Association of the SLC30A8 missense polymorphism R325W with proinsulin levels at baseline and after lifestyle, metformin or troglitazone intervention in the Diabetes Prevention Program.
Association of the SLC30A8 missense polymorphism R325W with proinsulin levels at baseline and after lifestyle, metformin or troglitazone intervention in the Diabetes Prevention Program.
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DOI：
10.1007/s00125-011-2234-1
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发表时间：
2011-10
期刊：
影响因子：
8.2
通讯作者：
Florez, J. C.
中科院分区：
文献类型：
--
作者：
Majithia, A. R.;Jablonski, K. A.;McAteer, J. B.;Mather, K. J.;Goldberg, R. B.;Kahn, S. E.;Florez, J. C.
关键词：
葡萄糖耐量受损的个体具有增加的胰岛素原水平，尽管正常的葡萄糖或C-肽水平。在糖尿病预防计划（DPP）中，胰岛素原水平升高可预测2型糖尿病，与安慰剂相比，二甲双胍、生活方式改变或曲格列酮治疗后胰岛素原水平显著降低。遗传和生理学研究表明锌转运蛋白基因SLC 30 A8在糖尿病风险中的作用，可能是通过影响β细胞中的胰岛素加工。我们假设SLC 30 A8中2型糖尿病相关错义多态性rs 13266634（R325 W）的风险等位基因可以预测2型糖尿病风险个体的胰岛素原水平，并可能调节对预防干预的反应。我们对3,007名DPP参与者进行rs 13266634基因分型，并在基线和干预后1年检查其与空腹胰岛素原和空腹胰岛素的相关性。我们发现，SLC 30 A8 rs 13266634处C风险等位基因剂量的增加与基线胰岛素原水平的升高显著相关（p=0.002）。这支持了SLC 30 A8的风险等位基因标记具有胰岛素加工缺陷的个体的假设。在1年分析中，接受积极干预的所有组中胰岛素原水平均显著降低，并且在基线和1年时调整胰岛素后，胰岛素原水平不再与SLC 30 A8基因型相关（p=0.86）。我们在1年时未发现基因型×治疗相互作用。在糖尿病前期个体中，SLC 30 A8基因型独立于胰岛素水平预测基线胰岛素原水平，但不能预测1年后胰岛素敏感性改善后的胰岛素原水平。
Individuals with impaired glucose tolerance have increased proinsulin levels, despite normal glucose or C-peptide levels. In the Diabetes Prevention Program (DPP), increased proinsulin levels predicted type 2 diabetes and proinsulin levels were significantly reduced following treatment with metformin, lifestyle modification or troglitazone compared with placebo. Genetic and physiological studies suggest a role for the zinc transporter gene SLC30A8 in diabetes risk, possibly through effects on insulin-processing in beta cells. We hypothesised that the risk allele at the type 2 diabetes-associated missense polymorphism rs13266634 (R325W) in SLC30A8 would predict proinsulin levels in individuals at risk of type 2 diabetes and may modulate response to preventive interventions. We genotyped rs13266634 in 3,007 DPP participants and examined its association with fasting proinsulin and fasting insulin at baseline and at 1 year post-intervention. We found that increasing dosage of the C risk allele at SLC30A8 rs13266634 was significantly associated with higher proinsulin levels at baseline (p=0.002) after adjustment for baseline insulin. This supports the hypothesis that risk alleles at SLC30A8 mark individuals with insulin-processing defects. At the 1 year analysis, proinsulin levels decreased significantly in all groups receiving active intervention and were no longer associated with SLC30A8 genotype (p=0.86) after adjustment for insulin at baseline and 1 year. We found no genotype × treatment interactions at 1 year. In prediabetic individuals, genotype at SLC30A8 predicts baseline proinsulin levels independently of insulin levels, but does not predict proinsulin levels after amelioration of insulin sensitivity at 1 year.
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