Tricò Domenico, Rebelos Eleni, Astiarraga Brenno, Baldi Simona, Scozzaro Tiziana, Sacchetta Luca, Chiriacò Martina, Mari Andrea, Ferrannini Ele, Muscelli Elza, Natali Andrea
Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy.
Laboratory of Metabolism, Nutrition, and Atherosclerosis, University of Pisa, 56126 Pisa, Italy.
J Clin Endocrinol Metab. 2025 Feb 18;110(3):e667-e674. doi: 10.1210/clinem/dgae276.
Hypertriglyceridemia is a risk factor for developing type 2 diabetes (T2D) and might contribute to its pathogenesis either directly or through elevation of nonesterified fatty acids (NEFAs).
This study aimed at comparing the glucometabolic effects of acute hypertriglyceridemia alone or combined with NEFA elevation in subjects without diabetes.
Twenty-two healthy lean volunteers underwent 5-hour intravenous infusions of either saline or Intralipid, without (n = 12) or with heparin (I + H; n = 10) to activate the release of NEFAs. Oral glucose tolerance tests (OGTTs) were performed during the last 3 hours of infusion. Insulin sensitivity, insulin secretion rate (ISR), model-derived β-cell function, and insulin clearance were measured after 2 hours of lipid infusion and during the OGTTs.
In fasting conditions, both lipid infusions increased plasma insulin and ISR and reduced insulin clearance without affecting plasma glucose and insulin sensitivity. These effects on insulin and ISR were more pronounced for I + H than Intralipid alone. During the OGTT, the lipid infusions markedly impaired glucose tolerance, increased plasma insulin and ISR, and decreased insulin sensitivity and clearance, without significant group differences. Intralipid alone inhibited glucose-stimulated insulin secretion (ie, β-cell glucose sensitivity) and increased β-cell potentiation, whereas I + H had neutral effects on these β-cell functions.
In healthy nonobese subjects, mild acute hypertriglyceridemia directly reduces glucose tolerance and insulin sensitivity and clearance, and has selective and opposite effects on β-cell function that are neutralized by NEFAs. These findings provide new insight into plausible biological signals that generate and sustain insulin resistance and chronic hyperinsulinemia in the development of T2D.
高甘油三酯血症是2型糖尿病（T2D）发生的一个危险因素，可能直接或通过非酯化脂肪酸（NEFAs）升高对其发病机制产生影响。
本研究旨在比较单纯急性高甘油三酯血症以及合并NEFAs升高对非糖尿病受试者糖代谢的影响。
22名健康瘦志愿者接受了5小时的静脉输注，分别输注生理盐水或英脱利匹特，其中12名不使用肝素，10名使用肝素（I + H）以激活NEFAs的释放。在输注的最后3小时进行口服葡萄糖耐量试验（OGTT）。在脂质输注2小时后以及OGTT期间测量胰岛素敏感性、胰岛素分泌率（ISR）、模型衍生的β细胞功能和胰岛素清除率。
在空腹状态下，两种脂质输注均增加了血浆胰岛素和ISR，并降低了胰岛素清除率，而不影响血浆葡萄糖和胰岛素敏感性。I + H对胰岛素和ISR的这些影响比单纯英脱利匹特更明显。在OGTT期间，脂质输注显著损害葡萄糖耐量，增加血浆胰岛素和ISR，并降低胰岛素敏感性和清除率，两组间无显著差异。单纯英脱利匹特抑制葡萄糖刺激的胰岛素分泌（即β细胞葡萄糖敏感性）并增加β细胞增强作用，而I + H对这些β细胞功能具有中性作用。
在健康非肥胖受试者中，轻度急性高甘油三酯血症直接降低葡萄糖耐量、胰岛素敏感性和清除率，并对β细胞功能产生选择性和相反的影响，而NEFAs可中和这些影响。这些发现为T2D发生过程中产生和维持胰岛素抵抗及慢性高胰岛素血症的可能生物学信号提供了新的见解。
