骨骼肌二酰甘油(DAG)和神经酰胺升高会损害胰岛素信号,和酰基肉碱(酰基CN)反映脂肪酸氧化受损,因此,肌内血脂谱表明胰岛素抵抗。急性(即,餐后)高胰岛素血症已被证明会升高健康肌肉中的脂质,并且是2型糖尿病(T2D)的独立危险因素。目前尚不清楚急性高胰岛素血症与肌肉脂质组之间的关系如何相互作用,从而导致或加剧胰岛素抵抗。我们调查了急性高胰岛素血症对肌肉脂质组的影响,以帮助表征高胰岛素血症升高T2D风险的生理基础。耐力运动员(n=12),久坐的瘦成年人(n=12),肥胖患者(n=13)和T2D患者(n=7)接受了高胰岛素-正常血糖钳夹术和肌肉活检。虽然总的1,2-DAG波动没有显著差异,运动员减少了2%,而T2D增加了53%.C181,2-DAG在仅使用T2D的夹具期间增加,与胰岛素敏感性呈负相关。基底肌肉C18:0神经酰胺随T2D升高,但不会被钳子改变。在高胰岛素血症期间,酰基肉碱普遍降低,与T2D的仅46%相比,运动员减少了80%。在雄性小鼠中观察到类似的波动,急性高胰岛素血症增加了胰岛素抵抗表型中的1,2DAG,并普遍降低了酰基肉碱。总之,急性高胰岛素血症会升高胰岛素抵抗表型的肌肉1,2-DAG水平。这表明胰岛素敏感性低的个体在进食状态下肌内脂质代谢可能失调。这可能会加剧胰岛素抵抗。
Elevated skeletal muscle diacylglycerols (DAGs) and ceramides can impair insulin signaling, and acylcarnitines (acylCNs) reflect impaired mitochondrial fatty acid oxidation, thus, the intramuscular lipid profile is indicative of insulin resistance. Acute (i.e., postprandial) hyperinsulinemia has been shown to elevate lipid concentrations in healthy muscle and is an independent risk factor for type 2 diabetes (T2D). However, it is unclear how the relationship between acute hyperinsulinemia and the muscle lipidome interacts across metabolic phenotypes, thus contributing to or exacerbating insulin resistance. We therefore investigated the impact of acute hyperinsulinemia on the skeletal muscle lipid profile to help characterize the physiological basis in which hyperinsulinemia elevates T2D risk. In a cross-sectional comparison, endurance athletes (n = 12), sedentary lean adults (n = 12), and individuals with obesity (n = 13) and T2D (n = 7) underwent a hyperinsulinemic-euglycemic clamp with muscle biopsies. Although there were no significant differences in total 1,2-DAG fluctuations, there was a 2% decrease in athletes versus a 53% increase in T2D during acute hyperinsulinemia (P = 0.087). Moreover, C18 1,2-DAG species increased during the clamp with T2D only, which negatively correlated with insulin sensitivity (P < 0.050). Basal muscle C18:0 total ceramides were elevated with T2D (P = 0.029), but not altered by clamp. Acylcarnitines were universally lowered during hyperinsulinemia, with more robust reductions of 80% in athletes compared with only 46% with T2D (albeit not statistically significant, main effect of group, P = 0.624). Similar fluctuations with acute hyperinsulinemia increasing 1,2 DAGs in insulin-resistant phenotypes and universally lowering acylcarnitines were observed in male mice. In conclusion, acute hyperinsulinemia elevates muscle 1,2-DAG levels with insulin-resistant phenotypes. This suggests a possible dysregulation of intramuscular lipid metabolism in the fed state in individuals with low insulin sensitivity, which may exacerbate insulin resistance.NEW & NOTEWORTHY Postprandial hyperinsulinemia is a risk factor for type 2 diabetes and may increase muscle lipids. However, it is unclear how the relationship between acute hyperinsulinemia and the muscle lipidome interacts across metabolic phenotypes, thus contributing to insulin resistance. We observed that acute hyperinsulinemia elevates muscle 1,2-DAGs in insulin-resistant phenotypes, whereas ceramides were unaltered. Insulin-mediated acylcarnitine reductions are also hindered with high-fat feeding. The postprandial period may exacerbate insulin resistance in metabolically unhealthy phenotypes.