Broussard Josiane L, Perreault Leigh, Macias Emily, Newsom Sean A, Harrison Kathleen, Bui Hai Hoang, Milligan Paul, Roth Kenneth D, Nemkov Travis, D'Alessandro Angelo, Brozinick Joseph T, Bergman Bryan C
Division of Endocrinology, Metabolism, and Diabetes, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Department of Health and Exercise Science, Colorado State University, Fort Collins, Colorado, USA.
Obesity (Silver Spring). 2021 Mar;29(3):550-561. doi: 10.1002/oby.23106.
Sex differences in insulin sensitivity are present throughout the life-span, with men having a higher prevalence of insulin resistance and diabetes compared with women. Differences in lean mass, fat mass, and fat distribution-particularly ectopic fat-have all been postulated to contribute to the sexual dimorphism in diabetes risk. Emerging data suggest ectopic lipid composition and subcellular localization are most relevant; however, it is not known whether they explain sex differences in obesity-induced insulin resistance.
To address this gap, this study evaluated insulin sensitivity and subcellular localization of intramuscular triacylglycerol, diacylglycerol, and sphingolipids as well as muscle acylcarnitines and serum lipidomics in people with obesity.
Insulin sensitivity was significantly lower in men (P < 0.05); however, no sex differences were found in localization of intramuscular triacylglycerol, diacylglycerol, or sphingolipids in skeletal muscle. In contrast, men had higher total muscle acylcarnitine (P < 0.05) and long-chain muscle acylcarnitine (P < 0.05), which were related to lower insulin sensitivity (r = -0.42, P < 0.05). Men also displayed higher serum ceramide (P = 0.05) and lysophosphatidylcholine (P < 0.01).
These data reveal novel sex-specific associations between lipid species involved in the coupling of mitochondrial fatty acid transport, β-oxidation, and tricarboxylic acid cycle flux that may provide therapeutic targets to improve insulin sensitivity.
胰岛素敏感性的性别差异贯穿一生，与女性相比，男性胰岛素抵抗和糖尿病的患病率更高。瘦体重、脂肪量和脂肪分布的差异，尤其是异位脂肪，都被认为是导致糖尿病风险性别差异的原因。新出现的数据表明，异位脂质组成和亚细胞定位最为相关；然而，尚不清楚它们是否能解释肥胖诱导的胰岛素抵抗中的性别差异。
为了填补这一空白，本研究评估了肥胖人群的胰岛素敏感性以及肌肉内三酰甘油、二酰甘油、鞘脂的亚细胞定位，以及肌肉酰基肉碱和血清脂质组学。
男性的胰岛素敏感性显著较低（P < 0.05）；然而，在骨骼肌中，肌肉内三酰甘油、二酰甘油或鞘脂的定位未发现性别差异。相比之下，男性的总肌肉酰基肉碱（P < 0.05）和长链肌肉酰基肉碱（P < 0.05）较高，这与较低的胰岛素敏感性相关（r = -0.42，P < 0.05）。男性的血清神经酰胺（P = 0.05）和溶血磷脂酰胆碱也较高（P < 0.01）。
这些数据揭示了参与线粒体脂肪酸转运、β-氧化和三羧酸循环通量耦合的脂质种类之间新的性别特异性关联，这可能为改善胰岛素敏感性提供治疗靶点。
