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

• 批准号: 10429977
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10429977
• 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; Injury to Kidney; Insulin; Intensive Care; Intravenous; Islet Cell; 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; Persons; 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; preservation; primary endpoint; prospective; protective effect; pyruvate dehydrogenase; randomized trial; response; secondary outcome

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.

摘要 糖尿病酮症酸中毒（DKA）是一种潜在的危及生命的疾病，也可能使患者暴露于明显或 亚临床发病率。即使有最佳的预防策略，一个子集的患者将不可避免地继续 发展DKA。硫胺素是代谢的几个关键酶，包括丙酮酸， 脱氢酶（Krebs循环的看门人）。硫胺素缺乏大鼠胰岛素生物合成受损， 这可能是由于葡萄糖氧化减少。此外，我们的初步数据显示， 中度至重度DKA有较高的硫胺素缺乏率，这与较高水平的 酸中毒此外，我们已经发现硫胺素会增加体外氧消耗的患者， 因此，无论血浆水平如何，DKA均提示潜在的功能需求。硫胺素缺乏症 已知导致继发于有氧代谢受损的乳酸酸中毒，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沉淀剂，我们已经证明，代谢应激， 会随着时间的推移耗尽硫胺素的含量因此，我们假设，静脉注射硫胺素， DKA患者将作为更快速逆转酸中毒的预防措施， 氧消耗可能对胰腺的β胰岛细胞具有保护作用。为了验证这一 假设，我们将进行一项前瞻性随机试验，提供硫胺素（与安慰剂）治疗DKA。我们 与安慰剂组相比，硫胺素组的主要终点是酸中毒的更快逆转。 我们的次要结果将包括确定硫胺素是否会改善细胞氧 消耗，减少乳酸酸中毒，缩短住院时间。我们还包括探索性的目标， 确定硫胺素是否会保留通过C肽测量估计的β细胞功能。 这一系列研究的长期目标是评估硫胺素作为DKA的辅助治疗方法。硫胺素 是安全的，廉价的，易于管理-因此，如果我们的假设被证明是正确的，未来的研究 疗效确切，采用该疗法是可行的，有意义的。