Koch M, Rett K, Maerker E, Volk A, Haist K, Deninger M, Rettig A, Renn W, Häring H U
Medizinische Klinik der Universität Tübingen, Abt. IV. Innere Medizin, Endokrinologie, Germany.
Exp Clin Endocrinol Diabetes. 2000;108(5):341-6. doi: 10.1055/s-2000-8126.
The peroxisome proliferator activated receptors-gamma (PPARgamma) belong to the superfamily of nuclear transcription factors acting as master genes regulating events in adipocyte differentiation. Thus, PPARgamma is a candidate gene for affecting insulin sensitivity and the pathogenesis of insulin resistance. PPARs trigger endocrine response of two important adipose tissue-derived signalling factors, leptin and tumor necrosis factor-alpha. Leptin is the afferent signal in a negative feedback loop regulating adipose tissue mass and energy balance. It generates insulin-like signals for glucose transport and glycogen synthesis via leptin receptors and the PI3-kinase and could, therefore, play a role as a mediator of obesity-related insulin resistance. Recently, a silent substitution in the coding sequence of the PPARgamma2 gene, leading to the substitution of a C by a T in exon 6 (nt 161), was described. In a recent study, it was proposed that mutations in PPARgamma could play a role in individuals who are at increased risk for developing obesity and type 2 diabetes mellitus by influencing leptin levels. We therefore examined the prevalence of the CAC(His) --> CAT(His) mutation in non-diabetic first degree relatives of subjects with type 2 diabetes to determine a possible association of this mutation to leptin levels and insulin sensitivity. 138 probands were characterised by oral glucose tolerance tests, euglycemic-hyperinsulinemic glucose-clamp and by measuring leptin levels. We found 93 (67.4%) probands without the CAC(His) --> CAT(His) substitution and 45 heterozygotes (36.6%). When the whole group was analysed for an association of the mutation with plasma leptin concentration and insulin sensitivity, no statistical significance could be demonstrated. Independently of the mutation, leptin levels were significantly (p<0.001) higher in female subjects.
过氧化物酶体增殖物激活受体γ（PPARγ）属于核转录因子超家族，作为调控脂肪细胞分化过程的主控基因发挥作用。因此，PPARγ是影响胰岛素敏感性及胰岛素抵抗发病机制的候选基因。PPAR可引发两种重要的脂肪组织衍生信号因子——瘦素和肿瘤坏死因子α的内分泌反应。瘦素是负反馈回路中的传入信号，调节脂肪组织质量和能量平衡。它通过瘦素受体、PI3激酶产生促进葡萄糖转运和糖原合成的胰岛素样信号，因此可能作为肥胖相关胰岛素抵抗的介质发挥作用。最近，有人描述了PPARγ2基因编码序列中的一个沉默替换，导致第6外显子（第161位核苷酸）中的C被T替换。在最近的一项研究中，有人提出PPARγ突变可能通过影响瘦素水平，在肥胖和2型糖尿病发病风险增加的个体中发挥作用。因此，我们检测了2型糖尿病患者非糖尿病一级亲属中CAC（组氨酸）→CAT（组氨酸）突变的发生率，以确定该突变与瘦素水平及胰岛素敏感性之间的可能关联。138名先证者通过口服葡萄糖耐量试验、正常血糖-高胰岛素血症葡萄糖钳夹试验及测量瘦素水平进行特征分析。我们发现93名（67.4%）先证者无CAC（组氨酸）→CAT（组氨酸）替换，45名杂合子（36.6%）。当对整个组分析该突变与血浆瘦素浓度及胰岛素敏感性的关联时，未发现统计学意义。与突变无关，女性受试者的瘦素水平显著更高（p<0.001）。
