BACKGROUND & AIMS: The effect of nutritional status on IGF-I mRNA expression in the liver and brain of juvenile barramundi (Lates calcarifer) was investigated. Fish were either fed a satiety ration (SAT) or starved (STV) for 6 weeks. Starved fish demonstrated significantly lower condition factor and hepatic IGF-I mRNA expression at 3 and 6 weeks, when compared with the SAT group. IGF-I mRNA expression in the brain was 10 fold lower than the liver and was not affected by ration size. These results suggest the liver is the major site of IGF-I mRNA synthesis and hepatic but not brain IGF-I mRNA expression is regulated by food availability in juvenile barramundi.

背景与目标： 研究了营养状况对少年肺鱼（Lates calcarifer）肝脏和脑中IGF-I mRNA表达的影响。给鱼喂饱口粮（SAT）或饿死（STV）6周。与SAT组相比，在3周和6周时，饥饿的鱼表现出明显较低的条件因子和肝脏IGF-I mRNA表达。脑中IGF-I mRNA表达比肝脏低10倍，并且不受口粮大小的影响。这些结果表明，肝脏是IGF-I mRNA合成的主要部位，肝而不是脑IGF-I mRNA的表达受幼鱼的食物供应量的调节。

BACKGROUND & AIMS: INTRODUCTION:Frequent use of modern imaging methods (such as ultrasound, CT and MRI) results in high incidence of accidentally discovered adrenal mass. Adrenal incidentalomas are accidentally discovered adrenal tumors by imaging methods without any prior suspicion of adrenal disease. Some studies have shown decreased insulin sensitivity in patients with adrenal incidentaloma. OBJECTIVE:The objective of our study was to assess the insulin sensitivity in patients with adrenal incidentalom a. METHOD:A total of 22 patients with accidentally discovered adrenal mass confirmed by CT/MRI were evaluated in our study. Average age was 53.31 +/- 26.5 years and average BMI 25.84 +/- 3.65 kg/m2. Control group consisted of 33 healthy subjects. Insulin sensitivity was assessed by short ITT (insulin tolerance test). Blood samples were taken before, 3, 6, 9, 12, 15, 20 and 30 minutes after i.v. bolus of regular insulin (0.05 IU/kg BW). Glycemia was determined by glucose oxidase method. Statistical analysis was done by ANCOVA, using BMI as covariate. RESULTS:Our results showed significantly lower insulin sensitivity in patients with adrenal incidentalomas comparing to the control group (4.95 +/- 0.58 vs. 6.62 +/- 0.47, p=0.015). CONCLUSION:Our patients with adrenal incidentalomas manifested lower insulin sensitivity what suggested further follow up and assessment of insulin sensitivity during endocrine evaluation of these patients.

背景与目标： 简介：频繁使用现代成像方法（例如超声，CT和MRI）会导致意外发现的肾上腺肿块的发生率很高。肾上腺偶发瘤是通过影像学方法意外发现的肾上腺肿瘤，而没有任何先前怀疑的肾上腺疾病。一些研究表明，肾上腺偶发瘤患者的胰岛素敏感性降低。
目的：本研究的目的是评估肾上腺偶然性a患者的胰岛素敏感性。
方法：本研究共评估22例经CT / MRI确诊的意外发现肾上腺肿块的患者。平均年龄为53.31 /-26.5岁，平均BMI为25.84 /-3.65 kg / m2。对照组由33名健康受试者组成。胰岛素敏感性通过短期ITT（胰岛素耐受性测试）进行评估。在静脉内注射之前，3、6、9、12、15、20和30分钟之前采集血样。大剂量普通胰岛素（0.05 IU / kg体重）。血糖测定采用葡萄糖氧化酶法。由ANCOVA使用BMI作为协变量进行统计分析。
结果：我们的结果显示，肾上腺偶发瘤患者的胰岛素敏感性明显低于对照组（4.95 /-0.58 vs. 6.62 /-0.47，p = 0.015）。
结论：我们的肾上腺偶发瘤患者表现出较低的胰岛素敏感性，这提示对这些患者进行内分泌评估时需要进一步随访和评估胰岛素敏感性。

BACKGROUND & AIMS: :The extracellular calcium-sensing receptor (CaR) is usually associated with systemic Ca(2+) homeostasis, but the CaR is also expressed in many other tissues, including pancreatic islets of Langerhans. In the present study, we have used human islets and an insulin-secreting cell line (MIN6) to investigate the effects of CaR activation using the calcimimetic R-568, a CaR agonist that activates the CaR at physiological concentrations of extracellular Ca(2+). CaR activation initiated a marked but transient insulin secretory response from both human islets and MIN6 cells at a sub-stimulatory concentration of glucose, and further enhanced glucose-induced insulin secretion. CaR-induced insulin secretion was reduced by inhibitors of phospholipase C or calcium-calmodulin-dependent kinases, but not by a protein kinase C inhibitor. CaR activation was also associated with an activation of p42/44 mitogen-activated protein kinases (MAPK), and CaR-induced insulin secretion was reduced by an inhibitor of p42/44 MAPK activation. We suggest that the beta-cell CaR is activated by divalent cations co-released with insulin, and that this may be an important mechanism of intra-islet communication between beta-cells.

背景与目标： ：细胞外钙敏感受体（CaR）通常与全身性Ca（2）稳态相关，但该CaR在许多其他组织中也表达，包括Langerhans的胰岛。在本研究中，我们已经使用人类胰岛和胰岛素分泌细胞系（MIN6）来研究使用拟钙剂R-568（CaR激动剂在生理浓度的细胞外Ca（2）激活CaR的CaR激活）的作用。 。 CaR激活在葡萄糖的亚刺激浓度下启动了来自人胰岛和MIN6细胞的显着但短暂的胰岛素分泌反应，并进一步增强了葡萄糖诱导的胰岛素分泌。 CaR诱导的胰岛素分泌通过磷脂酶C或钙钙调蛋白依赖性激酶的抑制剂降低，但不通过蛋白激酶C抑制剂降低。 CaR激活还与p42 / 44丝裂原激活的蛋白激酶（MAPK）激活相关，并且CaR诱导的胰岛素分泌被p42 / 44 MAPK激活的抑制剂减少。我们建议β细胞CaR被与胰岛素共释放的二价阳离子激活，这可能是β细胞之间胰岛内通讯的重要机制。

BACKGROUND & AIMS: :We present the case of an 80-year-old lady known to be sensitive to chlorocresol (4-chloro-3-methyl phenol) who developed severe erythrodermic exfoliative dermatitis with atypical features 2 weeks after commencing subcutaneous insulin. All medications except insulin were stopped, without major improvement. It was noted that the insulin contained m-cresol (m-methyl phenol) so a parabens-based insulin was substituted. There was a significant improvement in her clinical condition within 72 hr. Further patch and intradermal testing to the insulin and m-cresol was planned, but she developed a nosocomial infection and died. We hypothesize that the adverse cutaneous reaction was a systemic manifestation of cresol sensitivity, given the rapid clinical resolution on changing insulins and the previously demonstrated sensitivity to chlorocresol, particularly as cross-reactivity between different low molecular weight methyl phenols is documented. Local injection site reactions and systemic side-effects including nausea, diarrhoea and vomiting have previously been reported with cresol-containing insulins, although to our knowledge, this is the first reported case of a severe cutaneous reaction. It is important to be aware of m-cresol as a potential allergen, as it is contained in most commercially available insulins.

背景与目标： ：我们介绍了一位80岁的女士，她对氯甲酚（4-氯-3-甲基苯酚）敏感，在开始皮下注射胰岛素2周后发展出严重的非典型性红皮病性剥脱性皮炎。除胰岛素外，所有药物均已停止使用，无明显改善。注意到胰岛素包含间甲酚（间甲基苯酚），因此取代了基于对羟基苯甲酸酯的胰岛素。她的临床状况在72小时内有了显着改善。计划对胰岛素和间甲酚进行进一步的贴片和皮内测试，但她发生了医院感染并死亡。我们假设不利的皮肤反应是对甲酚敏感性的全身表现，考虑到快速变化的胰岛素临床解决方案和先前证明的对氯甲酚的敏感性，特别是由于记录了不同低分子量甲基酚之间的交叉反应性。含甲酚的胰岛素以前曾报道过局部注射部位反应和全身副作用，包括恶心，腹泻和呕吐，尽管据我们所知，这是首次报道的严重皮肤反应病例。重要的是要意识到间甲酚是一种潜在的过敏原，因为它包含在大多数市售胰岛素中。

BACKGROUND & AIMS: :Chondrogenesis occurs in vivo in a hypoxic environment, in which the hypoxia inducible factor 1, HIF-1, plays a regulatory role, possibly mediated through the transcription factor DEC1. We have analyzed the effect of hypoxia (1% oxygen) alone and in combination with insulin on the chondrogenic differentiation of the mouse embryonic stem cell line ATDC5. Hypoxic treatment alone induced early chondrogenesis as evidenced by enhanced expression of aggrecan and collagen II, whereas hypoxic incubation of insulin-treated cells delayed and suppressed insulin-mediated early chondrogenesis and almost completely blocked hypertrophic differentiation. Paradoxically, the transcriptional activation of DEC1 was invariably enhanced by the hypoxic exposure.

背景与目标： ：软骨形成发生在体内低氧环境中，在该环境中，缺氧诱导因子1（HIF-1）发挥调节作用，可能是通过转录因子DEC1介导的。我们已经分析了单独和与胰岛素联合使用低氧（1％氧气）对小鼠胚胎干细胞系ATDC5软骨分化的影响。单用低氧治疗可诱导早期软骨形成，聚集蛋白聚糖和胶原II的表达增强证明了这一点，而对胰岛素处理的细胞进行低氧培养可延迟并抑制胰岛素介导的早期软骨形成，并且几乎完全阻断了肥大细胞的分化。矛盾的是，低氧暴露总是增强了DEC1的转录激活。

BACKGROUND & AIMS: :In the last few years, our knowledge of genetically determined causes of short stature has greatly increased by reports of challenging patients, who offered the opportunity to study genes that play a role in growth. Since the first paper that showed the etiology of Laron syndrome [Godowski PJ, et al: Proc Natl Acad Sci USA 1989;86:8083-8087], many mutations in the growth hormone (GH) receptor have been identified. Recently, new mutations or deletions have been found in several components of the GH-insulin-like growth factor-I (IGF-I) axis: a homozygous mutation of the GH1 gene, resulting in a bio-inactive GH; mutations in the STAT5b gene, which plays a major role in the GH signal transduction; a homozygous missense mutation in the IGF-I gene; heterozygous mutations in the IGF-I receptor gene and a homozygous deletion of the acid-labile subunit gene. In this mini review, we describe the clinical and biochemical features of these genetic defects. Genetic analysis has become essential in the diagnostic workup of a patient with short stature. However, regarding the time consuming nature of molecular analysis, it is important to carefully select the patient for specific genetic evaluation. To help in this selection process, we developed flowcharts, based on the recently described patients, that can be used as guidelines in the diagnostic process of patients with severe short stature of unknown origin.

背景与目标： ：在过去的几年中，由于对挑战性患者的报道，我们对遗传决定的矮小身高原因的了解大大增加了，这些患者为研究在生长中起作用的基因提供了机会。自从第一篇显示Laron综合征病因的论文[Godowski PJ等人：Proc Natl Acad Sci USA 1989; 86：8083-8087]以来，已经确定了生长激素（GH）受体的许多突变。最近，在GH-胰岛素样生长因子-I（IGF-I）轴的几个组成部分中发现了新的突变或缺失：GH1基因的纯合突变，导致了生物失活的GH； STAT5b基因的突变，在GH信号转导中起主要作用； IGF-I基因的纯合错义突变； IGF-1受体基因中的杂合突变和对酸不稳定的亚基基因的纯合缺失。在这个小型综述中，我们描述了这些遗传缺陷的临床和生化特征。遗传分析已成为身材矮小的患者的诊断检查中必不可少的。但是，考虑到分子分析的耗时性质，重要的是要仔细选择患者进行特定的基因评估。为了帮助选择过程，我们根据最近描述的患者制定了流程图，可以将其用作诊断患有严重身材矮小，来源不明的患者的诊断过程中的指导原则。

BACKGROUND & AIMS: CONTEXT:Concern has been raised about the safety of assisted reproduction techniques for the offspring. OBJECTIVES:The objective of the study was to investigate postnatal growth and growth factors in children born after intra-cytoplasmatic sperm injection (ICSI) and in vitro fertilization (IVF). DESIGN:The study had two cohorts: a population-based longitudinal infant cohort 0-36 months [236 ICSI, 173 IVF, 1530 naturally conceived (NC)], and a cross-sectional child cohort at 5 yr (68 ICSI, 67 IVF, 70 NC). INTERVENTION:Anthropometrical measurements were made at birth, 3, 18, 36 (infant cohort), and 60 months (child cohort), and blood samples were collected at 3 or 60 months. MAIN OUTCOME MEASURES:Serum IGF-I, IGFBP-3, height, weight, head and abdominal circumference, body mass index, and fat folds were the main outcome measures. RESULTS:Anthropometrical measurements showed no significant differences between ICSI and IVF children and controls in either cohort. However, singleton ICSI girls [3.4 (0.6) kg, P = 0.008] had a slightly lower birth weight than IVF [3.5 (0.5) kg] and NC girls [3.5 (0.5) kg]. Birth weights of singleton boys [3.6 (0.5) kg], twin boys [2.6 (0.6) kg], and twin girls [2.4 (0.5) kg] did not differ between types of conception. In the infant cohort in 3-month-old singletons, serum IGF-I was lower in ICSI [78 (26) ng/ml] than NC boys [94 (27) ng/ml, P < 0.001] and IVF [74 (34) ng/ml], compared with NC girls [93 (43) ng/ml, P = 0.011]. ICSI children were also smaller than their target height (sd score) at 3 yr of age [mean -0.91 (1.2)], compared with NC children [-0.61 (0.9), P = 0.033]. In the child cohort, target height attainment (sd score) and growth factors did not differ among the three groups. CONCLUSIONS:The overall growth pattern of ICSI and IVF children in both cohorts was normal. Our findings of subtle differences in target height attainment and serum IGF-I levels between infants born after assisted reproduction techniques and controls may not be clinically significant. However, these observations indicate that further systematic follow-up of growth and puberty in these children is needed.

背景与目标： 背景：人们对后代辅助生殖技术的安全性表示关注。
目的：本研究的目的是调查胞浆内精子注射（ICSI）和体外受精（IVF）后出生的儿童的出生后生长和生长因子。
设计：该研究有两个队列：基于人群的纵向婴儿队列0-36个月[236 ICSI，173 IVF，1530自然受孕（NC）]和5岁时的横断面儿童队列（68 ICSI，67 IVF ，70 NC）。
干预措施：分别在出生时，3、18、36（婴儿队列）和60个月（儿童队列）进行人体测量，并在3或60个月时采集血样。
主要观察指标：血清IGF-I，IGFBP-3，身高，体重，头围和腹围，体重指数和脂肪褶皱是主要的观察指标。
结果：人体测量结果显示，ICSI和IVF儿童与对照组之间均无显着差异。但是，单身ICSI女孩[3.4（0.6）千克，P = 0.008]的出生体重略低于IVF [3.5（0.5）千克]和NC女孩[3.5（0.5）千克]。单胎男孩[3.6（0.5）千克]，双胞胎男孩[2.6（0.6）千克]和双胞胎女孩[2.4（0.5）千克]的出生体重在不同的受孕类型之间没有差异。在3个月大的单胎婴儿队列中，ICSI的血清IGF-I低于NC男孩[94（27）ng / ml，P <0.001]和IVF [74（ 34）ng / ml]，而NC女生则为[93（43）ng / ml，P = 0.011]。与3岁儿童相比，ICSI儿童在3岁时也小于其目标身高（sd评分）[平均-0.91（1.2）]，而NC儿童则为[-0.61（0.9），P = 0.033]。在儿童队列中，三组之间的目标身高获得（sd得分）和生长因子没有差异。
结论：两组人群ICSI和IVF儿童的总体生长方式均正常。我们在辅助生殖技术和对照后出生的婴儿之间的目标身高获得和血清IGF-I水平细微差异的发现可能在临床上并不重要。但是，这些观察结果表明，需要对这些儿童的生长和青春期进行进一步的系统随访。

BACKGROUND & AIMS: :The biological actions of the insulin-like growth factors, IGF-I and IGF-II, are mediated by the ligand-induced activation of the IGF-I receptor (IGF-IR), a transmembrane heterotetramer linked to the ras-raf-mitogen-activated protein kinase (MAPK) and phosphatidyl inositol 3 kinase (PI3K)-protein kinase B (PKB)/Akt signal transduction cascades. The Wilms' tumor suppressor gene (wt1) encodes a zinc finger transcription factor, WT1, which has been implicated in various cellular processes including proliferation, differentiation and apoptosis. In the present study we demonstrated that IGF-I modulates the WT1 gene expression in neurally derived PC12 cells in a dose- and time-dependent manner. This effect was mediated through both the MAPK and PI3-kinase signaling pathways, as shown by the ability of the specific inhibitors UO126 and LY294002 to abrogate IGF-I action. Moreover, using RT-PCR and transient transfection assays, we demonstrated that the IGF-I effect was associated with corresponding changes in WT1 mRNA levels and WT1 promoter activity. In addition, the results of the present study revealed that high WT1 levels were associated with the induction of apoptosis, whereas low WT1 levels were correlated with the inhibition of apoptosis, as demonstrated by poly ADP ribose polymerase (PARP) cleavage, Bax expression, Annexin V-FITC staining, and by the use of antisense oligonucleotides against WT1. In summary, our results show that the wt1 gene is a novel target for IGF-I action in neurally derived cells.

背景与目标： 胰岛素样生长因子IGF-I和IGF-II的生物学作用是由配体诱导的IGF-I受体（IGF-IR）活化而介导的，IGF-IR受体是与ras-raf-连接的跨膜异四聚体丝裂原活化蛋白激酶（MAPK）和磷脂酰肌醇3激酶（PI3K）-蛋白激酶B（PKB）/ Akt信号转导级联反应。威尔姆斯的肿瘤抑制基因（wt1）编码锌指转录因子WT1，该因子已参与多种细胞过程，包括增殖，分化和凋亡。在本研究中，我们证明了IGF-1以剂量和时间依赖性的方式调节神经源性PC12细胞中WT1基因的表达。这种作用是通过MAPK和PI3激酶信号传导途径介导的，如特异性抑制剂UO126和LY294002消除IGF-I作用的能力所示。此外，使用RT-PCR和瞬时转染试验，我们证明了IGF-I的作用与WT1 mRNA水平和WT1启动子活性的相应变化有关。此外，本研究结果表明，高WT1水平与凋亡诱导相关，而低WT1水平与凋亡抑制相关，如聚ADP核糖聚合酶（PARP）裂解，Bax表达，膜联蛋白所证明的。 V-FITC染色，并使用针对WT1的反义寡核苷酸。总而言之，我们的结果表明wt1基因是神经衍生细胞中IGF-I作用的新靶标。

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。