Pathogenesis of Ketosis Prone Diabetes

描述(由申请人提供)：酮症倾向糖尿病(KPD)是一种新出现的、广泛存在的糖尿病，其特征是表现为糖尿病酮症酸中毒(DKA)。KPD最常见的形式是一个称为“A-2+”KPD的亚群。除了初发时倾向于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的2型糖尿病患者非常相似--他们是中年、超重或肥胖的患者，代谢综合征的频率很高，并有残留的β细胞功能储备。这种新综合征的病理生理学尚不清楚。使用代谢组学方法在仔细分型的患者中与瘦和肥胖的非糖尿病对照组进行比较，我们发现临床稳定、新发的A-2+KPD患者的总脂肪酸和酰肉碱浓度较低，β-羟丁酸酯的酰肉碱标志物浓度较高，谷氨酰胺/谷氨酸浓度明显较高，同时鸟氨酸水平较高，瓜氨酸和精氨酸水平较低，通过修复进入TCA循环的氨基酸水平较低。我们假设A-2+KPD患者有较高的脂肪酸排泄率，其显著特征是通过TCA循环对酮生成的分流增加，与TCA循环中的氧化通量受损相关，并且在将氮从谷氨酰胺/谷氨酸转移到尿素循环以及将碳从谷氨酰胺/谷氨酸转移到TCA循环方面存在缺陷。总而言之，这些缺陷可能导致TCA循环受损，线粒体中的ATP生成减少，导致(肝脏中的)酮类生成增加，(在β细胞中)胰岛素分泌受损。我们建议使用稳定的同位素/质谱学方法来验证这些假说：在DKA的定义发作后8周，10名新发病的A-2+KPD男性患者接受稳定的胰岛素治疗，10名年龄、体重指数、性别和血糖匹配的新近诊断的2型糖尿病患者接受稳定的胰岛素治疗，以及10名年龄、体重指数和性别匹配的非糖尿病对照组，具体目标如下：1.测量全身总和净脂解以及脂肪氧化；2.确定乙酰辅酶A的产生、氧化及其对酮生成的利用；3.测定谷氨酰胺的全身产生率、脱酰胺为谷氨酸的速率和氨基氮向瓜氨酸的转移率。这些研究的结果可以明确一种独特形式的糖尿病的病理生理学，也可以阐明常见形式的2型糖尿病中β细胞衰竭的可能机制。公共卫生相关性：胰岛β细胞不能分泌胰岛素是2型糖尿病发展的关键，但造成胰岛细胞功能障碍的原因尚不清楚。我们描述了一种名为“A-2+酮症倾向糖尿病”的2型糖尿病患者的特征，这些患者的血液代谢产物模式指向了β细胞衰竭的独特机制。我们建议确定这些新的机制，从而阐明在2型糖尿病中β细胞如何无法分泌胰岛素。

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.