Peripheral and hepatic insulin sensitivity in healthy elderly human subjects

Insulin resistance has been reported in normal ageing but discrepancies between such studies may be related to compounding factors such as body composition and exercise patterns. We employed a two-step hyperinsulinaemic euglycaemic clamp to assess peripheral and hepatic tissue insulin sensitivity and glucose recycling in 13 elderly (E) and 14 young (Y) healthy subjects controlling for the above factors. There was no difference in basal hepatic glucose production (E: 2.36 +/- 0.06, Y: 2.47 +/- 0.1 mg kg-1 min-1; P = 0.4). At step 1 (insulin infusion 15 mU kg-1 h-1) glucose turnover was similar (E: 2.65 +/- 0.13, Y: 2.88 +/- 0.22 mg kg-1 min-1; P = 0.4) but hepatic glucose production was lower in the elderly group (0.20 +/- 0.16 vs 0.64 +/- 0.10 mg kg-1 min-1; P = 0.03). At step 2 (insulin infusion 50 mU kg-1 h-1) glucose turnover was similar (E: 7.60 +/- 0.24, Y: 8.05 +/- 0.34 mg kg-1 min-1; P = 0.3) and hepatic glucose production was equal but negative (E: -1.35 +/- 0.18, Y: -1.34 +/- 0.22 mg kg-1 min-1; P = 0.9). Glucose recycling did not differ between the groups at any stage. Similar serum insulin levels were achieved in both groups at each step. Decreased glucose tolerance was confirmed in E with a higher 2 h blood glucose after an OGTT (5.3 +/- 0.4 vs 4.1 +/- 0.3 mmol l-1; P = 0.03) but incremental insulin response was similar (E: 3236 +/- 289, Y: 3586 +/- 463 mU l-1 min-1; P = 0.5). We conclude that changes in hepatic tissue insulin sensitivity do not cause the deterioration in glucose tolerance observed with age. A small reduction in both peripheral tissue insulin sensitivity and late insulin secretion may be responsible.     

Inhibition of growth hormone action improves insulin sensitivity in liver IGF-1-deficient mice

Liver IGF-1-deficient (LID) mice have a 75% reduction in circulating IGF-1 levels and, as a result, a fourfold increase in growth hormone (GH) secretion. To block GH action, LID mice were crossed with GH antagonist (GHa) transgenic mice. Inactivation of GH action in the resulting LID + GHa mice led to decreased blood glucose and insulin levels and improved peripheral insulin sensitivity. Hyperinsulinemic-euglycemic clamp studies showed that LID mice exhibit severe insulin resistance. In contrast, expression of the GH antagonist transgene in LID + GHa mice led to enhanced insulin sensitivity and increased insulin-stimulated glucose uptake in muscle and white adipose tissue. Interestingly, LID + GHa mice exhibit a twofold increase in white adipose tissue mass, as well as increased levels of serum-free fatty acids and triglycerides, but no increase in the triglyceride content of liver and muscle. In conclusion, these results show that despite low levels of circulating IGF-1, insulin sensitivity in LID mice could be improved by inactivating GH action, suggesting that chronic elevation of GH levels plays a major role in insulin resistance. These results suggest that IGF-1 plays a role in maintaining a fine balance between GH and insulin to promote normal carbohydrate and lipid metabolism.     

Lysophospholipid acylation modulates plasma membrane lipid organization and insulin sensitivity in skeletal muscle

Aberrant lipid metabolism promotes the development of skeletal muscle insulin resistance, but the exact identity of lipid-mediated mechanisms relevant to human obesity remains unclear. A comprehensive lipidomic analysis of primary myocytes from individuals who were insulin-sensitive and lean (LN) or insulin-resistant with obesity (OB) revealed several species of lysophospholipids (lyso-PLs) that were differentially abundant. These changes coincided with greater expression of lysophosphatidylcholine acyltransferase 3 (LPCAT3), an enzyme involved in phospholipid transacylation (Lands cycle). Strikingly, mice with skeletal muscle–specific knockout of LPCAT3 (LPCAT3-MKO) exhibited greater muscle lysophosphatidylcholine/phosphatidylcholine, concomitant with improved skeletal muscle insulin sensitivity. Conversely, skeletal muscle–specific overexpression of LPCAT3 (LPCAT3-MKI) promoted glucose intolerance. The absence of LPCAT3 reduced phospholipid packing of cellular membranes and increased plasma membrane lipid clustering, suggesting that LPCAT3 affects insulin receptor phosphorylation by modulating plasma membrane lipid organization. In conclusion, obesity accelerates the skeletal muscle Lands cycle, whose consequence might induce the disruption of plasma membrane organization that suppresses muscle insulin action.     

Insulin-mediated skeletal muscle vasodilation contributes to both insulin sensitivity and responsiveness in lean humans.

Whether insulin-mediated vasodilation is important in determining insulin's overall action to stimulate glucose uptake is unknown. To this end, we measured leg glucose uptake during euglycemic hyperinsulinemic clamps performed at two insulin doses (40 mU/m2 per min, n = 6 and 120 mU/m2 per min, n = 15) alone and during a superimposed intrafemoral artery infusion of GN-monomethyl-L-arginine (L-NMMA) designed to blunt insulin-mediated vasodilation. During the higher dose study, hyperinsulinemia resulted in about a twofold rise in basal leg blood flow from 0.24 +/- 0.02 to 0.45 +/- 0.05 liter/min, P < 0.0001. L-NMMA infusion resulted in a net 21% reduction in leg glucose uptake from 114 +/- 18 mg/min to 85 +/- 13 mg/min, P < 0.001. We also found a significant relationship between the rate of insulin-stimulated whole body glucose uptake and the magnitude of flow dependent glucose uptake (r = 0.57, P = 0.02). Data obtained during the lower dose insulin infusion resulted in similar findings. In conclusion, in healthy lean subjects, insulin-stimulated muscle blood flow contributes to both insulin responsiveness and insulin sensitivity. The most insulin-sensitive subjects appear to be the most reliant on muscle perfusion for insulin action. Insulin-mediated vasodilation is an important physiological determinant of insulin action.     

二陈汤方加减对2型糖尿病并发脂肪肝模型大鼠血糖、血脂、胰岛素抵抗以及肝功能和肝脏脂肪变的影响

目的：观察具有化痰利湿、活血化瘀功效的二陈汤方加减干预2型糖尿病并发脂肪肝大鼠血糖、血脂、胰岛素的抵抗状况，以及脂肪肝模型病理形态学的变化。 方法：实验于2004—04／11在厦门大学医学院动物实验中心完成。①选用健康Wistar大鼠40只，7周龄，雌雄各半。随机抽取12只为正常对照组，喂以普通饲料（其中各成分质量分数如下：碳水化合物0．6、蛋白质0．22．脂肪0．1，其他0．08，脂肪以豆油为主），其余则喂养高热量饲料（其中各成分质量分数如下：碳水化合物0．4，蛋白质0．13，脂肪0．4，其他0．07．脂肪以动物油脂为主）。2个月后，正常对照组的大鼠一次性腹腔注射0．1In0帆pH4．2枸椽酸缓冲液，其余28只大鼠则一次性腹腔注射链脲佐菌素25mg／kg。72h后查血糖≥16．7mmol／L为糖尿病大鼠，造模成功24只。②将24只糖尿病大鼠随机分为2组：模型组和二陈汤方加减组，每组12只。正常对照组喂以普通饲料，其余2组均喂养高热量饲料。二陈汤方加减组大鼠按8mL／（kg&;#183;d）剂量灌胃二陈汤方加减药物，由陈皮、半夏、茯苓、僵蚕及地龙等组成（上述中药由本院中药房提供），由本院药剂科制备成浓缩液（含生药2g／mL），1次／d；正常对照组和模型组灌胃等量的自来水，均连续干预16周。（固然后采用ELISA法测血胰岛素水平，计算肝指数（肝湿重／体质量x100％）和胰岛素敏感指数In｜[1／（空腹血糖&;#215;空腹胰岛素）]｜；光镜下评估肝脂肪变性和炎症坏死程度。炎症活动度计分[慢性肝炎炎症活动度及纤维化计分方案炎症活动度计分分为汇管区（P）、小叶内（L）、碎屑坏死（PN）及桥接坏死（BN）4项，每项依病变轻、中、重程度分别计以1，3，4分，计分公式为P＋L＋2（PN＋BN）]。按照上海九强生物技术有限公司提供相应试剂盒说明书测定血清三酰甘油、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇、谷草转氨酶、谷丙转氨酶、白蛋白及总蛋白水平。分别于造模前、造模后8周及造模后16周采用氧化酶法测定空腹血糖。④计量资料、等级资料、率差异比较分别采用两样本均数t检验、秩和检验、两样本率差别的统计意义检验。 结果：由于造模失败脱失4只，最终进入结果分析36只。①肝指数：造模后16周模型组和二陈汤方加减组明显高于正常对照组（P〈0．01）。②空腹血糖水平：造模后8和16周模型组及二陈汤方加减组均明显高于造模前和正常对照组（P〈0．01）。造模后8和16周二陈汤方加减组明显低于模型组（P〈0．05）。③血胰岛素水平：造模后16周模型组明显高于正常对照组和二陈汤方加减组（P〈0．01）。④胰岛素敏感指数：造模后16周模型组明显低于正常对照组和陈汤方加减组（P〈0．01）。⑤血清三酰甘油和低密度脂蛋白胆固醇水平：造模后16周．模型组和二陈汤方加减组明显高于正常对照组（P〈0.0_01），二陈汤方加减组明显低于模型组（P〈0．05）。⑥血清高密度脂蛋白胆固醇水平：造模后16周，模型组和二陈汤方加减组明显低于正常对照组（P〈0．05）．二陈汤方加减组明显高于模型组（P〈0．05）。⑦血清谷丙转氨酶和谷草转氨酶活性：造模后16周，模型组和二陈汤方加减组明显高于正常对照组（P〈0．05-0．01），二陈汤方加减组低于模型组，但差异不明显（P〉0．05）。⑧肝脏炎症活动度计分：造模后16周，模型组及二陈汤方加减组明显高于正常对照组（P〈0．01），但模型组与二陈汤方加减组差异不明显。⑨肝脏病理学形态变化：造模后16周，正常对照组大鼠肝脏无异常病变。模型组及二陈汤方加减组均出现弥漫性肝细胞脂肪变性．且两组肝脂变情况无区别。 结论：二陈汤方加减可在一定程度上能改善糖尿病并发脂肪肝大鼠的血糖、血脂水平，胰岛素抵抗状况及肝功能指标，但不能减轻肝脏组织学病变。     

二陈汤方加减对2型糖尿病并发脂肪肝模型大鼠血糖、血脂、胰岛素抵抗以及肝功能和肝脏脂肪变的影响

目的:观察具有化痰利湿、活血化瘀功效的二陈汤方加减干预2型糖尿病并发脂肪肝大鼠血糖、血脂、胰岛素的抵抗状况,以及脂肪肝模型病理形态学的变化。方法:实验于2004-04/11在厦门大学医学院动物实验中心完成。①选用健康Wistar大鼠40只,7周龄,雌雄各半。随机抽取12只为正常对照组,喂以普通饲料(其中各成分质量分数如下:碳水化合物0.6、蛋白质0.22,脂肪0.1,其他0.08,脂肪以豆油为主),其余则喂养高热量饲料(其中各成分质量分数如下:碳水化合物0.4,蛋白质0.13,脂肪0.4,其他0.07,脂肪以动物油脂为主)。2个月后,正常对照组的大鼠一次性腹腔注射0.1mol/LpH4.2枸椽酸缓冲液,其余28只大鼠则一次性腹腔注射链脲佐菌素25mg/kg。72h后查血糖≥16.7mmol/L为糖尿病大鼠,造模成功24只。②将24只糖尿病大鼠随机分为2组:模型组和二陈汤方加减组,每组12只。正常对照组喂以普通饲料,其余2组均喂养高热量饲料。二陈汤方加减组大鼠按8mL/(kg·d)剂量灌胃二陈汤方加减药物,由陈皮、半夏、茯苓、僵蚕及地龙等组成(上述中药由本院中药房提供),由本院药剂科制备成浓缩液(含生药2g/mL),1次/d;正常对照组和模型组灌胃等量的自来水,均连续干预16周。③然后采用ELISA法测血胰岛素水平,计算肝指数(肝湿重/体质量×100%)和胰岛素敏感指数ln｛[1/(空腹血糖×空腹胰岛素)]｝;光镜下评估肝脂肪变性和炎症坏死程度。炎症活动度计分[慢性肝炎炎症活动度及纤维化计分方案炎症活动度计分分为汇管区(P)、小叶内(L)、碎屑坏死(PN)及桥接坏死(BN)4项,每项依病变轻、中、重程度分别计以1,3,4分,计分公式为P L 2(PN BN)]。按照上海九强生物技术有限公司提供相应试剂盒说明书测定血清三酰甘油、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇、谷草转氨酶、谷丙转氨酶、白蛋白及总蛋白水平。分别于造模前、造模后8周及造模后16周采用氧化酶法测定空腹血糖。④计量资料、等级资料、率差异比较分别采用两样本均数t检验、秩和检验、两样本率差别的统计意义检验。结果:由于造模失败脱失4只,最终进入结果分析36只。①肝指数:造模后16周模型组和二陈汤方加减组明显高于正常对照组(P<0.01)。②空腹血糖水平:造模后8和16周模型组及二陈汤方加减组均明显高于造模前和正常对照组(P<0.01)。造模后8和16周二陈汤方加减组明显低于模型组(P<0.05)。③血胰岛素水平:造模后16周模型组明显高于正常对照组和二陈汤方加减组(P<0.01)。④胰岛素敏感指数:造模后16周模型组明显低于正常对照组和陈汤方加减组(P<0.01)。⑤血清三酰甘油和低密度脂蛋白胆固醇水平:造模后16周,模型组和二陈汤方加减组明显高于正常对照组(P<0.01),二陈汤方加减组明显低于模型组(P<0.05)。⑥血清高密度脂蛋白胆固醇水平:造模后16周,模型组和二陈汤方加减组明显低于正常对照组(P<0.05),二陈汤方加减组明显高于模型组(P<0.05)。⑦血清谷丙转氨酶和谷草转氨酶活性:造模后16周,模型组和二陈汤方加减组明显高于正常对照组(P<0.05～0.01),二陈汤方加减组低于模型组,但差异不明显(P>0.05)。⑧肝脏炎症活动度计分:造模后16周,模型组及二陈汤方加减组明显高于正常对照组(P<0.01),但模型组与二陈汤方加减组差异不明显。⑨肝脏病理学形态变化:造模后16周,正常对照组大鼠肝脏无异常病变。模型组及二陈汤方加减组均出现弥漫性肝细胞脂肪变性,且两组肝脂变情况无区别。结论:二陈汤方加减可在一定程度上能改善糖尿病并发脂肪肝大鼠的血糖、血脂水平,胰岛素抵抗状况及肝功能指标,但不能减轻肝脏组织学病变。     

Effects of comicronised fenofibrate on lipid and insulin sensitivity in patients with polymetabolic syndrome X

BACKGROUND: This study investigated the effects of comicronised fenofibrate in patients with dyslipidemia and polymetabolic syndrome X. DESIGN: After a 6-week dietary run-in phase, 37 male patients eligible on lipid criteria entered a 12-week treatment phase consisting of diet plus one capsule daily containing 200 mg of comicronised fenofibrate (Lipanthyl(R)). RESULTS: A significant reduction in plasma concentrations of total cholesterol, LDL cholesterol and triglyceride was observed after 4, 8 and 12 weeks of treatment with fenofibrate. The improvement in the atherogenic index LDL/HDL cholesterol from a pretreatment 3.8 to 3.0 after treatment was highly statistically significant and may be judged as satisfactory. Significant changes were also observed in haemostatic factors (fibrinogen reduced by 19%, factor VII activity reduced by 18%). Fasting serum insulin levels and insulin response (area under the curve) after oral glucose load were significantly reduced by 26.8% and 18.7%, respectively, indicating an improvement of insulin sensitivity. Systolic and diastolic blood pressure were significantly reduced. Uric acid was significantly reduced by 21.6%. CONCLUSION: These favourable effects of comicronised fenofibrate both on lipid and non lipid parameters, including insulin sensitivity, may confer to this product a particular interest in the treatment of patients with polymetabolic syndrome X.     

Long-term oral L-arginine administration improves peripheral and hepatic insulin sensitivity in type 2 diabetic patients

The aim of this study was to evaluate whether long-term administration of arginine acting through a normalization of NO/cyclic-guanosine-3' 5'-cyclic monophosphate (cGMP) pathway was able to ameliorate peripheral and hepatic insulin sensitivity in 12 lean type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A double-blind study was performed for 3 months. In the first month, patients were treated with their usual diet. Then they were randomly allocated into to groups. In group 1, patients were treated with diet plus placebo (orally three times per day) for 2 months. In group 2 patients were treated for 1 month with diet plus placebo orally, three times per day) and then for 1 month with diet plus L-arginine (3 g three times per day). At the end of the first and the second month of therapy, patients underwent a euglycemic-hyperinsulinemic clamp combined with [6,6-2H2] glucose infusion. A total of 10 normal subjects underwent the same test as control subjects. RESULTS: In group 1, no changes in basal cGMP levels, systolic blood pressure, forearm blood flow, glucose disposal, and endogenous glucose production were observed throughout. In group 2, L-arginine normalized basal cGMP levels and significantly increased forearm blood flow by 36% and glucose disposal during the clamp by 34% whereas it decreased systolic blood pressure and endogenous glucose production by 14 and 29%, respectively. However, compared with normal subjects, L-arginine treatment was not able to completely overcome the defect in glucose disposal. CONCLUSIONS: L-Arginine treatment significantly improves but does not completely normalizc peripheral and hepatic insulin sensitivity in type 2 diabetic patients.     

有氧运动及其联合饮食干预影响非酒精性脂肪肝患者血浆SREBP-1c、RBP4水平的研究

目的:探讨有氧运动、饮食控制对非酒精性脂肪性肝病(NAFLD)患者血清SREBP-1c、RBP4水平的影响。方法:将NAFLD患者共53例随机分为对照组(C)、运动组(E)、饮食控制组(D)和运动+饮食控制组(ED);另有12例健康自愿者组成健康对照组(N)。E组运动处方干预,D组饮食干预,ED组运动联合饮食干预。实验前后分别检测身体形态(BMI;WHR)和血液生化指标(SREBP-1c;RBP4;TNF-a等)。结果:1WHR指数实验后E组、DE组较实验前显著下降(P0.05);实验后DE组较C、E组显著下降(P0.05)。2血浆TG及LDL/HDL实验后E组、DE组较实验前显著下降(P0.05);实验后DE组血浆TG、E组和DE组LDL/HDL较C组显著降低(P0.05)。3血浆FINS水平及HOMA-IR实验后E、DE组较实验前显著下降(P0.05);实验后HOMA-IR指数E组和DE组较C组显著下降(P0.05)。4E组RBP4、D组SREBP-1c和DE组TNF-α、RBP4、SREBP-1c血浆水平实验后较实验前显著下降(P0.05);实验后E组SREBP-1c水平和DE组血浆RBP4、SREBP-1c水平较C组显著降低(P0.05)。结论:116周有氧运动、饮食控制以及有氧运动联合饮食控制,NAFLD患者血浆SREBP-1c、RBP4、TNF-α水平分别呈不同程度降低,IR缓解,脂质代谢紊乱改善,有利于NAFLD转归。2有氧运动联合饮食控制对NAFLD的干预效果更佳。     

Composition of ascitic fluid in liver cirrhosis: bile acid and lipid content

Abstract. The concentrations of lipids, bile acids and proteins were evaluated in the ascitic fluid and plasma of 23 cirrhotics. Ascitic fluid density was highly correlated with its protein content, represented mostly by low molecular weight proteins. The ratio of plasma to ascitic fluid concentrations of nine examined proteins increased with molecular weight, indicating a selective ultrafiltration of the peritoneal transudate. Low density lipoproteins in ascitic fluid had modified electrophoretic mobility. Total cholesterol had a higher plasma to ascitic fluid ratio than high density lipoprotein cholesterol, whereas bile acids and proteins had similar plasma to ascitic fluid ratios. Indeed, bile acids strongly bind to circulating albumin: consequently ascitic fluid contains more cholic acid (less hydrophobic) than other bile acids. Analysis of both plasma and ascitic fluid composition in cirrhotics provides useful information on processes regulating passage of blood components into the peritoneal cavity.     

3.0T 1H-MRS测定大鼠肝内脂肪含量的可行性

目的 探讨利用3.0T临床型MR仪行¹H-MRS测定非酒精性脂肪肝（NAFLD）大鼠模型肝内脂肪含量的可行性。方法 将75只SD大鼠随机分为高脂饲养实验组（n=50）与正常对照组（n=25）;分别在第2、4、6、8、10周时行肝脏¹H-MRS扫描及组织病理学检查。将¹H-MRS原始数据导入LC model软件进行分析,并对各代谢物浓度行T1、T2纠正;将¹H-MRS结果与组织病理学结果加以对照,将肝内饱和脂肪酸含量、总非不饱和脂肪酸含量及组织病理学检测含量分别记为Lip_MRS1、Lip_MRS2和FI。结果 大鼠肝脏同一部位相同参数（r₁）及同一部位不同时间点（r₂）¹H-MRS测量结果（r₁=0.99,r₂=0.96,P均<0.01）呈高度正相关;Lip_MRS1、FI呈高度正相关,回归方程为：LogY=0.37+1.21LogX（r=0.95,P<0.01）,NAFLD大鼠模型中Lip_MRS1及Lip_MRS2含量无明显相关性（r=－0.11,P=0.66）;Bland & Altman曲线分析显示Lip_MRS1与FI的一致性好。结论 采用3.0T临床型MR仪行¹H-MRS可作为在体评价NAFLD大鼠模型肝内脂肪含量的无创的影像学方法;LC model软件能区分肝内脂肪组分并精确定量。     

Overexpression of visfatin/PBEF/Nampt alters whole-body insulin sensitivity and lipid profile in rats

Background. Visfatin/PBEF/Nampt is an adipose-derived hormone proposed to exert insulin-mimicking effects and play a positive role in attenuating insulin resistance. However, the precise mechanisms underlying the beneficial effects of visfatin/PBEF/Nampt on insulin sensitivity remain unknown.

Method. Euglycemic-hyperinsulinemic clamps were used in the same groups of rats to study the in vivo effect of visfatin/PBEF/Nampt on insulin sensitivity and glucose/lipid metabolism before and after the overexpression of visfatin/PBEF/Nampt protein, which was carried out by injection of pcDNA3.1-visfatin plasmid.

Results. On day 4 after plasmid injection, plasma visfatin/PBEF/Nampt protein levels were significantly increased and displayed a hypocholesterolemic effect in both normal-chow (NC) and high-fat diet (HT) animals with pcDNA3.1-visfatin treatment. A second glucose clamp also demonstrated increased insulin sensitivity in pcDNA3.1-visfatin animals. Consistent with the clamp data, the extent of insulin receptor substrate (IRS)-1 tyrosine phosphorylation in response to insulin was significantly enhanced in the liver and adipose tissues. In addition, the mRNA expression of peroxisome proliferator-activated receptor-γ (PPARγ) and sterol regulatory element-binding proteins 2 (SREBP-2) in the liver and adipose tissues was also significantly upregulated in these animals.

Conclusion. These results demonstrate that visfatin/PBEF/Nampt improves insulin sensitivity and exerts its hypocholesterolemic effects at least partially through upregulation of the tyrosine phosphorylation of IRS-1 protein and the mRNA levels of PPARγ and SREBP-2.     

Oral vanadyl sulfate improves hepatic and peripheral insulin sensitivity in patients with non-insulin-dependent diabetes mellitus.

We examined the in vivo metabolic effects of vanadyl sulfate (VS) in non-insulin-dependent diabetes mellitus (NIDDM). Six NIDDM subjects treated with diet and/or sulfonylureas were examined at the end of three consecutive periods: placebo for 2 wk, VS (100 mg/d) for 3 wk, and placebo for 2 wk. Euglycemic hyperinsulinemic (30 mU/m2.min) clamps and oral glucose tolerance tests were performed at the end of each study period. Glycemic control at baseline was poor (fasting plasma glucose 210 +/- 19 mg/dl; HbA1c 9.6 +/- 0.6%) and improved after treatment (181 +/- 14 mg/dl [P < 0.05], 8.8 +/- 0.6%, [P < 0.002]); fasting and post-glucose tolerance test plasma insulin concentrations were unchanged. After VS, the glucose infusion rate during the clamp was increased (by approximately 88%, from 1.80 to 3.38 mg/kg.min, P < 0.0001). This improvement was due to both enhanced insulin-mediated stimulation of glucose uptake (rate of glucose disposal [Rd], +0.89 mg/kg.min) and increased inhibition of HGP (-0.74 mg/kg.min) (P < 0.0001 for both). Increased insulin-stimulated glycogen synthesis (+0.74 mg/kg.min, P < 0.0003) accounted for > 80% of the increased Rd after VS, and the improvement in insulin sensitivity was maintained after the second placebo period. The Km of skeletal muscle glycogen synthase was lowered by approximately 30% after VS treatment (P < 0.05). These results indicate that 3 wk of treatment with VS improves hepatic and peripheral insulin sensitivity in insulin-resistant NIDDM humans. These effects were sustained for up to 2 wk after discontinuation of VS.     

Hemin arginate-induced heme oxygenase 1 expression improves liver microcirculation and mediates an anti-inflammatory cytokine response after hemorrhagic shock

Microvascular failure is a major determinant for the development of hepatocellular dysfunction after hemorrhagic shock. Induction of heme oxygenase (HO) 1 may confer hepatocellular protection. Hemin arginate (HAR) induces HO-1 and protects against shock-induced organ failure. The mechanisms are not completely understood, but HO-1-mediated protective effects on the microcirculation and on the inflammatory response may contribute. Therefore, the aim of the present study was to investigate the influence of HAR pretreatment on liver microcirculation and cytokine response to assess the role of HO-1-mediated effects under these conditions. Male Sprague-Dawley rats (200-300 g; n=8 per group) were subjected to hemorrhage (MAP, 30-40 mmHg for 1 h) 24 h after pretreatment with vehicle (Ringer solution) or HAR (5 mg kg(-1)), followed by 2 h of resuscitation. The microcirculation and the redox state (nicotinamide adenine dinucleotide phosphate [reduced form; NADPH] autofluorescence) of the liver were assessed using intravital microscopy. Cytokine levels (TNF-alpha and IL-10) were quantified using an enzyme-linked immunosorbent assay. A profound induction of HO-1 was observed 24 h after pretreatment with HAR. Hemorrhage significantly reduced sinusoidal perfusion and increased NADPH autofluorescence and cytokine levels. Hemin arginate pretreatment significantly improved liver microcirculation, reduced NADPH autofluorescence, significantly increased IL-10, and tended to decrease TNF-alpha serum levels compared with shock vehicle. Blockade of the HO pathway with tin-mesoporphyrin-IX after HAR pretreatment abolished the observed beneficial effects, whereas the additional administration of the carbon monoxide donor dichloromethane reversed the tin-mesoporphyrin-IX-mediated changes. These results suggest that HAR pretreatment improves liver microcirculation and mediates an anti-inflammatory cytokine response after hemorrhagic shock through induction of HO-1 and in part through an increased carbon monoxide release.