Children's Nutrition Research Center, Agricultural Research Service, U.S. Department of Agriculture, and Department of Pediatrics, Baylor College of Medicine, Houston, TX.
Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston, TX.
Diabetes. 2021 Aug;70(8):1898-1909. doi: 10.2337/db21-0066. Epub 2021 May 21.
When stable and near-normoglycemic, patients with "A-β+" ketosis-prone diabetes (KPD) manifest accelerated leucine catabolism and blunted ketone oxidation, which may underlie their proclivity to develop diabetic ketoacidosis (DKA). To understand metabolic derangements in A-β+ KPD patients during DKA, we compared serum metabolomics profiles of adults during acute hyperglycemic crises, without ( = 21) or with ( = 74) DKA, and healthy control subjects (n = 17). Based on 65 kDa GAD islet autoantibody status, C-peptide, and clinical features, 53 DKA patients were categorized as having KPD and 21 type 1 diabetes (T1D); 21 nonketotic patients were categorized as having type 2 diabetes (T2D). Patients with KPD and patients with T1D had higher counterregulatory hormones and lower insulin-to-glucagon ratio than patients with T2D and control subjects. Compared with patients withT2D and control subjects, patients with KPD and patients with T1D had lower free carnitine and higher long-chain acylcarnitines and acetylcarnitine (C2) but lower palmitoylcarnitine (C16)-to-C2 ratio; a positive relationship between C16 and C2 but negative relationship between carnitine and β-hydroxybutyrate (BOHB); higher branched-chain amino acids (BCAAs) and their ketoacids but lower ketoisocaproate (KIC)-to-Leu, ketomethylvalerate (KMV)-to-Ile, ketoisovalerate (KIV)-to-Val, isovalerylcarnitine-to-KIC+KMV, propionylcarnitine-to-KIV+KMV, KIC+KMV-to-C2, and KIC-to-BOHB ratios; and lower glutamate and 3-methylhistidine. These data suggest that during DKA, patients with KPD resemble patients with T1D in having impaired BCAA catabolism and accelerated fatty acid flux to ketones-a reversal of their distinctive BCAA metabolic defect when stable. The natural history of A-β+ KPD is marked by chronic but varying dysregulation of BCAA metabolism.
当病情稳定且接近正常血糖时，“A-β+”酮症易发性糖尿病（KPD）患者表现出加速的亮氨酸分解代谢和酮氧化减弱，这可能是他们易发生糖尿病酮症酸中毒（DKA）的基础。为了了解 DKA 期间 A-β+KPD 患者的代谢紊乱，我们比较了急性高血糖危象期间成年人的血清代谢组学谱，无（=21）或有（=74）DKA 以及健康对照组（n=17）。基于 65 kDa GAD 胰岛自身抗体状态、C 肽和临床特征，53 例 DKA 患者被归类为 KPD，21 例为 1 型糖尿病（T1D）；21 例非酮症患者被归类为 2 型糖尿病（T2D）。与 T2D 患者和对照组相比，KPD 患者和 T1D 患者的应激激素更高，胰岛素-胰高血糖素比值更低。与 T2D 患者和对照组相比，KPD 患者和 T1D 患者的游离肉碱更低，长链酰基肉碱和乙酰肉碱（C2）更高，但棕榈酰肉碱（C16）与 C2 的比值更低；C16 与 C2 呈正相关，而肉碱与 β-羟丁酸（BOHB）呈负相关；支链氨基酸（BCAA）及其酮酸更高，但酮异己酸（KIC）与亮氨酸、酮基缬氨酸（KMV）与异亮氨酸、酮基异戊酸（KIV）与缬氨酸、异戊酰肉碱与 KIC+KMV、丙酰肉碱与 KIV+KMV、KIC+KMV 与 C2 以及 KIC 与 BOHB 的比值更低；谷氨酸和 3-甲基组氨酸更低。这些数据表明，在 DKA 期间，KPD 患者与 T1D 患者相似，存在支链氨基酸分解代谢受损和脂肪酸向酮加速流动，这是其稳定时独特的支链氨基酸代谢缺陷的逆转。A-β+KPD 的自然史以慢性但不同程度的支链氨基酸代谢失调为特征。
