Division of Endocrinology, Metabolism and Diabetes, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States.
School of Exercise, Sport, and Health Sciences, College of Health, Oregon State University, Corvallis, Oregon, United States.
Am J Physiol Endocrinol Metab. 2024 Aug 1;327(2):E183-E193. doi: 10.1152/ajpendo.00368.2023. Epub 2024 Jun 19.
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 ( = 12), sedentary lean adults ( = 12), and individuals with obesity ( = 13) and T2D ( = 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 ( = 0.087). Moreover, C18 1,2-DAG species increased during the clamp with T2D only, which negatively correlated with insulin sensitivity ( < 0.050). Basal muscle C18:0 total ceramides were elevated with T2D ( = 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, = 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. 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.
骨骼肌中二酰基甘油（DAG）和神经酰胺的升高可损害胰岛素信号，酰基辅酶 A（acylCNs）反映了线粒体脂肪酸氧化受损，因此，肌肉内脂质谱是胰岛素抵抗的指标。已经证明，急性（即餐后）高胰岛素血症会升高健康肌肉中的脂质浓度，并且是 2 型糖尿病（T2D）的独立危险因素。然而，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在代谢表型之间相互作用，从而导致或加剧胰岛素抵抗。因此，我们研究了急性高胰岛素血症对骨骼肌脂质谱的影响，以帮助描述高胰岛素血症升高 T2D 风险的生理基础。在一项横断面比较中，耐力运动员（n=12）、久坐的瘦成年人（n=12）、肥胖者（n=13）和 2 型糖尿病患者（n=7）接受了高胰岛素-正常血糖钳夹术，并进行了肌肉活检。尽管 1,2-DAG 的总波动没有显著差异，但在急性高胰岛素血症期间，运动员的下降了 2%，而 2 型糖尿病患者的增加了 53%（P=0.087）。此外，仅在 2 型糖尿病患者中，C18 1,2-DAG 种类在钳夹期间增加，这与胰岛素敏感性呈负相关（P<0.050）。基础肌肉 C18:0 总神经酰胺在 2 型糖尿病患者中升高（P=0.029），但钳夹术并未改变。酰基辅酶 A 在高胰岛素血症期间普遍降低，运动员的降幅比 2 型糖尿病患者的降幅更大，达到 80%（尽管无统计学意义，组间主要效应，P=0.624）。在雄性小鼠中，也观察到了类似的变化，即急性高胰岛素血症增加了胰岛素抵抗表型中的 1,2-DAG，并普遍降低了酰基辅酶 A。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。这表明在胰岛素敏感性较低的人群中，在进食状态下，肌肉内脂质代谢可能存在失调，这可能会加剧胰岛素抵抗。餐后高胰岛素血症是 2 型糖尿病的危险因素，并可能增加肌肉脂质。然而，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在代谢表型之间相互作用，从而导致或加剧胰岛素抵抗。我们观察到，急性高胰岛素血症会升高胰岛素抵抗表型中的肌肉 1,2-DAG，而神经酰胺则保持不变。高脂肪喂养也会阻碍胰岛素介导的酰基辅酶 A 减少。餐后期间可能会使代谢不健康的表型中的胰岛素抵抗恶化。
