Tozzo Effie, Ponticiello Randolph, Swartz JoAnn, Farrelly Dennis, Zebo Rachel, Welzel Gustav, Egan Donald, Kunselman Lori, Peters Andrew, Gu Liqun, French Michele, Chen Sean, Devasthale Pratik, Janovitz Evan, Staal Ada, Harrity Thomas, Belder Rene, Cheng Peter T, Whaley Jean, Taylor Simeon, Hariharan Narayanan
Metabolic and Cardiovascular Diseases Discovery Biology, HPW-21-2.02, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA.
J Pharmacol Exp Ther. 2007 Apr;321(1):107-15. doi: 10.1124/jpet.106.115337. Epub 2007 Jan 26.
There are two major defects in type 2 diabetes: 1) insulin resistance and 2) insulin deficiency due to loss of beta-cell function. Here we demonstrated that treatment with muraglitazar (a dual peroxisome proliferator-activated receptor alpha/gamma activator), when initiated before or after the onset of diabetes in mice, is effective against both defects. In study 1, prediabetic db/db mice were treated for 12 weeks. The control mice developed diabetes, as evidenced by hyperglycemia, hyperinsulinemia, reduced insulin levels in the pancreas, blunted insulin response to glucose, and impaired glucose tolerance. The muraglitazar-treated mice had normal plasma glucose, and insulin levels, equivalent or higher pancreatic insulin content than normal mice, showed a robust insulin response to glucose and exhibited greater glucose tolerance. In study 2, diabetic db/db mice were treated for 4 weeks. The control mice displayed increased glucose levels, severe loss of islets, and their isolated islets secreted reduced amounts of insulin in response to glucose and exendin-4 compared with baseline. In muraglitazar-treated mice, glucose levels were reduced to normal. These mice showed reduced loss of islets, and their isolated islets secreted insulin at levels comparable to baseline. Thus, muraglitazar treatment decreased both insulin resistance and preserved beta-cell function. As a result, muraglitazar treatment, when initiated before the onset of diabetes, prevented development of diabetes and, when initiated after the onset of diabetes, prevented worsening of diabetes in db/db mice.
2型糖尿病存在两个主要缺陷：1）胰岛素抵抗；2）由于β细胞功能丧失导致的胰岛素缺乏。在此我们证明，用muraglitazar（一种双重过氧化物酶体增殖物激活受体α/γ激活剂）进行治疗，无论在小鼠糖尿病发病之前还是之后开始，对这两个缺陷均有效。在研究1中，对糖尿病前期的db/db小鼠进行了12周的治疗。对照小鼠患上了糖尿病，表现为高血糖、高胰岛素血症、胰腺中胰岛素水平降低、胰岛素对葡萄糖的反应迟钝以及糖耐量受损。用muraglitazar治疗的小鼠血糖和胰岛素水平正常，胰腺胰岛素含量与正常小鼠相当或更高，对葡萄糖表现出强烈的胰岛素反应，并且糖耐量更高。在研究2中，对糖尿病db/db小鼠进行了4周的治疗。对照小鼠血糖水平升高，胰岛严重丧失，与基线相比，其分离的胰岛对葡萄糖和艾塞那肽-4的胰岛素分泌量减少。在用muraglitazar治疗的小鼠中，血糖水平降至正常。这些小鼠胰岛丧失减少，其分离的胰岛分泌的胰岛素水平与基线相当。因此，muraglitazar治疗降低了胰岛素抵抗并保留了β细胞功能。结果，在糖尿病发病前开始用muraglitazar治疗可预防糖尿病的发生，而在糖尿病发病后开始治疗则可防止db/db小鼠的糖尿病恶化。
