DETEMIR: ROLE IN TYPE 1 DIABETES

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 1型糖尿病（T1 DM）的最佳治疗应侧重于生理性胰岛素替代。甘精胰岛素用作长效胰岛素（LAI）类似物。甘精胰岛素在减少夜间低血糖和改善血糖控制方面优于NPH，但其效果上级。根据生产商的要求，甘精胰岛素必须与速效胰岛素（RAI）分开给药，导致不希望的多次胰岛素注射。这在儿童T1 DM中尤其成问题。在儿科患者中，甘精胰岛素的作用小于24小时。我们之前已经证明，与单独注射RAI和甘精胰岛素相比，将甘精胰岛素与RAI混合并每日两次给药不会对葡萄糖波动产生不良影响。此外，我们证明，与NPH和RAI标准治疗相比，每日两次甘精胰岛素与RAI混合治疗3个月可使HbA 1C改善30%。地特胰岛素是一种新型长效胰岛素类似物。在本提案中，我们旨在研究地特米在儿童T1 DM中的疗效，并将其与使用甘精胰岛素的金标准进行比较。由于没有关于混合胰岛素的数据，在本方案中，地特胰岛素将与RAI在同一注射器中混合，并与每日两次单独注射进行比较。 1.在儿童T1 DM治疗中，地特胰岛素与RAI类似物每日两次混合给药与地特胰岛素和RAI每日两次单独注射给药相比，对降低血糖的作用相当。 2.当地特或甘精胰岛素与RAI混合作为每日两次注射剂给药时，使用地特或甘精胰岛素的血糖波动相似。 甘精胰岛素是第一种通过重组DNA技术生产的长效胰岛素类似物[2，3]。在健康志愿者中进行的甘精胰岛素早期药代动力学（PK）研究报告，作用持续时间长达30小时[4]。然而，持续时间显著较短，在正常血糖钳夹研究中，甘精胰岛素给药后16小时平均血糖水平升高，整个研究人群的平均作用持续时间为20.5小时[5]。儿科人群中的PK数据有限，临床实践表明，甘精胰岛素在某些T1 DM患者中的持续时间要短得多[6]。 尽管强化胰岛素管理的好处，长效类似物的使用与依从性差[7]和坚持治疗计划有关。这是由于与作为基础注射的NPH标准治疗相比，维持正常所需的注射次数增加。为了克服这一障碍，我们假设，尽管甘精胰岛素与短效类似物混合时可能存在一些pK变化，但可能不会显著影响药效学（pD）特征。为了证明这一点，我们招募了每天接受一次甘精胰岛素治疗的受试者，并使用连续葡萄糖监测系统（CGMS）获得3天的葡萄糖曲线。然后将受试者随机分配接受甘精胰岛素与RAI类似物混合，每日两次，或甘精胰岛素与RAI类似物分开，每日两次。在这些治疗计划后获得CGMS，当甘精胰岛素与RAI混合或单独给药时，未检测到葡萄糖浓度差异[8]。然而，由于受试者仅接受该方案10天，因此无法评价混合对血糖控制的长期影响。 在目前正在进行的试验2中，正在检查甘精胰岛素与RAI混合并每日两次给药的长期血糖效应，并将其效应与每日两次NPH进行比较（见初步数据）。招募新发T1 DM受试者，并在3个月时随机分配至接受NPH和RAI混合并每日两次给药方案与甘精胰岛素和RAI混合并每日两次给药方案。在3个月结束时，我们发现，与NPH组相比，每日两次甘精胰岛素与甘精胰岛素混合的受试者的血红蛋白A1 c（HbA 1c）（NPH vs.甘精胰岛素7.5% Vs 6.3%）显著更好（p<0.03）。这些研究表明，甘精胰岛素与RAI混合时的某些pK变化（与Sanofi-Aventis讨论）可能不具有临床意义。此外，混合胰岛素的能力导致更少的注射，这增加了所有T1 DM受试者的依从性，但在T1 DM儿童中产生了巨大的差异。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Optimal treatment of type 1 diabetes mellitus (T1DM) should focus on physiologic insulin replacement. Insulin glargine is used as a long acting insulin (LAI) analog. Glargine is superior to NPH in decreasing nocturnal hypoglycemia and improving glycemic control. Glargine, as per manufacturer, must be given separate from rapid acting insulin (RAI), resulting in undesired multiple insulin injections. This is especially problematic in pediatric T1DM. In pediatric patients, glargine action is less than 24 hrs. We have previously demonstrated that mixing glargine with RAI, and given twice daily compared to separately given injections of RAI and glargine does not adversely affect glucose excursions. Furthermore, we demonstrated that 3 months of twice-daily glargine mixed with RAI results in a 30% improvement in HbA1C as compared to standard therapy of NPH and RAI. Detemir is a new long-acting insulin analog. In this proposal, we aim to study the efficacy of detemir in pediatric T1DM, and compare it to the gold standard of using glargine. Since there is no data regarding mixing insulin, in this protocol, detemir will be mixed with RAI in the same syringe, and be compared with giving them as separate injections twice-daily. 1. Insulin detemir mixed with RAI analog given twice daily will have equivalent effects on lowering blood glucose vs. giving insulin detemir and RAI as separate injections twice daily, in the treatment of pediatric T1DM. 2. Glucose excursions will be similar with the use of either detemir or glargine when either of the two is given mixed with RAI as a twice-daily injection. Insulin glargine was the first long-acting insulin analog to be produced by recombinant DNA technology [2,3]. Early pharmacokinetic (pK) studies with insulin glargine in healthy volunteers reported a duration of action of up to 30 h [4]. However, the duration was significantly shorter with mean plasma glucose levels in euglycemic clamp studies rising 16 h after glargine administration with the mean duration of action for the entire study population being 20.5 h [5]. There are limited pK data available in the pediatric population and clinical practice suggests that glargine lasts for a much shorter period of time in some patients with T1DM [6]. Despite the benefits of intensive insulin management, the use of long-acting analogs is associated with poor compliance [7] and adherence to treatment plans. This is due to the increased number of injections that are required to maintain euglycemia as compared to standard therapy of NPH as a basal injection. To overcome this obstacle we hypothesized that although there may be some pK variation when insulin glargine is mixed with short acting analogs it may not affect pharmacodynamic (pD) profile significantly. To prove this, we recruited subjects who were on once a day insulin glargine and used continuous glucose monitoring system (CGMS) to obtain 3 days glucose profiles. Subjects were then randomized to either receiving insulin glargine twice a day mixed with RAI analogs or insulin glargine given twice a day separate from the RAI analogs. CGMS was obtained after each of these treatment plans and no difference in glucose concentrations were detected when insulin glargine was given mixed or given separately from the RAI [8]. However, the long-term effects of mixing on glycemic control could not be evaluated because subjects were on this regimen for only 10 days. In trial 2, currently in progress, long-term glycemic effects of mixing insulin glargine with RAI and administering it as a twice-daily dose and comparing its effect to twice-a-day NPH is being examined (See preliminary data). New onset T1DM subjects were recruited and at 3 months were randomized to either receiving NPH and RAI mixed and given as a twice a day regimen vs. insulin glargine and RAI mixed and given as a twice a day regimen. At the end of 3 months, we found that subjects on twice daily glargine mixed with had a significantly better hemoglobin A1c (HbA1c) (NPH vs. glargine 7.5% Vs 6.3%) as compared to the NPH arm (p<0.03). These studies suggest that some pK variation when insulin glargine is mixed with RAI (discussions with Sanofi-Aventis) may not be of clinical significance. Furthermore, the ability to mix insulins results in fewer injections, which increases compliance in all T1DM subjects but makes an immense difference in children with T1DM.