Olefsky J M, Saltiel A R
University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0673, USA.
Trends Endocrinol Metab. 2000 Nov;11(9):362-8. doi: 10.1016/s1043-2760(00)00306-4.
Numerous studies across several population groups have indicated that insulin resistance plays a central role in the development of type 2 diabetes mellitus (T2DM). Moreover, this disorder is also strongly associated with other metabolic syndromes, including hypertension, dyslipidemias and polycystic ovarian syndrome (PCOS). Recent advances have demonstrated that pharmacological agents of the thiazolidinedione class can reverse insulin resistance and profoundly improve many of these associated symptoms. These effects have been documented in a variety of genetic and acquired animal models of insulin resistance, as well as in numerous clinical trials in patients with insulin resistance. These compounds appear to enhance insulin action by modulating the activity of the nuclear receptor peroxisome proliferator-activated receptor (PPAR) gamma. This activation results in changes in the expression of a number of genes that are critically involved in glucose and lipid metabolism, as well as in insulin signal transduction. While precise events that occur downstream from PPAR gamma modulation remain uncertain, new insights are emerging from knockout studies in mice and the identification of genetic variants in humans. These findings indicate that there is still much to learn about the molecular biology and physiology of these interesting receptors, and that research in this area can lead to more effective and safer drugs to treat insulin resistance and associated syndromes.
针对多个群体开展的大量研究表明，胰岛素抵抗在2型糖尿病（T2DM）的发生发展过程中起着核心作用。此外，这种病症还与其他代谢综合征密切相关，包括高血压、血脂异常和多囊卵巢综合征（PCOS）。最近的研究进展表明，噻唑烷二酮类药物能够逆转胰岛素抵抗，并显著改善许多相关症状。这些作用已在多种胰岛素抵抗的遗传和获得性动物模型中得到证实，同时也在众多胰岛素抵抗患者的临床试验中得到验证。这些化合物似乎通过调节核受体过氧化物酶体增殖物激活受体（PPAR）γ的活性来增强胰岛素作用。这种激活导致许多在葡萄糖和脂质代谢以及胰岛素信号转导中起关键作用的基因表达发生变化。虽然PPARγ调节下游发生的精确事件仍不确定，但小鼠基因敲除研究和人类基因变异的鉴定正在带来新的见解。这些发现表明，关于这些有趣受体的分子生物学和生理学仍有许多有待了解之处，并且该领域的研究能够带来更有效、更安全的药物来治疗胰岛素抵抗及相关综合征。
