BACKGROUND & AIMS: :Insulin resistance affecting skeletal muscle metabolism is present in the prehypertensive state. The aim of our study was to test the hypothesis that blood pressure value is related to skeletal muscle composition, measured by (31)P magnetic resonance (MR) spectroscopy, and to insulin sensitivity in the offspring of hypertensive parents (OH) and healthy controls. Study groups consisted of 10 healthy young lean OH with normal glucose tolerance, confirmed with oral glucose tolerance test, and 13 controls matched for age, sex, and body mass index. Insulin action was estimated as glucose disposal (M), glucose metabolic clearance rate (MCR), and insulin sensitivity index (M/I) during a 10-hour hyperinsulinemic euglycemic clamp. The sum of immunoreactive insulin values from the oral glucose tolerance test was calculated. (31)P MR spectroscopy was performed on a whole-body MR scanner (Siemens Vision, Erlangen, Germany) operating at 1.5 T and equipped with actively shielded gradient coils. There were no differences in common metabolic and anthropometric parameters between OH and controls except for the blood pressure, which was in the range of normal to high-normal level in OH. Mean blood pressure was significantly higher in OH (95.73 +/- 4.39 vs 83.76 +/- 3.95 mm Hg; P < .001). Trend toward insulin resistance was registered in OH with significantly lower M/I (0.74 +/- 0.47 vs 1.42 +/- 0.65 mg x kg(-1) x min(-1) x mIU(-1) x L(-1); P < .05). There were no significant differences in total serum magnesium (sMg) levels between OH and controls, although a positive correlation exists between sMg and insulin sensitivity expressed as M (r = 0.63, P < .01), MCR (r = 0.54, P < .01), and M/I (r = 0.51, P < .05). No differences in signal intensities of phosphocreatine (PCr), phosphomonoesters, phosphodiesters, inorganic phosphates (Pi), adenosine triphosphates (Patp and betaATP), and calculated concentrations of intracellular ionized magnesium (Mgi) and H(+) ions between the groups were detected. Systolic blood pressure correlates positively with PCr/Patp (r = 0.43, P < .05), Pi/Patp (r = 0.413, P < .05), and Pi/betaATP (r = 0.48, P < .05). Diastolic blood pressure correlates positively only with the ratio Pi/betaATP (r = 0.42, P < .05). The sum of immunoreactive insulin values correlates with PCr/betaATP (r = 0.53, P < .01) and with Pi/betaATP (r = 0.6, P < .01). In conclusion, increase in blood pressure and insulin resistance were confirmed in offspring of OH. Insulin sensitivity is related to sMg and the elevation of blood pressure is associated with the activation of energy metabolism in skeletal muscle. The relationship between muscle energetic characteristics and markers of insulin resistance suggests that the alteration of energy metabolism may be present in early stages of metabolic syndrome.

背景与目标： ：在高血压前状态下，会影响骨骼肌新陈代谢的胰岛素抵抗。我们研究的目的是检验以下假设：血压值与通过（31）P磁共振（MR）光谱法测量的骨骼肌成分以及高血压父母（OH）和健康对照的后代的胰岛素敏感性有关。研究组包括10名健康正常的年轻瘦肉OH，其葡萄糖耐量正常，经口服葡萄糖耐量试验确认，另有13个对照的年龄，性别和体重指数匹配。在10小时高胰岛素正常血糖钳制期间，胰岛素作用估计为葡萄糖处置（M），葡萄糖代谢清除率（MCR）和胰岛素敏感性指数（M / I）。计算来自口服葡萄糖耐量试验的免疫反应性胰岛素值的总和。 （31）P MR光谱是在全身MR扫描仪（Siemens Vision，Erlangen，德国）上以1.5 T操作并配备有源屏蔽梯度线圈进行的。 OH和对照组之间的共同代谢和人体测量学参数没有差异，除了血压处于OH正常水平到高正常水平的范围之内。 OH的平均血压显着升高（95.73 /-4.39与83.76 /-3.95 mm Hg； P <.001）。在OH中出现胰岛素抵抗的趋势，M / I显着降低（0.74 /-0.47对1.42 /-0.65 mg x kg（-1）x min（-1）x mIU（-1）x L（-1）; P <.05）。尽管sMg与胰岛素敏感性之间呈正相关，以M（r = 0.63，P <.01），MCR（r = 0.54，P < .01）和M / I（r = 0.51，P <.05）。在两组之间没有发现磷酸肌酸（PCr），磷酸单酯，磷酸二酯，无机磷酸盐（Pi），三磷酸腺苷（Patp和betaATP）的信号强度以及计算出的细胞内离子化镁（Mgi）和H（）浓度的差异。收缩压与PCr / Patp（r = 0.43，P <.05），Pi / Patp（r = 0.413，P <.05）和Pi / betaATP（r = 0.48，P <.05）正相关。舒张压仅与Pi / betaATP比率呈正相关（r = 0.42，P <.05）。免疫反应性胰岛素值的总和与PCr / betaATP（r = 0.53，P <.01）和Pi / betaATP（r = 0.6，P <.01）相关。总之，在OH的后代中证实了血压升高和胰岛素抵抗。胰岛素敏感性与sMg有关，血压升高与骨骼肌能量代谢的激活有关。肌肉能量特性与胰岛素抵抗标志物之间的关系表明，能量代谢的改变可能在代谢综合征的早期出现。

BACKGROUND & AIMS: OBJECTIVE:We investigated the impact of two different injection strategies on the pharmacokinetics and pharmacodynamics of insulin aspart in vivo in an open-label, two-period crossover study and verified changes in the surface-to-volume ratio ex vivo. RESEARCH DESIGN AND METHODS:Before the clinical trial, insulin aspart was injected ex vivo into explanted human abdominal skin flaps. The surface-to-volume ratio of the subcutaneous insulin depot was assessed by microfocus computed tomography that compared 1 bolus of 18 IU with 9 dispersed boluses of 2 IU. These two injection strategies were then tested in vivo, in 12 C-peptide-negative type 1 diabetic patients in a euglycemic glucose clamp (glucose target 5.5 ± 1.1 mmol/L) for 8 h after the first insulin administration. RESULTS:The ex vivo experiment showed a 1.8-fold higher mean surface-to-volume ratio for the dispersed injection strategy. The maximum glucose infusion rates (GIR) were similar for the two strategies (10 ± 4 vs. 9 ± 4; P = 0.5); however, times to reach maximum GIR and 50% and 10% of the maximum GIR were significantly reduced by using the 9 × 2 IU strategy (68 ± 33 vs. 127 ± 93 min; P = 0.01; 38 ± 9 vs. 49 ± 16 min; P < 0.01; 23 ± 6 vs. 30 ± 10 min; P < 0.05). For 9 × 2 IU, the area under the GIR curve was greater during the first 60 min (219 ± 89 vs. 137 ± 75; P < 0.01) and halved until maximum GIR (242 ± 183 vs. 501 ± 396; P < 0.01); however, it was similar across the whole study period (1,361 ± 469 vs. 1,565 ± 527; P = 0.08). CONCLUSIONS:A dispersed insulin injection strategy enhanced the effect of a fast-acting insulin analog. The increased surface-to-volume ratio of the subcutaneous insulin depot can facilitate insulin absorption into the vascular system.

背景与目标： 目的：我们在开放标签，两期交叉研究中研究了两种不同的注射策略对体内门冬胰岛素的药代动力学和药效学的影响，并验证了离体表面积与体积比的变化。
研究设计和方法：在临床试验之前，将门冬胰岛素离体注射到植入的人腹部皮肤皮瓣中。皮下胰岛素贮存库的表面体积比是通过微焦点计算机断层扫描评估的，该技术比较了1推注的18 IU和9分散推注的2 IU。然后，在首次胰岛素注射后的正常血糖葡萄糖钳位（葡萄糖靶标5.5±1.1 mmol / L）中的12名C肽阴性1型糖尿病患者体内测试了这两种注射策略。
结果：离体实验显示，分散注射策略的平均表面体积比高1.8倍。两种策略的最大葡萄糖输注速率（GIR）相似（10±4 vs. 9±4； P = 0.5）；但是，通过使用9×2 IU策略，达到最大GIR以及达到最大GIR的时间分别减少了50％和10％（68±33 vs. 127±93 min； P = 0.01； 38±9 vs. 49± 16分钟； P <0.01； 23±6 vs. 30±10分钟； P <0.05）。对于9×2 IU，在最初的60分钟内GIR曲线下的面积更大（219±89对137±75; P <0.01），并且减半直到最大GIR（242±183对501±396对; P < 0.01）;但是，在整个研究期间，情况相似（1361±469对1,565±527； P = 0.08）。
结论：分散胰岛素注射策略增强了速效胰岛素类似物的作用。皮下胰岛素贮存库增加的表面积与体积之比可以促进胰岛素吸收进入血管系统。

BACKGROUND & AIMS: :Obesity, diabetes, hypertension, and hyperlipidemia constitute risk factors for morbidity and premature mortality. Based on animal and in vitro studies, resveratrol reverts these risk factors via stimulation of silent mating type information regulation 2 homolog 1 (SIRT1), but data in human subjects are scarce. The objective of this study was to examine the metabolic effects of high-dose resveratrol in obese human subjects. In a randomized, placebo-controlled, double-blinded, and parallel-group design, 24 obese but otherwise healthy men were randomly assigned to 4 weeks of resveratrol or placebo treatment. Extensive metabolic examinations including assessment of glucose turnover and insulin sensitivity (hyperinsulinemic euglycemic clamp) were performed before and after the treatment. Insulin sensitivity, the primary outcome measure, deteriorated insignificantly in both groups. Endogenous glucose production and the turnover and oxidation rates of glucose remained unchanged. Resveratrol supplementation also had no effect on blood pressure; resting energy expenditure; oxidation rates of lipid; ectopic or visceral fat content; or inflammatory and metabolic biomarkers. The lack of effect disagrees with persuasive data obtained from rodent models and raises doubt about the justification of resveratrol as a human nutritional supplement in metabolic disorders.

背景与目标： 肥胖，糖尿病，高血压和高脂血症是发病率和过早死亡的危险因素。根据动物和体外研究，白藜芦醇通过刺激无声交配类型信息调节2同源物1（SIRT1）来逆转这些危险因素，但人类受试者的数据却很少。这项研究的目的是检查高剂量白藜芦醇在肥胖人类受试者中的代谢作用。在随机，安慰剂对照，双盲和平行组设计中，将24名肥胖但其他方面健康的男性随机分配到白藜芦醇或安慰剂治疗4周。在治疗之前和之后进行了广泛的代谢检查，包括评估葡萄糖更新和胰岛素敏感性（高胰岛素正常血糖钳夹）。两组的主要结果指标胰岛素敏感性均无显着性恶化。内源性葡萄糖的产生以及葡萄糖的周转率和氧化率保持不变。补充白藜芦醇对血压也没有影响。静态能量消耗；脂质的氧化速率；异位或内脏脂肪含量；或炎症和代谢生物标志物。缺乏效果与从啮齿动物模型获得的有说服力的数据不同，并引起人们对白藜芦醇作为代谢障碍中人类营养补充剂的合理性的怀疑。

BACKGROUND & AIMS: OBJECTIVES:To determine the effects of calcium antagonists on hyperinsulinemia, hypertriglyceridemia and hypertension, we examined the long-term effects of a new calcium channel blocker, mibefradil, on plasma insulin levels, plasma triglyceride levels and systolic blood pressure in insulin-resistant and hyperinsulinemic fructose-hypertensive (FH) rats. To this aim, both prevention and reversal protocols were employed.

METHODS:Prevention study: Male Sprague-Dawley rats were procured at 6 weeks of age and were divided into: control (C, n = 6), control-treated (CT, n = 5), fructose (F, n = 7) and fructose-treated (FT, n = 6). Baseline measurements of plasma glucose, insulin and systolic blood pressure were conducted in all groups. At week 7, chronic mibefradil treatment (30 mg/kg/day, orally for 6 weeks) was initiated in the CT and FT groups. At week 8, the rats in the F and FT groups were started on a 66% fructose diet to induce hyperinsulinemia and hypertension. Weekly measurements of plasma insulin, plasma triglycerides and systolic blood pressure were conducted for the following 4 weeks. Reversal protocol: In a separate study, 8-week-treated FH rats and their age-matched controls were used to examine the effects of mibefradil on reversing fructose-induced hyperinsulinemia and hypertension.

RESULTS:The F group exhibited hyperinsulinemia (3.2 +/- 0.1 vs. C 2.3 +/- 0.07 ng/ml, P < 0.05), hypertension (148 +/- 3 vs. C 121 +/- 1 mmHg, P < 0.002) and elevated triglyceride levels (5.4 +/- 0.8 vs. C 1.6 +/- 0.3 mM, P < 0.05). Chronic mibefradil treatment prevented the development of hyperinsulinemia (1.6 +/- 0.08 ng/ml, P < 0.004 vs. F) and hypertension (123 +/- 1 mmHg. P < 0.001 vs. F) and attenuated the development of hypertriglyceridemia. In the reversal study, mibefradil treatment reversed the development of hyperinsulinemia, hypertriglyceridemia and elevated BP in FH rats. Treatment did not affect the plasma glucose levels in any group (prevention or reversal).

CONCLUSIONS:Long-term treatment with the calcium antagonist, mibefradil, both prevents and reverses the development of hyperinsulinemia, hypertriglyceridemia and hypertension in FH rats. These data indicate beneficial effects of mibefradil on carbohydrate and lipid metabolism in hyperinsulinemic and insulin-resistant states.

背景与目标： 目标：为了确定钙拮抗剂对高胰岛素血症，高甘油三酯血症和高血压的影响，我们研究了新型钙通道阻滞剂米贝拉地对血浆胰岛素水平，血浆甘油三酸酯水平和收缩期血液的长期影响胰岛素抵抗和高胰岛素果糖高血压（FH）大鼠的血压升高。为此目的，采用了预防和逆转方案。

方法：预防研究：雄性Sprague-Dawley大鼠在6周龄时采购，分为：对照组（C组） ，n = 6），对照处理（CT，n = 5），果糖（F，n = 7）和果糖处理（FT，n = 6）。在所有组中进行血浆葡萄糖，胰岛素和收缩压的基线测量。在第7周时，在CT和FT组中开始了慢性米贝地尔治疗（30 mg / kg /天，口服6周）。在第8周，F和FT组的大鼠开始以66％的果糖饮食开始，以诱导高胰岛素血症和高血压。在接下来的4周中每周进行一次血浆胰岛素，血浆甘油三酸酯和收缩压的测量。逆转方案：在一项单独的研究中，使用经过8周治疗的FH大鼠及其年龄匹配的对照，检查了米贝拉地尔对逆转果糖诱导的高胰岛素血症和高血压的作用。

结果：F组表现出高胰岛素血症（3.2 /-0.1 vs. C 2.3 /-0.07 ng / ml，P <0.05），高血压（148 /-3 vs. C 121 /-1 mmHg，P <0.002）并升高甘油三酸酯水平（5.4 /-0.8 vs. C 1.6 /-0.3 mM，P <0.05）。慢性米贝拉地尔治疗可预防高胰岛素血症（1.6 /-0.08 ng / ml，P <0.004 vs. F）和高血压（123 /-1 mmHg。P <0.001 vs. F）的发生，并减轻高甘油三酯血症的发生。在逆转研究中，米贝拉地尔治疗逆转了FH大鼠高胰岛素血症，高甘油三酸酯血症和BP升高的发展。治疗并未影响任何组的血浆葡萄糖水平（预防或逆转）。

结论：长期用钙拮抗剂米贝拉地尔治疗既能预防又能逆转糖尿病的发展。 FH大鼠的高胰岛素血症，高甘油三酸酯血症和高血压。这些数据表明米贝拉地尔在高胰岛素血症和胰岛素抵抗状态下对碳水化合物和脂质代谢的有益作用。