Treatment of insulin resistance with peroxisome proliferator-activated receptor γ agonists
Treatment of insulin resistance with peroxisome proliferator-activated receptor γ agonists
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DOI：
10.1172/jci10843
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发表时间：
2000-08-01
影响因子：
15.9
通讯作者：
Olefsky, JM
中科院分区：
文献类型：
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作者：
Olefsky, JM
糖尿病：胰岛素抵抗：人类胰岛素抵抗研究组。在人体研究方面，TZDs在2型糖尿病患者中得到了最广泛的评估。TZDs的初步临床研究清楚地表明，使用这些药物治疗2型糖尿病患者可以降低空腹和餐后血糖水平，以及循环胰岛素水平（15,16）。这些发现与假定的这些化合物作为胰岛素增敏剂的作用是一致的，正如在TZD治疗前后对2型糖尿病患者进行葡萄糖夹夹直接证明的那样。这些研究表明，基本上所有患者在药物治疗期后都表现出胰岛素刺激的葡萄糖处理的改善，平均而言，胰岛素的这种作用增加了30%（15）。肝产糖率升高是2型糖尿病空腹高血糖患者的特征(1)，也是胰岛素抵抗的一种表现。TZD治疗对2型糖尿病患者基础肝糖生成率的影响有些不同。一些研究表明，这种异常显著减少（15），而另一些研究则表明，tzd要么没有影响（17），要么只有在高剂量的tzd下才有影响（18）。此外，尚不清楚TZDs降低肝脏葡萄糖生成率的作用是直接作用于肝脏，还是间接有益作用于这些药物改善代谢环境的其他方面。例如，TZD治疗降低FFA水平，这可能继发降低肝脏葡萄糖输出。tzd也被用于治疗非糖尿病人胰岛素抵抗状态。例如，对肥胖的非糖尿病患者、糖耐量受损（IGT）患者和多囊卵巢综合征（PCOS）患者的治疗均显示胰岛素敏感性的改善（19-21）。几乎可以肯定，胰岛素抵抗的机制在所有这些人类条件下都是不同的。因此，这些结果与从动物研究中了解到的结果是一致的，即tzd在改善胰岛素抵抗方面是有效的，而不管潜在的遗传和获得机制的多样性。同样重要的是要指出，与动物研究不同，TZDs的作用只能部分改善胰岛素抵抗。因此，与胰岛素抵抗动物相比，TZD治疗可使人类胰岛素抵抗状态下胰岛素刺激的葡萄糖处理改善20-40%。因此，即使在有效的TZD治疗后，2型糖尿病、肥胖、IGT和PCOS患者仍保持中度胰岛素抵抗。对TZDs患者的治疗似乎对X综合征的大部分成分（如果不是全部的话）都有有益的效果（见Ginsberg， this Perspective series, ref. 22）。例如，不仅是TZD治疗
On diabetes: insulin resistance insulin-resistant study groups in man. In terms of human studies, TZDs have been most extensively evaluated in patients with type 2 diabetes. Initial clinical research studies with TZDs clearly demonstrated that treatment of type 2 diabetic patients with these agents lowered both fasting and postprandial glucose levels, as well as circulating insulin levels (15, 16). This combination of findings is consistent with the presumed action of these compounds as insulin-sensitizing agents, as was directly demonstrated by performing glucose clamps in type 2 diabetic patients before and after a period of TZD treatment. These studies showed that essentially all patients exhibited an improvement in insulin-stimulated glucose disposal after the drug treatment period, and on average this amounted to a 30% increase in this action of insulin (15). Elevated hepatic glucose production rates are a characteristic feature of type 2 diabetic patients with fasting hyperglycemia (1), and this is also a manifestation of insulin resistance. The effects of TZD treatment on basal hepatic glucose production rates in type 2 diabetic patients have been somewhat variable. Some studies have shown striking decreases in this abnormality (15), while others have shown either no effect (17) or effects only at higher doses of TZDs (18). Furthermore, it is not clear whether the effects of TZDs to lower hepatic glucose production rates represent direct actions on the liver, or indirect beneficial effects secondary to some other aspect of the improved metabolic environment produced by these drugs. For example, TZD treatment reduces FFA levels, which may secondarily lower hepatic glucose output.TZDs have also been used in the treatment of nondiabetic human insulin-resistant states. For example, treatment of obese nondiabetic subjects, subjects with impaired glucose tolerance (IGT), and women with PCOS have all demonstrated an improvement in insulin sensitivity (19–21). The mechanisms of insulin resistance are almost certainly heterogeneous across all these human conditions. Thus, these results are consistent with what has been learned from animal studies in that TZDs are effective at ameliorating insulin resistance regardless of the diverse underlying genetic and acquired mechanisms. It is also important to point out that, unlike in the animal studies, the effects of TZDs result in only partial improvement in insulin resistance. Thus, TZD treatment leads to anywhere from a 20–40% improvement in insulin-stimulated glucose disposal in human insulin-resistant states, compared with near normalization in insulin-resistant animals. Therefore, even after effective TZD treatment, patients with type 2 diabetes, obesity, IGT, and PCOS still remain moderately insulin-resistant. Treatment of patients with TZDs seems to have beneficial effects on most, if not all, of the components of syndrome X (see Ginsberg, this Perspective series, ref. 22). For example, not only does TZD treatment