Pathogenesis of Ketosis Prone Diabetes

描述（由申请人提供）：酮症易感性糖尿病（KPD）是一种新兴的、广泛存在的糖尿病形式，其特征是糖尿病酮症酸中毒（DKA）。最常见的KPD形式是称为“a -2+”KPD的亚组。a -2+ KPD患者除了在最初表现时容易出现酮症和非免疫介导的严重β细胞功能障碍外，其临床特征与“典型”2型糖尿病患者非常相似——中年、超重或肥胖、代谢综合征发生率高、β细胞功能储备残留。这种新型综合征的病理生理机制尚不清楚。与瘦和肥胖的非糖尿病对照组相比，我们使用代谢组学方法对仔细表型的患者进行了研究，发现临床稳定的新发病a- 2+ KPD患者总脂肪酸和酰基肉碱浓度较低，酰基肉碱标记物β -羟基丁酸浓度较高，谷氨酰胺/谷氨酸浓度明显较高，鸟氨酸含量较高，瓜氨酸和精氨酸含量较低。并降低了通过过敏症进入TCA循环的氨基酸水平。我们假设a -2+ KPD患者具有较高的脂肪酸处理率，其特征是与TCA循环氧化通量受损相关的酮生成分流增加，并且在将氮从谷氨酰胺/谷氨酸转移到尿素循环和将碳从谷氨酰胺/谷氨酸转移到TCA循环方面存在缺陷。总的来说，这些缺陷可能导致线粒体中TCA循环受损和ATP生成减少，导致（肝脏中）生酮增加和（β细胞中）胰岛素分泌受损。我们建议使用稳定同位素/质谱方案来验证这些假设，在10例新发A- 2+ KPD患者中，在DKA确定发作8周后接受稳定胰岛素治疗，10例年龄、BMI、性别和血糖匹配，最近诊断为2型糖尿病患者接受稳定胰岛素治疗，10例年龄、BMI和性别匹配的非糖尿病对照组中，进行以下研究：测定全身总脂解和净脂解及脂肪氧化；2. 测定乙酰辅酶a的生成、氧化及其在生酮中的利用3. 测定谷氨酰胺的全身生产速率，谷氨酸脱酰胺和谷氨酸氮向瓜氨酸转移的速率。这些研究结果可以明确一种独特形式的糖尿病的病理生理学，也揭示了常见形式的2型糖尿病中β细胞衰竭的可能机制。公共卫生相关性：胰腺β细胞分泌胰岛素的功能障碍对2型糖尿病的发展至关重要，但β细胞功能障碍的原因尚不清楚。我们描述了一种被称为“a -2+酮症易感性糖尿病”的2型糖尿病患者的特征，他们的血液代谢物模式表明了独特的β细胞衰竭机制。我们建议确定这些新机制，从而阐明β细胞在2型糖尿病中如何不能分泌胰岛素。

DESCRIPTION (provided by applicant): Ketosis-prone Diabetes (KPD) is an emerging, widespread form of diabetes characterized by presentation with diabetic ketoacidosis (DKA). The most common form of KPD is a subgroup termed "A-2+" KPD. Apart from their proneness to ketosis and non-immune mediated, severe beta cell dysfunction at the time of initial presentation, the clinical features of A-2+ KPD patients are very similar to those of "typical" patients with type 2 diabetes - they are middle-aged, overweight or obese, have a high frequency of metabolic syndrome, and have residual beta cell functional reserve. The pathophysiology of this novel syndrome is unknown. Using a metabolomic approach in carefully phenotyped patients compared to lean and obese non-diabetic controls, we have found that clinically stable, new onset A-2+ KPD patients have lower concentrations of total fatty acids and acyl carnitines, higher concentrations of an acyl carnitine marker of beta-hydroxybutyrate, and markedly higher concentrations of glutamine / glutamate, together with higher ornithine, lower citrulline and arginine, and depressed levels of amino acids that enter the TCA cycle via anaplerosis. We hypothesize that A-2+ KPD patients have a high rate of disposal of fatty acids, marked by an increased shunt towards ketogenesis associated with impaired oxidative flux through the TCA cycle, and defects in transfering nitrogen from glutamine / glutamate to the urea cycle and carbon from glutamine / glutamate to the TCA cycle. Collectively, these defects could result in impaired TCA cycling and decreased ATP generation in mitochondria, leading to increased ketogenesis (in the liver) and impaired insulin secretion (in beta cells). We propose to test these hypotheses using stable isotope / mass spectrometric protocols by carrying out, in 10 men with new onset A- 2+ KPD on stable insulin therapy 8 weeks after the defining episode of DKA, 10 age-, BMI-, gender- and glycemia-matched, recently diagnosed type 2 diabetic patients on stable insulin therapy, and 10 age-, BMI- and gender-matched non-diabetic controls, the following Specific Aims: 1. Measure whole body total and net lipolysis and fat oxidation; 2. Determine acetyl CoA production, oxidation and its utilization for ketogenesis; 3. Determine whole body rate of production of glutamine, its deamidation to glutamate and rate of transfer of its amide nitrogen to citrulline. The results of these investigations could specify the pathophysiology of a unique form of diabetes, and also shed light on possible mechanisms of beta cell failure in common forms of type 2 diabetes. PUBLIC HEALTH RELEVANCE: Failure of the pancreatic beta cell to secrete insulin is critical to the development of type 2 diabetes, but the causes of beta cell dysfunction are unknown. We have characterized patients with a distinct syndrome of type 2 diabetes termed "A-2+ Ketosis-prone Diabetes", who have patterns of blood metabolites that point to unique mechanisms of beta cell failure. We propose to identify these novel mechanisms, and thereby shed light on how the beta cell fails to secrete insulin in type 2 diabetes.