Warshauer Jeremy T, Lopez Ximena, Gordillo Ruth, Hicks Jessica, Holland William L, Anuwe Estelle, Blankfard Martin B, Scherer Philipp E, Lingvay Ildiko
University of Texas Southwestern Medical Center, Dallas, TX, USA.
American Laboratory Products Company, Salem, NH, USA.
Diabetes Metab Res Rev. 2015 Oct;31(7):734-44. doi: 10.1002/dmrr.2662. Epub 2015 Jun 17.
Metabolic syndrome (MetS) appears closely linked with ceramide accumulation, inducing insulin resistance and toxicity to multiple cell types. Animal studies demonstrate that thiazolidinediones (TZDs) reduce ceramide concentrations in plasma and skeletal muscle and support lowering of ceramide levels as a potential mediator of TZDs' mechanism of action in reducing insulin resistance; however, studies in humans have yet to be reported. This study investigated the effects of pioglitazone therapy on plasma ceramides to understand the mechanism by which TZDs improve insulin resistance in MetS.
Thirty-seven subjects with MetS were studied in a single-centre, randomized, double-blind, placebo-controlled trial comparing pioglitazone to placebo. Data were collected at baseline and after 6 months of therapy. The primary endpoint was the change from baseline in plasma ceramide concentrations.
Treatment with pioglitazone for 6 months, compared with placebo, significantly reduced multiple plasma ceramide concentrations: C18:0 (p = 0.001), C20:0 (p = 0.0004), C24 : 1 (p = 0.009), dihydroceramide C18 :0 (p = 0.005), dihydroceramide C24:1 (p = 0.004), lactosylceramide C16:0 (p = 0.02) and the hexosylceramides C16:0 (p = 0.0003), C18 : 0 (p = 0.00001), C22:0 (p = 0.00002) and C24:1 (p = 0.0006). Additionally, significant reductions were found when ceramides were grouped by species: ceramides (p = 0.03), dihydroceramides (p = 0.02), hexosylceramides (p = 0.00001) and lactosylceramides (p = 0.02). The total of all measured ceramides was also significantly reduced (p = 0.001). Following treatment with pioglitazone, the decrease in some ceramide species correlated negatively with the change in insulin sensitivity (dihydroceramide C16:0, r = -0.54; p = 0.02) and positively with total (lactosylceramide C24:0, r = 0.53; p = 0.02) and high molecular weight (lactosylceramide C24:0, r = 0.48; p = 0.05) adiponectin measurements; however, significant associations with changes in liver fat and glycemic control reduction were not found.
Pioglitazone in individuals with MetS induces a potent decrease in plasma ceramides, and some of the changes correlate with changes in insulin resistance and adiponectin levels.
代谢综合征（MetS）似乎与神经酰胺蓄积密切相关，可诱导胰岛素抵抗并对多种细胞类型产生毒性。动物研究表明，噻唑烷二酮类药物（TZDs）可降低血浆和骨骼肌中的神经酰胺浓度，并支持降低神经酰胺水平，这是TZDs降低胰岛素抵抗作用机制的潜在介质；然而，尚未有关于人类的研究报道。本研究调查了吡格列酮治疗对血浆神经酰胺的影响，以了解TZDs改善MetS患者胰岛素抵抗的机制。
在一项单中心、随机、双盲、安慰剂对照试验中，对37例MetS患者进行了研究，比较吡格列酮与安慰剂的效果。在基线和治疗6个月后收集数据。主要终点是血浆神经酰胺浓度相对于基线的变化。
与安慰剂相比，吡格列酮治疗6个月可显著降低多种血浆神经酰胺浓度：C18:0（p = 0.001）、C20:0（p = 0.0004）、C24:1（p = 0.009）、二氢神经酰胺C18:0（p = 0.005）、二氢神经酰胺C24:1（p = 0.004）、乳糖基神经酰胺C16:0（p = 0.02）以及己糖基神经酰胺C16:0（p = 0.0003）、C18:0（p = 0.00001）、C22:0（p = 0.00002）和C24:1（p = 0.0006）。此外，按种类分组的神经酰胺也有显著降低：神经酰胺（p = 0.03）、二氢神经酰胺（p = 0.02）、己糖基神经酰胺（p = 0.00001）和乳糖基神经酰胺（p = 0.02）。所有测量的神经酰胺总量也显著降低（p = 0.001）。吡格列酮治疗后，某些神经酰胺种类的降低与胰岛素敏感性的变化呈负相关（二氢神经酰胺C16:0，r = -0.54；p = 0.02），与总脂联素（乳糖基神经酰胺C24:0，r = 0.53；p = 0.02）和高分子量脂联素（乳糖基神经酰胺C24:0，r = 0.48；p = 0.05）的测量值呈正相关；然而，未发现与肝脏脂肪变化和血糖控制降低有显著关联。
MetS患者使用吡格列酮可使血浆神经酰胺显著降低，且其中一些变化与胰岛素抵抗和脂联素水平的变化相关。
