Thiamine as Adjunctive Therapy for Diabetic Ketoacidosis

硫胺素作为糖尿病酮症酸中毒的辅助治疗

基本信息

批准号：
9762891
负责人：
Michael William Donnino
金额：
$ 41.22万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9762891
关键词：
Acetyl Coenzyme A Acidosis Admission activity Adoption Anabolism Anemia Animal Model Beta Cell Bicarbonates Blood Glucose Blood specimen Brain C-Peptide Carrier Proteins Cell Respiration Cell physiology Cells Cerebral Edema Citric Acid Cycle Clinical Consumption Data Depressed mood Development Diabetes Mellitus Diabetic Ketoacidosis Disease Double-blind trial Enzymes Evaluation Fasting Gatekeeping Genetic Diseases Glucose Glycolysis Goals Healthcare Hospitals Hour Human Hyperglycemia Hypovolemia IV Fluid Impairment In Vitro Injury Insulin Intensive Care Intravenous Islet Cell Kidney Lactic Acidosis Lactic acid Length of Stay Life Measurement Measures Memory Disorders Metabolic stress Metabolism Modeling Mononuclear Morbidity - disease rate Nervous System Trauma Neurological outcome Nosocomial Infections Observational Study Oral Administration Oxygen Consumption Pancreas Patients Pentosephosphates Peripheral Placebos Plasma Population Prevention strategy Production Pyruvate Randomized Randomized Clinical Trials Rattus Recovery Reporting Research Residual state Resources Secondary to Serum Severities Structure of beta Cell of islet Survivors Testing Thiamine Thiamine Deficiency Time Transketolase United States Wernicke-Korsakoff Syndrome Work alpha ketoglutarate arm base cell injury diabetic diabetic patient glucose tolerance improved insulin secretion ketoglutarate dehydrogenase nervous system disorder oxidation patient subsets placebo group polypeptide C preservation primary endpoint prospective protective effect pyruvate dehydrogenase randomized trial response secondary outcome

项目摘要

Abstract Diabetic Ketoacidosis (DKA) is a potentially life-threatening disorder that may also expose patients to overt or sub-clinical morbidity. Even with optimal preventative strategies, a sub-set of patients will inevitably continue to develop DKA. Thiamine is an essential co-factor for several key enzymes of metabolism including pyruvate dehydrogenase (gatekeeper for Krebs Cycle). Insulin biosynthesis is impaired in thiamine deficiency rats and this is likely due to the decreased glucose oxidation. In addition, our preliminary data reveals that patients with moderate to severe DKA have high rates of thiamine deficiency which is associated with higher levels of acidosis. Moreover, we have found that thiamine will increase oxygen consumption in vitro for patients with DKA therefore suggesting a potential functional need regardless of plasma levels. Thiamine deficiency is well known to result in lactic acidosis secondary to impaired aerobic metabolism and is a causal component of neurological and memory disorders, specifically the Wernicke-Korsakoff Syndrome. Moreover, glucose loading has been described as a precipitant of thiamine deficiency and we have demonstrated that metabolic stress can deplete thiamine levels over time. Thus, we hypothesize that the provision of intravenous thiamine to patients with DKA will serve as adjunctive measure to more rapidly reverse acidosis and will improve cellular oxygen consumption potentially with protective effects on beta islet cells of the pancreas. To test this hypothesis, we will perform a prospective, randomized trial providing thiamine (versus placebo) for DKA. Our primary endpoint will be more rapid reversal of acidosis in the thiamine group as compared to the placebo arm. Our secondary outcomes will include determination of whether thiamine will improve cellular oxygen consumption, reduce lactic acidosis, and shorten hospital length of stay. We also include the exploratory aim of determining whether thiamine will preserve beta cell function as estimated through C-peptide measurements. The long-term goal of this line of research is to evaluate thiamine as an adjunctive therapy for DKA. Thiamine is safe, inexpensive, and easily administered – thus, if our hypothesis is proven true and future research proves efficacy, adoption of this adjunctive therapy is feasible and significant.

抽象的糖尿病性酮症酸中毒（DKA）是一种潜在的威胁生命的疾病，也可能使患者暴露于公开或次临床发病率。即使采用最佳的预防策略，一组患者也将不可避免地继续开发DKA。硫胺素是多种新陈代谢的几种关键酶（包括丙酮酸）的必不可少的共同因素脱氢酶（克雷布斯周期的守门人）。胰岛素生物合成在硫胺素缺乏大鼠和这可能是由于葡萄糖氧化下降所致。此外，我们的初步数据表明中度至重度DKA具有较高的硫胺素缺乏率，这与较高的水平有关酸中毒。此外，我们发现硫胺素会在体外增加体外的氧气消耗量因此，DKA表明，无论血浆水平如何，潜在的功能需求。硫胺素缺乏良好已知会导致继发于有氧代谢受损的乳酸酸中毒，并且是神经和记忆障碍，特别是Wernicke-Korsakoff综合征。此外，葡萄糖负荷已被描述为硫胺素缺乏的造成沉淀剂，我们证明了代谢应激可以随着时间的推移耗尽硫胺素水平。那我们假设提供静脉硫胺素的 DKA患者将作为更快逆转酸中毒的辅助测量，并将改善细胞氧气消耗可能会受到对胰腺β胰岛细胞的受保护作用的影响。测试这个假设，我们将进行一项前瞻性，随机试验，为DKA提供硫胺素（与安慰剂）。我们的与安慰剂组相比，硫胺素组酸中毒的主要终点将更快地逆转。我们的次要结果将包括确定硫胺素是否会改善细胞氧气消费，减少乳酸性酸中毒和缩短住院时间。我们还包括确定硫胺素是否会通过C肽测量估计的β细胞功能保留β细胞功能。这项研究线的长期目标是评估硫胺素作为DKA的辅助疗法。安全，便宜且容易管理 - 因此，如果我们的假设被证明是真实的和未来的研究证明效率是可行且重要的。