Nakata M, Nagasaka S, Kusaka I, Matsuoka H, Ishibashi S, Yada T
Department of Physiology, Division of Integrative Physiology, Jichi Medical University, School of Medicine, Shimotsuke, Tochigi 329-0498, Japan.
Diabetologia. 2006 Aug;49(8):1881-92. doi: 10.1007/s00125-006-0269-5. Epub 2006 May 10.
AIMS/HYPOTHESIS: Hyperlipidaemia often occurs in patients with type 2 diabetes mellitus. Though HMG-CoA reductase inhibitors (statins) are widely used for controlling hypercholesterolemia, atorvastatin has also been reported to have an adverse effect on glucose metabolism. Based on these findings, the aim of this study was to investigate the effects of statins on adipocytes, which play pivotal roles in glucose metabolism.
In 3T3-L1 cells, effects of statins on adipocyte maturation were determined morphologically. Protein and mRNA levels of SLC2A4 and adipocyte marker proteins were determined by immunoblotting and RT-PCR, respectively. Type 2 diabetic NSY mice were treated with atorvastatin for 15 weeks, followed by glucose and insulin tolerance tests and examination of SLC2A4 expression in white adipose tissue (WAT). Seventy-eight Japanese subjects with type 2 diabetes and hypercholesterolaemia were treated with atorvastatin (10 mg/day), and its effects on lipid and glycaemic profiles were measured 12 weeks after treatment initiation.
Treatment with atorvastatin inhibited adipocyte maturation, SLC2A4 and C/EBPalpha expressions and insulin action in 3T3-L1 cells. Atorvastatin also attenuated SLC2A4 and C/EBPalpha expressions in differentiated 3T3-L1 adipocytes. These effects were reversed by L. mevalonate or geranylgeranyl pyrophosphate. In NSY mice, atorvastatin accelerated glucose intolerance as a result of insulin resistance and decreased SLC2A4 expression in WAT. In addition to improving hyperlipidaemia, atorvastatin treatment significantly increased HbA(1c) but not fasting glucose levels in diabetic patients, and this effect was greater in the non-obese subgroup.
CONCLUSIONS/INTERPRETATION: These results demonstrate that atorvastatin attenuates adipocyte maturation and SLC2A4 expression by inhibiting isoprenoid biosynthesis, and impairs glucose tolerance. These actions of atorvastatin could potentially affect the control of type 2 diabetes.
目的/假设：高脂血症常发生于2型糖尿病患者中。尽管HMG-CoA还原酶抑制剂（他汀类药物）被广泛用于控制高胆固醇血症，但也有报道称阿托伐他汀对糖代谢有不良影响。基于这些发现，本研究旨在探讨他汀类药物对在糖代谢中起关键作用的脂肪细胞的影响。
在3T3-L1细胞中，通过形态学方法确定他汀类药物对脂肪细胞成熟的影响。分别通过免疫印迹法和逆转录聚合酶链反应测定SLC2A4的蛋白质和mRNA水平以及脂肪细胞标志物蛋白。对2型糖尿病NSY小鼠给予阿托伐他汀治疗15周，随后进行葡萄糖和胰岛素耐量试验，并检测白色脂肪组织（WAT）中SLC2A4的表达。78名患有2型糖尿病和高胆固醇血症的日本受试者接受阿托伐他汀（10毫克/天）治疗，并在治疗开始12周后测量其对血脂和血糖谱的影响。
阿托伐他汀治疗可抑制3T3-L1细胞中的脂肪细胞成熟、SLC2A4和C/EBPα表达以及胰岛素作用。阿托伐他汀还可减弱分化的3T3-L1脂肪细胞中SLC2A4和C/EBPα的表达。这些作用可被甲羟戊酸或香叶基香叶基焦磷酸逆转。在NSY小鼠中，阿托伐他汀由于胰岛素抵抗而加速葡萄糖不耐受，并降低WAT中SLC2A4的表达。除改善高脂血症外，阿托伐他汀治疗可显著提高糖尿病患者的糖化血红蛋白（HbA1c）水平，但不影响空腹血糖水平，且这种作用在非肥胖亚组中更为明显。
结论/解读：这些结果表明，阿托伐他汀通过抑制类异戊二烯生物合成减弱脂肪细胞成熟和SLC2A4表达，并损害葡萄糖耐量。阿托伐他汀的这些作用可能会影响2型糖尿病的控制。
