Nephropathy in type I diabetes: A manifestation of insulin resistance and multiple genetic susceptibilities? Further evidence from the Pittsburgh Epidemiology of Diabetes Complication Study
Nephropathy in type I diabetes: A manifestation of insulin resistance and multiple genetic susceptibilities? Further evidence from the Pittsburgh Epidemiology of Diabetes Complication Study
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DOI：
10.1046/j.1523-1755.2002.00507.x
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发表时间：
2002-09-01
影响因子：
19.6
通讯作者：
Ellis, DE
中科院分区：
文献类型：
--
作者：
Orchard, TJ;Chang, YF;Ellis, DE
背景资料。糖尿病肾病的发病机制尚不清楚，尽管先前的报道涉及广泛的可能的遗传和代谢因素。研究了匹兹堡糖尿病并发症流行病学研究(一项关于儿童发病的1型糖尿病患者发病队列的前瞻性流行病学研究)中的显性肾病(ON)事件和流行病例，其定义为三个计时尿中至少两个尿白蛋白排泄率为200µg/min。发病率分析显示，单变量基线风险因素在测量后5年内[低密度脂蛋白(LDL)胆固醇、甘油三酯、白细胞计数和高血压]与长期预测(即基线后6至10年)的血红蛋白A(1)(Hb A(1))存在差异。然而，估计的葡萄糖处置速率(使用正常血糖-高胰岛素钳夹研究得出的公式计算)，在整个随访过程中强烈预测(P<；0.001)。比较最易患ON的个体(在1型糖尿病病程20年前和其他晚期并发症发生之前)和最不易感的个体(尽管有其他晚期并发症，但迟发或未发生ON)，发现其他未被检测到的遗传关联[即载脂蛋白E(ApoE)、血管紧张素转换酶插入/缺失(ACE I/D)和脂蛋白脂酶(LPL)HindIll多态性]，优势比为2.9~7.1。在1型糖尿病中，胰岛素抵抗是ON的潜在风险状态，其他干扰因素(例如高血压和血脂异常)可能会加速ON的发生。一种新的对受试者进行分类(即表型)的方法，通过比较那些处于极端易感状态的受试者，揭示了与其他不明显的风险因素之间的强烈遗传关联和重要相互作用。
Background. The pathogenesis of diabetic nephropathy remains unclear, although previous reports implicate a wide range of putative genetic and metabolic factors.Methods. Incident and prevalent cases of overt nephropathy (ON), defined as an albumin excretion rate >200 mug/min in at least two of the three timed urines, from the Pittsburgh Epidemiology of Diabetes Complication Study (a prospective epidemiologic study of an incident cohort of childhood onset type 1 diabetic subjects) were studied.Results. Incidence analyses reveal differences in univariate baseline risk factors that predict ON within 5 years of measurement [low-density lipoprotein (LDL) cholesterol, triglycerides, white blood cell count, and hypertension] and those that predict in the long-term, that is, 6 to 10 years after baseline, hemoglobin A(1) (Hb A(1)). Estimated glucose disposal rate (calculated using a formula derived from euglycemic-hyperinsulinemic clamp studies), however, strongly (P < 0.001) predicted ON throughout follow-up. Comparing individuals who were most susceptible to ON (those with an onset before 20 years duration of type 1 diabetes and before the development of other advanced complications) with the least susceptible (late or no occurrence of ON despite the development of other advanced complications) revealed otherwise undetected genetic associations [that is, apolipoprotein E (Apo E), angtiotensin-converting enzyme insertion/deletion (ACE I/D), and lipoprotein lipase (LPL) HindIll polymorphism) with odds ratios ranging from 2.9 to 7.1.Conclusions. In type 1 diabetes insulin resistance is an underlying risk state for ON, which may be accelerated by other disturbances (for example, hypertension and dyslipidemia). A novel approach to classifying (that is, phenotyping) subjects, which compares those at the extremes of susceptibility, reveals strong genetic associations and important interactions with other risk factors not otherwise apparent.