Globerman H, Zauberman Y, Makarov T, Beamer B A, Yen C J, Shuldiner A R, Harel C, Karnieli E
Institute of Endocrinology, Diabetes & Metabolism, Rambam Medical Centre and B. Rappaport Faculty of Medicine Technion, Haifa, Israel.
Clin Endocrinol (Oxf). 2000 Apr;52(4):479-85. doi: 10.1046/j.1365-2265.2000.00950.x.
To test the hypothesis that the triad of hyperandrogenism, insulin resistance and acanthosis nigricans (HAIRAN syndrome) in the presence of obesity, also known as type C insulin resistance, is caused by mutations in the gene for peroxisome proliferator activated receptor gamma (PPARgamma), a receptor for the thiazolidinedione drugs that enhance sensitivity to insulin. To investigate possible correlations between mutations in PPARgamma and the degree of insulin resistance.
A candidate gene approach to study the molecular basis for a syndrome of obesity; a comparison of genotype with in vivo phenotype.
Fifteen unrelated patients with HAIRAN syndrome and obesity. Controls for the gene analysis: 25 unrelated non-diabetic non-obese individuals. Controls for the metabolic studies: six unrelated patients with type 2 diabetes mellitus and nine unrelated non-diabetic non-obese individuals.
Analysis of polymerase chain reaction (PCR) products of the 7 exons that constitute the entire coding region of both PPARgamma isoforms (PPARgamma1 and PPARgamma2) for single-stranded conformational polymorphisms (SSCP); in exons with variant patterns: restriction fragment length polymorphism (RFLP) analysis; and, where relevant, direct sequencing. Evaluation of insulin resistance using the insulin euglycaemic clamp technique.
A synonymous substitution in codon 477 (CACHis --> CATHis) was found in one patient. A missense mutation in codon 12 of PPARgamma2 (CCAPro --> GCAAla) was found in another patient, but not in any of 25 non-diabetic, non-obese control individuals. The patient with the Pro12Ala variant had the highest steady state glucose infusion rate (SSGIR) and most marked suppression of hepatic glucose production rate (HGPR) of all of the patients studied.
Mutations in the PPARgamma gene are unlikely to be major contributors to HAIRAN syndrome with obesity. The Pro12Ala variant may correlate with a lesser degree of insulin resistance in these patients.
检验以下假设，即肥胖情况下的高雄激素血症、胰岛素抵抗和黑棘皮症三联征（HAIRAN综合征，也称为C型胰岛素抵抗）是由过氧化物酶体增殖物激活受体γ（PPARγ）基因的突变所引起，PPARγ是噻唑烷二酮类药物的受体，这类药物可增强胰岛素敏感性。研究PPARγ突变与胰岛素抵抗程度之间可能存在的相关性。
采用候选基因方法研究肥胖综合征的分子基础；对基因型与体内表型进行比较。
15名患有HAIRAN综合征和肥胖症的无血缘关系患者。基因分析的对照：25名无血缘关系的非糖尿病非肥胖个体。代谢研究的对照：6名无血缘关系的2型糖尿病患者和9名无血缘关系的非糖尿病非肥胖个体。
对构成两种PPARγ亚型（PPARγ1和PPARγ2）整个编码区的7个外显子的聚合酶链反应（PCR）产物进行单链构象多态性（SSCP）分析；对于具有变异模式的外显子：进行限制性片段长度多态性（RFLP）分析，并在相关情况下进行直接测序。使用胰岛素正常血糖钳夹技术评估胰岛素抵抗。
在一名患者中发现密码子477处的同义替换（CACHis --> CATHis）。在另一名患者中发现PPARγ2的密码子12处存在错义突变（CCAPro --> GCAAla），但在25名非糖尿病、非肥胖对照个体中均未发现。在所有研究的患者中，具有Pro12Ala变异的患者稳态葡萄糖输注率（SSGIR）最高，肝葡萄糖生成率（HGPR）的抑制最为明显。
PPARγ基因的突变不太可能是伴有肥胖的HAIRAN综合征的主要病因。Pro12Ala变异可能与这些患者中较轻程度的胰岛素抵抗相关。
