Department of Endocrinology, Diabetes and Metabolism, University Hospital Basel and University of Basel, Basel, Switzerland.
Institute of Diagnostic and Interventional Radiology, University Hospital Zurich/University of Zurich, Zurich, Switzerland.
Front Endocrinol (Lausanne). 2021 Nov 10;12:765807. doi: 10.3389/fendo.2021.765807. eCollection 2021.
Statins are commonly prescribed for primary and secondary prevention of atherosclerotic disease. They reduce cholesterol biosynthesis by inhibiting hydroxymethylglutaryl-coenzyme A-reductase (HMG-CoA-reductase) and therefore mevalonate synthesis. Several studies reported a small, but significant increase in the diagnosis of diabetes mellitus with statin treatment. The molecular mechanisms behind this adverse effect are not yet fully understood. Brown adipose tissue (BAT), which plays a role in thermogenesis, has been associated with a reduced risk of insulin resistance. Statins inhibit adipose tissue browning and have been negatively linked to the presence of BAT in humans. We therefore speculated that inhibition of BAT by statins contributes to increased insulin resistance in humans.
A prospective study was conducted in 17 young, healthy men. After screening whether significant cold-induced thermogenesis (CIT) was present, participants underwent glucose tolerance testing (oGTT) and assessment of BAT activity by FDG-PET/MRI after cold-exposure and treatment with a β3-agonist. Fluvastatin 2x40mg per day was then administered for two weeks and oGTT and FDG-PET/MRI were repeated.
Two weeks of fluvastatin treatment led to a significant increase in glucose area under the curve (AUC) during oGTT (p=0.02), reduction in total cholesterol and LDL cholesterol (both p<0.0001). Insulin AUC (p=0.26), resting energy expenditure (REE) (p=0.44) and diet induced thermogenesis (DIT) (p=0.27) did not change significantly. The Matsuda index, as an indicator of insulin sensitivity, was lower after fluvastatin intake, but the difference was not statistically significant (p=0.09). As parameters of BAT activity, mean standard uptake value (SUV) (p=0.12), volume (p=0.49) and total glycolysis (p=0.74) did not change significantly during the intervention. Matsuda index, was inversely related to SUV and the respiratory exchange ratio (RER) (both R 0.44, p=0.005) at baseline, but not after administration of fluvastatin (R 0.08, p=0.29, and R 0.14, p=0.16, respectively).
Treatment with fluvastatin for two weeks reduced serum lipid levels but increased glucose AUC in young, healthy men, indicating reduced glucose tolerance. This was not associated with changes in cold-induced BAT activity.
他汀类药物常用于动脉粥样硬化疾病的一级和二级预防。它们通过抑制羟甲基戊二酰基辅酶 A 还原酶（HMG-CoA 还原酶）从而减少甲羟戊酸的合成，以此来降低胆固醇的生物合成。一些研究报告称，他汀类药物治疗会导致糖尿病的诊断略有增加，但具有统计学意义。这种不良反应的分子机制尚不完全清楚。棕色脂肪组织（BAT）在产热中起作用，与胰岛素抵抗风险降低有关。他汀类药物抑制脂肪组织的褐变，并与人类 BAT 的存在呈负相关。因此，我们推测他汀类药物对 BAT 的抑制作用导致人类胰岛素抵抗增加。
对 17 名年轻健康男性进行了一项前瞻性研究。在筛选出是否存在显著的冷诱导产热（CIT）后，参与者接受了口服葡萄糖耐量试验（oGTT）和 FDG-PET/MRI 评估，以检测 BAT 活性，然后在冷暴露和β3-激动剂治疗后进行。随后，给予氟伐他汀 2x40mg/天，连续两周，重复进行 oGTT 和 FDG-PET/MRI。
氟伐他汀治疗两周导致 oGTT 期间葡萄糖曲线下面积（AUC）显著增加（p=0.02），总胆固醇和 LDL 胆固醇均降低（均 p<0.0001）。胰岛素 AUC（p=0.26）、静息能量消耗（REE）（p=0.44）和饮食诱导的产热（DIT）（p=0.27）没有明显变化。氟伐他汀摄入后，Matsuda 指数作为胰岛素敏感性的指标降低，但差异无统计学意义（p=0.09）。作为 BAT 活性的参数，平均标准摄取值（SUV）（p=0.12）、体积（p=0.49）和总糖酵解（p=0.74）在干预期间没有明显变化。Matsuda 指数与 SUV 和呼吸交换率（RER）呈负相关（均 r=0.44，p=0.005），但在氟伐他汀给药后无相关性（r=0.08，p=0.29，r=0.14，p=0.16）。
氟伐他汀治疗两周可降低年轻健康男性的血清脂质水平，但增加葡萄糖 AUC，表明葡萄糖耐量降低。这与冷诱导 BAT 活性的变化无关。
