DETEMIR: ROLE IN TYPE 1 DIABETES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 1型糖尿病(T1 DM)的最佳治疗应以生理性胰岛素替代为主。甘精胰岛素被用作长效胰岛素(LAI)类似物。甘精在降低夜间低血糖和改善血糖控制方面优于NPH。根据制造商的说法，甘精必须与速效胰岛素(RAI)分开给药，导致不必要的多次胰岛素注射。这在儿科T1 DM中尤其成问题。在儿科患者中，甘精作用时间不到24小时。我们之前已经证明，甘精与RAI混合，每天给药两次，与单独注射RAI和甘精比较，不会对血糖漂移产生不利影响。此外，我们证明，与NPH和RAI的标准治疗相比，每日两次甘精与RAI混合服用3个月可使HbA1C改善30%。地替米尔是一种新的长效胰岛素类似物。在这项建议中，我们旨在研究地替米治疗儿童T1 DM的疗效，并将其与使用甘精的金标准进行比较。由于没有关于混合胰岛素的数据，在该方案中，地替米尔与RAI将在同一注射器中混合，并与每天两次单独注射进行比较。 1.地特米胰岛素与RAI类似物每日两次联合应用治疗儿童T1 DM的降糖效果与单独应用地特米胰岛素和RAI相当。 2.每日两次注射地替米尔或甘精时，两者中的任何一种与RAI混合使用时，血糖漂移将类似于使用地替米尔或甘精。 甘精胰岛素是第一个通过重组DNA技术生产的长效胰岛素类似物[2，3]。甘精胰岛素在健康志愿者中的早期药代动力学(PK)研究报告了长达30小时的作用时间[4]。然而，持续时间显著缩短，正常血糖钳夹研究的平均血糖水平在给予甘精后16小时上升，整个研究人群的平均作用时间为20.5小时[5]。儿科人群中可用的PK数据有限，临床实践表明，在一些T1 DM患者中，甘精胰岛素持续的时间要短得多[6]。 尽管强化胰岛素治疗有好处，但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NPH作为基础注射的标准疗法相比，维持正常血糖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会有一些PK变化，但可能不会显着影响药效学(PD)。为了证明这一点，我们招募了每天服用一次甘精胰岛素的受试者，并使用连续血糖监测系统(CGMS)获得了3天的血糖曲线。然后，受试者被随机分为两组，一组每天接受两次甘精胰岛素与RAI类似物的混合，另一组每天两次单独给予RAI类似物。在每个治疗计划后都得到CGMS，当甘精胰岛素与RAI混合给药或单独给药时，血糖浓度没有检测到差异[8]。然而，混合疗法对血糖控制的长期效果无法评估，因为受试者只接受了10天的治疗。 在目前正在进行的试验2中，正在研究将甘精胰岛素与RAI混合，每天两次给药，并将其效果与一天两次的NPH进行比较的长期血糖效应(见初步数据)。招募新发的T1 DM患者，在3个月时随机接受NPH和RAI混合给药，每天两次给药，与甘精胰岛素和RAI混合给药，每天两次。在3个月结束时，我们发现每天服用两次甘精的受试者的糖化血红蛋白(HbA1c)显著高于服用非精氨酸组(P&lt；0.03)(NPH与甘精7.5%VS 6.3%)。这些研究表明，当甘精胰岛素与RAI(与赛诺菲-安万特讨论)混合时，一些PK变化可能没有临床意义。此外，混合胰岛素的能力导致注射更少，这增加了所有T1 DM受试者的依从性，但对患有T1 DM的儿童产生了巨大的差异。

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.