Coletta D K, Fernandez M, Cersosimo E, Gastaldelli A, Musi N, DeFronzo R A
Mayo Clinic in Arizona, Scottsdale; School of Life Sciences, Arizona State University, Tempe; Department of Basic Medical Sciences, University of Arizona College of Medicine - Phoenix.
Diabet Med. 2015 May;32(5):657-64. doi: 10.1111/dme.12664. Epub 2015 Jan 7.
The molecular mechanisms by which muraglitazar (peroxisome proliferator-activated receptor γ/α agonist) improves insulin sensitivity in Type 2 diabetes mellitus are not fully understood. We hypothesized that muraglitazar would increase expression of 5'-monophosphate-activated protein kinase and genes involved in adiponectin signalling, free fatty acid oxidation and mitochondrial function in skeletal muscle.
Sixteen participants with Type 2 diabetes received muraglitazar, 5 mg/day (n = 12) or placebo (n = 4). Before and after 16 weeks, participants had vastus lateralis muscle biopsy followed by 180 min euglycaemic hyperinsulinaemic clamp.
Muraglitazar increased plasma adiponectin (9.0 ± 1.1 to 17.8 ± 1.5 μg/ml, P < 0.05), while no significant change was observed with placebo. After 16 weeks with muraglitazar, fasting plasma glucose declined by 31%, fasting plasma insulin decreased by 44%, insulin-stimulated glucose disposal increased by 81%, HbA1c decreased by 21% and plasma triglyceride decreased by 39% (all P < 0.05). Muraglitazar increased mRNA levels of 5'-monophosphate-activated protein kinase, adiponectin receptor 1, adiponectin receptor 2, peroxisome proliferator-activated receptor gamma coactivator-1 alpha and multiple genes involved in mitochondrial function and fat oxidation. In the placebo group, there were no significant changes in expression of these genes.
Muraglitazar increases plasma adiponectin, stimulates muscle 5'-monophosphate-activated protein kinase expression and increases expression of genes involved in adiponectin signalling, mitochondrial function and fat oxidation. These changes represent important cellular mechanisms by which dual peroxisome proliferator-activated receptor agonists improve skeletal muscle insulin sensitivity.
muraglitazar（过氧化物酶体增殖物激活受体γ/α激动剂）改善2型糖尿病胰岛素敏感性的分子机制尚未完全明确。我们推测muraglitazar会增加5'-单磷酸激活蛋白激酶的表达以及参与脂联素信号传导、游离脂肪酸氧化和骨骼肌线粒体功能的基因的表达。
16名2型糖尿病患者接受muraglitazar治疗，剂量为5毫克/天（n = 12）或安慰剂（n = 4）。在16周前后，参与者进行股外侧肌活检，随后进行180分钟的正常血糖高胰岛素钳夹试验。
muraglitazar使血浆脂联素水平升高（从9.0±1.1微克/毫升升至17.8±1.5微克/毫升，P < 0.05），而安慰剂组未观察到显著变化。接受muraglitazar治疗16周后，空腹血糖下降31%，空腹血浆胰岛素下降44%，胰岛素刺激的葡萄糖处置增加81%，糖化血红蛋白下降21%，血浆甘油三酯下降39%（均P < 0.05）。muraglitazar增加了5'-单磷酸激活蛋白激酶mRNA水平、脂联素受体1、脂联素受体2、过氧化物酶体增殖物激活受体γ辅激活因子-1α以及参与线粒体功能和脂肪氧化的多个基因的mRNA水平。在安慰剂组中，这些基因的表达无显著变化。
muraglitazar可增加血浆脂联素水平，刺激肌肉中5'-单磷酸激活蛋白激酶的表达，并增加参与脂联素信号传导、线粒体功能和脂肪氧化的基因的表达。这些变化代表了双过氧化物酶体增殖物激活受体激动剂改善骨骼肌胰岛素敏感性的重要细胞机制。
