Pathogenesis of Ketosis Prone Diabetes

描述（由申请人提供）： 酮症倾向性糖尿病（KPD）是一种新出现的、广泛分布的糖尿病，其特征在于表现为糖尿病酮症酸中毒（DKA）。KPD最常见的形式是称为“A-2+”KPD的亚组。除了他们在最初表现时容易发生酮症和非免疫介导的严重β细胞功能障碍外，A-2+ KPD患者的临床特征与“典型”2型糖尿病患者非常相似-他们是中年人，超重或肥胖，代谢综合征的发生频率高，并且具有残余的β细胞功能储备。这种新型综合征的病理生理学尚不清楚。在仔细分型的患者中使用代谢组学方法，与瘦型和肥胖型非糖尿病对照相比，我们发现临床稳定的新发A-2+ KPD患者具有较低的总脂肪酸和酰基肉毒碱浓度，较高浓度的β-羟基丁酸酯的酰基肉毒碱标记物，以及显著较高浓度的谷氨酰胺/谷氨酸盐，以及较高的鸟氨酸，较低的瓜氨酸和精氨酸，并降低通过回补作用进入TCA循环的氨基酸水平。我们假设A-2+ KPD患者的脂肪酸处置率较高，其特征为与TCA循环中氧化通量受损相关的酮生成分流增加，以及从谷氨酰胺/谷氨酸盐向尿素循环转移氮和从谷氨酰胺/谷氨酸盐向TCA循环转移碳的缺陷。总的来说，这些缺陷可能导致TCA循环受损和线粒体中ATP生成减少，导致酮生成增加（肝脏中）和胰岛素分泌受损（β细胞中）。我们建议使用稳定同位素/质谱方案来检验这些假设，在DKA定义发作后8周接受稳定胰岛素治疗的10名新发A- 2+ KPD男性中，10名年龄、BMI、性别和血糖匹配的最近诊断为2型糖尿病的接受稳定胰岛素治疗的患者，以及10名年龄、BMI和性别匹配的非糖尿病对照者中，具体目标如下：1。测量全身总的和净的脂肪分解和脂肪氧化; 2.测定乙酰辅酶A的产生、氧化及其在生酮中的利用; 3.测定全身谷氨酰胺的生成率、谷氨酰胺脱酰胺转化为谷氨酸的速率以及谷氨酰胺氮转化为瓜氨酸的速率。这些研究的结果可以详细说明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细胞分泌胰岛素的失败对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。我们已经描述了具有称为“A-2+酮症倾向性糖尿病”的2型糖尿病的独特综合征的患者，其具有指向β细胞衰竭的独特机制的血液代谢物模式。我们建议确定这些新的机制，从而阐明β细胞在2型糖尿病中无法分泌胰岛素的原因。

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.