days increased the sensitivity of glycolysis, but did not affect the sensitivity of glycogen synthesis to insulin. Cold-exposure for 0.5 or 14 days had no effect on the sensitivity of either process to insulin. The increased sensitivity to insulin after exposure of animals to the cold for 2 days was completely reversed by addition of the adenosine receptor agonist, 2-chloroadenosine, to the incubation medium. This suggests that cold exposure may increase insulin sensitivity in the muscle, either by a decrease in the concentration of adenosine in the muscle, or by a decrease in the number or affinity of the adenosine receptors.     

Maximum activities of enzymes involved in adenosine metabolism in adipose tissue of rats and mice under conditions of variations in insulin sensitivity

Changes in the maximum activities of 5′-nucleotidase, adenosine kinase and adenosine deaminase in adipose tissue from obese mice, starved mice and rats, and adrenalectomised rats lead to the suggestion that changes in the adenosine concentration may be involved in changes in insulin sensitivity in these conditions.     

CO2激光照射足三里穴对大鼠运动疲劳的缓解作用

目的:观察cO:激光照射及传统艾灸足三里穴对运动疲劳大鼠运动耐力、骨骼肌微循环及抗氧化酶活性的影响,初步探讨CO2激光照射足三里缓解运动疲劳的作用及其机制.方法:SD成年雄性大鼠,适应性游泳后随机分为正常对照组、模型组、艾灸组及激光组.采用无负重游泳方式建立大鼠运动疲劳模型,艾灸组及激光组在游泳运动的同时,分别采用CO2激光照射及艾灸足三里穴.末次力竭运动结束后,检测大鼠骨骼肌微循环,分离大鼠骨骼肌线粒体,检测线粒体内超氧化物歧化酶(SOD)、谷胱甘肽过氧化酶(GSH-Px)的活性.结果:艾灸组和激光组大鼠的力竭运动时间显著高于模型组照组(P<0.05),仍显著低于正常对照组(P<0.05);艾灸组双侧胫骨前肌的血流灌注量、线粒体内SOD、GSH-Px含量均显著高于模型组(P<0.05).激光组腹直肌线粒体血流灌注量、线粒体内SOD、GSH-Px含量显著高于模型组(P<0.05);艾灸组与激光组的力竭运动时间、骨骼肌血流灌注量、线粒体内的SOD、GSH-Px含量相比,无显著性差异(P>0.05).结论:CO2激光照射足三里穴能够模拟传统的燃艾灸疗中的生物物理过程,从而实现仿生灸疗,可有效提高运动疲劳大鼠骨骼肌线粒体抗氧化酶活性、增加骨骼肌血流灌注,从而缓解运动疲劳.     

坐式八段锦联合足三里穴位按压对社区高龄衰弱患者效果分析

摘要 目的：探讨坐式八段锦联合足三里穴位按压对社区高龄衰弱患者效果分析。方法：前瞻性纳入2021年3月至2022年3月南京某社区50例高龄衰弱患者为研究对象,分为两组,对照组进行常规治疗及健康指导,观察组以对照组为基础,进行为期12周的坐式八段锦锻炼及足三里穴位按压,应用简化营养食欲问卷（SNAQ）、匹兹堡睡眠质量指数表（PSQI）、Tilburg衰弱量表、汉密尔顿焦虑量表（HAMA）和抑郁量表（HAMD）和SF-36生活质量评定量表评估干预前后两组患者的食欲、睡眠、衰弱、焦虑情绪、抑郁情绪和生活质量状况。结果：干预前,两组患者HAMA、HAMD评分、躯体衰弱维度、心理衰弱维度、社会衰弱维度、总分评分、食欲、睡眠、握力和各维度生活质量评分比较无差异（P＞0.05）;干预后,两组HAMA和HAMD评分均降低,且观察组较对照组低（P<0.05）;干预后,两组躯体衰弱维度、心理衰弱维度、社会衰弱维度、总分评分均降低,且观察组较对照组低（P<0.05）;干预后,两组食欲、睡眠均降低,而握力升高,且观察组食欲、睡眠均低于对照组,而握力高于对照组（P<0.05）;干预后,两组各维度生活质量评分均升高,且观察组较对照组高（P<0.05）。结论：社区高龄衰弱患者采用坐式八段锦联合足三里穴位按压干预,可有效改善食欲促进睡眠质量升高和促进衰弱病情转归,进而有利于调节患者负性情绪和促进预后生活质量改善。     

Improved insulin sensitivity and metabolic flexibility in ghrelin receptor knockout mice

Stimulation of the ghrelin receptor (GhrR) by ghrelin results in a variety of metabolic changes including increased food intake, fat storage and insulin resistance. Loss of ghrelin signaling is protective against diet-induced obesity, suggesting that ghrelin plays a significant homeostatic role in conditions of metabolic stress. We examined glycemic control in GhrR −/− mice fed a high-fat diet, and used indirect calorimetry to assess fuel substrate usage and energy expenditure. GhrR −/− mice fed a high-fat diet had several measures of greater insulin sensitivity, including: lower fasted blood glucose and plasma insulin, lower %Hb_A1c, lower insulin levels during glucose tolerance tests, and improved performance in hyperinsulinemic-euglycemic and hyperglycemic clamp studies. GhrR −/− mice fed a high-fat diet did not develop hepatic steatosis and had lower total cholesterol, relative to controls. Furthermore, GhrR −/− mice demonstrated a lower intestinal triglyceride secretion rate of dietary lipid. GhrR −/− mice have higher respiratory quotients (RQ), indicating a preference for carbohydrate as fuel. The range of RQ values was wider in GhrR −/− mice, indicating greater metabolic flexibility and insulin sensitivity in these animals. We therefore propose that loss of ghrelin signaling promotes insulin sensitivity and metabolic flexibility, and protects against several fatty diet-induced features of metabolic syndrome due to convergent changes in the intake, absorption and utilization of energy.     

Effects of analogues of adenosine and methyl xanthines on insulin sensitivity in soleus muscle of the rat

The concentration of insulin that produces half-maximal stimulation of glycolysis by stripped soleus muscle preparations is markedly increased by the adenosine analogues, 2-chloroadenosine and N6-phenylisopropyladenosine, but is markedly decreased by the methyl xanthine analogue, 8-phenyltheophylline. 2-Chloroadenosine increases the concentration of insulin required to stimulate glycolysis half maximally, from about 100 to 2000 mu units/ml. 8-Phenyltheophylline decreases this concentration of insulin from about 100 to 10 mu units/ml, an effect which is similar to that produced either by addition of adenosine deaminase to the medium or to exercise-training of the donor animals for 4 weeks.     

Exercise-induced enhancement of insulin sensitivity is associated with accumulation of M2-polarized macrophages in mouse skeletal muscle

Exercise enhances insulin sensitivity in skeletal muscle, but the underlying mechanism remains obscure. Recent data suggest that alternatively activated M2 macrophages enhance insulin sensitivity in insulin target organs such as adipose tissue and liver. Therefore, the aim of this study was to determine the role of anti-inflammatory M2 macrophages in exercise-induced enhancement of insulin sensitivity in skeletal muscle. C57BL6J mice underwent a single bout of treadmill running (20 m/min, 90 min). Twenty-four hours later, ex vivo insulin-stimulated 2-deoxy glucose uptake was found to be increased in plantaris muscle. This change was associated with increased number of CD163-expressing macrophages (i.e. M2-polarized macrophages) in skeletal muscle. Systemic depletion of macrophages by pretreatment of mice with clodronate-containing liposome abrogated both CD163-positive macrophage accumulation in skeletal muscle as well as the enhancement of insulin sensitivity after exercise, without affecting insulin-induced phosphorylation of Akt and AS160 or exercise-induced GLUT4 expression. These results suggest that accumulation of M2-polarized macrophages is involved in exercise-induced enhancement of insulin sensitivity in mouse skeletal muscle, independently of the phosphorylation of Akt and AS160 and expression of GLUT4.     

Chromium picolinate supplementation improves insulin sensitivity in Goto-Kakizaki diabetic rats

Chromium picolinate (CrP) supplementation has been studied as a potential therapy of insulin resistance and lipid abnormalities. There have been some reports involving chromium supplementation in patients with diabetes, but the results are varied. The present study was conducted to assess the effects of CrP on insulin sensitivity and body weight in Goto-Kakizaki (GK) diabetic rats. We supplemented normal Sprague-Dawley (SD) rats and GK diabetic rats with supplemental CrP, 100 mg/kg/day once a day for 4 weeks. In the normal SD rats, the mean body weight of the control group increased by 50.5%, whereas that of the CrP-treated group increased by 65.9% (P < 0.05 vs control). Similarly, in the diabetic GK rats, CrP supplementation showed increased weight gain compared to the control group (133.4% vs 119.6% of the baseline weight, P < 0.01). Glucose tolerance tests (GTT) [ip injection of glucose; 2 g/kg] and insulin sensitivity tests [SQ injection of insulin (5 U/kg) plus ip injection of glucose (30 min after insulin injection)] were conducted. During insulin sensitivity tests at the end of treatment, the glucose levels were significantly lower in CrP-treated rats compared with the control rats (AUC_0→120; 113.1 ± 32.0 vs 170.5 ± 49.0 mg-min/mL, P < 0.05). During GTTs, the glucose levels and insulin concentrations in the CrP-treated rats were not different from those in the control rats.

The results of these studies suggest that CrP supplementation in GK diabetic rats leads to increase of weight gain and improvement of insulin sensitivity. This raises the possibility that CrP supplementation can be considered to improve carbohydrate metabolism in patients with type 2 diabetes mellitus.     

Activation of mu-opioid receptors improves insulin sensitivity in obese Zucker rats

In the current study we investigated the effect of mu-opioid receptor activation on insulin sensitivity. In obese Zucker rats, an intravenous injection of loperamide (18 microg/kg, three times daily for 3 days) decreased plasma glucose levels and the glucose-insulin index. Both effects of loperamide were subsequently inhibited by the administration of 10 microg/kg of naloxone or 10 microg/kg of naloxonazine, doses sufficient to block mu-opioid receptors. Other metabolic defects characteristic of obese Zucker rats, such as defects in insulin signaling, the decreased expression of insulin receptor substrate (IRS)-1, the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3 kinase), and the glucose transporter subtype 4 (GLUT 4), and the reduction of phosphorylation in IRS-1 or Akt serine, were also studied. These defects were all reversed by loperamide treatment in a dose which overcame mu-opioid receptor blockade. Moreover, loss of tolbutamide-induced plasma glucose lowering action (10 mg/kg) in wild-type mice given a fructose-rich diet was markedly delayed by repeated treatment with loperamide; however, this delay induced by loperamide did not occur in mu-opioid receptor knockout mice. These results indicate an important role of peripheral mu-opioid receptors in the loperamide-induced improvement of insulin sensitivity. Our results suggest that activation of peripheral mu-opioid receptors can ameliorate insulin resistance in animals, and provide a new target for therapy of insulin resistance.     

Metabolomics as a tool to evaluate exercise-induced improvements in insulin sensitivity

Exercise affects substrate utilisation and insulin sensitivity, which in turn improve blood glucose and lipid levels in subjects with type 2 diabetes (T2D). However, making long-lasting lifestyle-changes might be more realistic if the results were easier to record. Screening for biomarkers reflecting metabolic fitness could thus serve as a tool for maintained motivation. The aim of this study was to test the possibility that metabolomics can be used to identify individuals with improved insulin sensitivity as a result of increased physical activity. Healthy and diabetic subjects were investigated before and after 3 months of exercise to determine various metabolic parameters. Insulin sensitivity was determined by hyperinsulinemic euglycemic clamps and found to be improved in the diabetic men. Plasma was collected during the clamp and analyzed through GC/TOFMS. Healthy subjects could be distinguished from diabetics by means of low molecular-weight compounds (LMC) in plasma independently of gender or exercise, and exercise induced differences in LMC patterns both for healthy and T2D subjects. Forty-four significant metabolites were found to explain differences between LMC patterns obtained from trained and non-trained diabetics. Among these compounds, 17 could be annotated and 5 classified. Inositol-1-phosphate showed the highest correlation to insulin sensitivity in diabetic men, whereas an as yet unknown fatty acid correlated best with insulin sensitivity in women. Both metabolites were better correlated to insulin sensitivity than glucose. Finally, the finding that inostitol-1-phosphate negatively correlates with insulin sensitivity in diabetic men, was validated using samples obtained from a similar training study on diabetic men. Jeanette Kuhl and Thomas Moritz contributed equally to this study.     

Stimulation of insulin secretion by corticotropin-releasing factor (CRF) in anesthetized rats

Corticotropin-releasing factor-containing cells have been recently found in the endocrine pancreas of several vertebrate species by immunocytochemistry. In order to clarify the possible physiological significance of these findings, we have studied the effect of the administration of CRF on endocrine pancreatic function. Five minutes, after injection of ovine CRF 1-41 into the jugular vein, a dose-related increase in insulin levels in the hepatic-portal vein of anesthetized rats was found. This dose-dependent insulin increase was delayed to fifteen minutes after CRF injection into rats exposed to greater surgical stress and was partially blunted in adrenalectomized animals. Glucose and glucagon levels were not altered after CRF administration under these conditions. These results suggest that CRF may play a modulatory role in insulin secretion; however, whether CRF acts directly on the beta-cell or through some CRF-stimulated mediator remains to be established.     

Alpha-lipoic acid increases insulin sensitivity by activating AMPK in skeletal muscle

Triglyceride accumulation in skeletal muscle contributes to insulin resistance in obesity. We recently showed that alpha-lipoic acid (ALA) reduces body weight and prevents the development of diabetes in diabetes-prone obese rats by reducing triglyceride accumulation in non-adipose tissues. AMP-activated protein kinase (AMPK) is a major regulator of cellular energy metabolism. We examined whether ALA lowers triglyceride accumulation in skeletal muscle by activating AMPK. Alpha2-AMPK activity was decreased in obese rats compared to control rats. Administration of ALA to obese rats increased insulin-stimulated glucose disposal in whole body and in skeletal muscle. ALA also increased fatty acid oxidation and activated AMPK in skeletal muscle. Adenovirus-mediated administration of dominant negative AMPK into skeletal muscle prevented the ALA-induced increases in fatty acid oxidation and insulin-stimulated glucose uptake. These results suggest that ALA-induced improvement of insulin sensitivity is mediated by activation of AMPK and reduced triglyceride accumulation in skeletal muscle.     

Effects of short-term chromium supplementation on insulin sensitivity and body composition in overweight children: randomized, double-blind, placebo-controlled study

Excessive body weight is inversely associated with insulin sensitivity in children and adults. Chromium supplementation produces modest improvement in insulin sensitivity in adults. The aim of this study was to examine the beneficial effects of chromium supplementation on insulin sensitivity and body composition in overweight children simultaneously modifying lifestyle. Twenty-five overweight children aged 9–12 years were randomized to receive either 400 μg of chromium chloride or placebo in double-blind fashion, during a 6-week lifestyle modification regimen that included nutritional education and 3×90 min of aerobic physical activity weekly. Insulin sensitivity was demonstrated using homeostasis model assessment-insulin resistance and quantitative insulin sensitivity check index (QUICKI). Changes in body mass index (BMI; kg/m²), BMI Z-score, waist circumference, body composition and fasting plasma glucose were measured. Although no significant benefit of chromium supplementation over placebo was evident for BMI, BMI Z-score and fasting insulin level, children who received chromium chloride demonstrated more positive changes versus the placebo group in HOMA (−1.84±1.07 vs. 0.05±0.42, P=.05), QUICKI (0.02±0.01 vs. −0.002±0.01, P=.05), lean body mass (2.43±0.68kg vs. 1.36±1.61kg, P=.02) and percentage body fat (−3.32±1.29% vs. 0.65±1.05%, P=.04). The desirable effects of chromium supplementation on insulin sensitivity and body composition were more apparent in pre-pubertal children. These results suggest that short-term chromium supplementation can improve insulin sensitivity and body composition in overweight children.     

17beta-Estradiol and/or progesterone protect from insulin resistance in STZ-induced diabetic rats

Recent clinical and experimental evidences suggest that sex steroids protect from insulin resistance associated with diabetes. Therefore, we have assessed the influence of E2 and/or P4 on insulin sensitivity by euglicaemic-hyperinsulinaemic clamp in ovariectomized streptozotocin-induced diabetic rats, focusing on key proteins of insulin signaling in skeletal muscle. Although low plasma levels of E2 (days 6 and 11) increased Glut-4 plasma membrane content and subsequent improved insulin sensitivity, they could not fully reverse hyperglycaemia negative effects on p85alpha-IRS-1 association and IRS-1 content during 11 days. However, high plasma levels of E2 (day 16) could reverse hyperglycaemia effects not only on Glut-4 plasma membrane content but also on p85alpha-IRS-1 association and IRS-1 protein content level. In contrast, P4 treatment only improved insulin sensitivity when its plasma concentration was low (days 6 and 11) and its effects were not associated with any proteins study in this paper. The combined therapy had a synergic effect on insulin sensitivity when their plasma levels were low (day 6) or high (day 16), that could be associated with Glut-4 plasma membrane content modulation, p85alpha-IRS-1 association and IRS-1 amount. These new findings improve our understanding of biochemical basis of insulin resistance due to hyperglycaemia and could open up new possibilities of treatment in uncontrolled type 1 DM.     

Hepatic hexokinase domain containing 1 (HKDC1) improves whole body glucose tolerance and insulin sensitivity in pregnant mice

Hexokinase domain containing 1, a recently discovered putative fifth hexokinase, is hypothesized to play key roles in glucose metabolism. Specifically, during pregnancy in a recent genome wide association study (GWAS), a strong correlation between HKDC1 and 2-h plasma glucose in pregnant women from different ethnic backgrounds was shown. Our earlier work also reported diminished glucose tolerance during pregnancy in our whole body HKDC1 heterozygous mice. Therefore, we hypothesized that HKDC1 plays important roles in gestational metabolism, and designed this study to assess the role of hepatic HKDC1 in whole body glucose utilization and insulin action during pregnancy. We overexpressed human HKDC1 in mouse liver by injecting a human HKDC1 adenoviral construct; whereas, for the liver-specific HKDC1 knockout model, we used AAV-Cre constructs in our HKDC1^fl/fl mice. Both groups of mice were subjected to metabolic testing before and during pregnancy on gestation day 17–18. Our results indicate that hepatic HKDC1 overexpression during pregnancy leads to improved whole-body glucose tolerance and enhanced hepatic and peripheral insulin sensitivity while hepatic HKDC1 knockout results in diminished glucose tolerance. Further, we observed reduced gluconeogenesis with hepatic HKDC1 overexpression while HKDC1 knockout led to increased gluconeogenesis. These changes were associated with significantly enhanced ketone body production in HKDC1 overexpressing mice, indicating that these mice shift their metabolic needs from glucose reliance to greater fat oxidation and ketone utilization during fasting. Taken together, our results indicate that hepatic HKDC1 contributes to whole body glucose disposal, insulin sensitivity, and aspects of nutrient balance during pregnancy.     

诺沙坦改善非胰岛素依赖型糖尿病大鼠胰岛素敏感性的作用机制

本文研究血管紧张素Ⅱ受体拮抗剂诺沙坦对非胰岛素依赖型糖尿病(non-insulin-dependent diabetes mellitus,NIDDM)大鼠胰岛素敏感性的改善作用,并探讨其作用机制。从饮水中给予正常或高脂喂养加小剂量链脲佐菌素(STZ)诱发的NIDDM大鼠诺沙坦(4 mg/kg),连续6周。分离骨骼肌,用免疫印迹法检测诺沙坦对胰岛素受体底物1(insulin receptor substrate 1,IRS-1)、蛋白激酶B(protein kinase B,PKB)和葡萄糖转运因子4(glucose transporter 4,GLUT4)的表达,以及IRS-1的磷酸化、IRS-1与磷脂酰肌醇3激酶(phosphatidylinositol(PI)3-kinase)的结合。口服葡萄糖耐量试验表明,口服诺沙坦可改善糖尿病大鼠胰岛素敏感性。在骨骼肌组织,NIDDM和正常大鼠的IRS-1、PKB和GLUT4蛋白表达无差异,且不受诺沙坦处理的影响。NIDDM大鼠胰岛素刺激后的骨骼肌IRS-1酪氨酸磷酸化水平、PI 3-kinase结合IRS-1的活性和PKB活性较对照组显著降低(P<0.01),且不能被诺沙坦改善。诺沙坦显著增加NIDDM大鼠肌细胞质膜(plasma membrane,PM)和T管(T-tubules,TT)胰岛素诱导的GLUT4的 含量(P<0.05)。与该结果一致的是,诺沙坦处理的NIDDM大鼠血糖水平较未处理NIDDM大鼠下降(P<0.05)。结果表明,诺沙坦可改善胰岛素抵抗状态,主要是通过非PI 3-kinase依赖的