Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
AstraZeneca R&D, Mölndal, Sweden; Department of Endocrinology, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Metabolism. 2016 Dec;65(12):1768-1780. doi: 10.1016/j.metabol.2016.09.008. Epub 2016 Sep 28.
Elevated levels of circulating non-esterified fatty acids (NEFA) mediate many adverse metabolic effects. In this work we aim to determine the impact of type 2 diabetes (T2D), glycemic control and obesity on lipolysis regulation.
20 control and 20 metformin-treated T2D subjects were matched for sex (10M/10 F), age (58±11 vs 58±9 y) and BMI (30.8±4.6 vs 30.7±4.9kg/m). In vivo lipolysis was assessed during a 3h-OGTT with plasma glycerol and NEFA levels. Subcutaneous adipose tissue (SAT) biopsies were obtained to measure mRNA and metabolite levels of factors related to lipolysis and lipid storage and to assess in vitro lipolysis in isolated subcutaneous adipocytes.
Plasma NEFA AUC during the OGTT where higher 30% (P=0.005) in T2D than in control subjects, but plasma glycerol AUC and subcutaneous adipocyte lipolysis in vitro were similar, suggesting that adipose tissue lipolysis is not altered. Expression in SAT of genes involved in lipid storage (FABP4, DGAT1, FASN) were reduced in T2D subjects compared with controls, but no differences were seen for genes involved in lipolysis. T2D subjects had elevated markers of beta-oxidation, α-hydroxybutyrate (1.4-fold, P<0.01) and β-hydroxybutyrate (1.7-fold, P<0.05) in plasma. In multivariate analysis, HbA1c, visceral adipose tissue volume and sex (male) were significantly associated with NEFA AUC in T2D subjects.
In T2D subjects, NEFA turnover is impaired, but not due to defects in lipolysis or lipid beta-oxidation. Impaired adipose NEFA re-esterification or de novo lipogenesis is likely to contribute to higher NEFA plasma levels in T2D. The data suggest that hyperglycemia and adiposity are important contributing factors for the regulation of plasma NEFA concentrations.
循环非酯化脂肪酸（NEFA）水平升高介导许多不良代谢效应。在这项工作中，我们旨在确定 2 型糖尿病（T2D）、血糖控制和肥胖对脂肪分解调节的影响。
20 名对照和 20 名二甲双胍治疗的 T2D 患者按性别（10M/10F）、年龄（58±11 与 58±9 岁）和 BMI（30.8±4.6 与 30.7±4.9kg/m²）匹配。通过 3 小时 OGTT 评估体内脂肪分解，检测血浆甘油和 NEFA 水平。取皮下脂肪组织（SAT）活检，测量与脂肪分解和脂质储存相关的因子的 mRNA 和代谢物水平，并评估分离的皮下脂肪细胞中的体外脂肪分解。
OGTT 期间，T2D 患者的血浆 NEFA AUC 升高 30%（P=0.005），但血浆甘油 AUC 和体外皮下脂肪细胞脂肪分解相似，提示脂肪组织脂肪分解未改变。与对照组相比，T2D 患者的 SAT 中参与脂质储存的基因（FABP4、DGAT1、FASN）的表达降低，但参与脂肪分解的基因无差异。T2D 患者的血浆中β-氧化标志物 α-羟丁酸（1.4 倍，P<0.01）和β-羟丁酸（1.7 倍，P<0.05）升高。多元分析显示，HbA1c、内脏脂肪组织体积和性别（男性）与 T2D 患者的 NEFA AUC 显著相关。
在 T2D 患者中，NEFA 周转率受损，但不是由于脂肪分解或脂质β-氧化缺陷。脂肪组织 NEFA 再酯化或从头合成受损可能导致 T2D 患者的血浆 NEFA 水平升高。数据表明，高血糖和肥胖是调节血浆 NEFA 浓度的重要因素。
