Study to Understand the Genetics of the Acute Response to Metformin & Glipizide

描述(由申请人提供)：越来越多的常见基因变异与2型糖尿病(T2D)密切相关，并具有重复性。尽管取得了这些进展，但与增加T2D风险相关的基因的确切身份尚未确定。我们建议使用药物遗传学和代谢组学方法来为因果变异的搜索提供信息，并更好地定义所涉及的分子途径。通过用磺酰尿素或在二甲双胍存在的情况下用葡萄糖挑战受试者，我们希望1)区分依赖于与T2D或相关血糖特征相关的基因座上的基因型的反应，或影响这两种药物的新陈代谢的基因座；2)通过检测人类对380种代谢物(包括脂肪代谢物)对葡萄糖负荷的反应，确认并扩大胰岛素抵抗的新出现的代谢特征；3)通过区分对葡萄糖的反应和对胰岛素促分泌剂的反应，区分这种反应的胰岛素和葡萄糖成分；以及4)评估精炼的代谢特征与预测胰岛素抵抗的遗传基因座之间的关联程度。如果成功，这项建议将有助于阐明基因变异增加T2D风险的机制，并评估它们对常用疗法的影响。基因缺陷是否足以阻止任何一种药物的预期作用，或者是否可以通过药物克服，都将是临床上感兴趣的问题。此外，这项研究应该为一项更长期的以结果为基础的药物遗传学试验奠定基础。

DESCRIPTION (provided by applicant): A growing number of common genetic variants have been robustly and reproducibly associated with type 2 diabetes (T2D). Despite these advances, the precise identity of the genes involved in increasing T2D risk has not yet been established. We propose to use pharmacogenetic and metabolomic approaches to inform the searches for causal variants and better define the molecular pathways involved. By challenging human subjects with a sulfonylurea or with glucose in the presence of metformin we hope to 1) distinguish responses depending on genotype at loci associated with T2D or related glycemic traits, or which impact metabolism of either drug; 2) confirm and expand an emerging metabolomic signature of insulin resistance by examining the human response to a glucose load with a larger panel of 380 metabolites (including lipid metabolites), 3) distinguish between the insulin and the glucose components of such response by discriminating the metabolomic profile in response to glucose versus the response to an insulin secretagogue; and 4) evaluate to what extent the refined metabolomic signature is correlated with genetic loci that predict insulin resistance. If successful, this proposal should help clarify the mechanisms by which genetic variants increase risk of T2D, and assess their impact on commonly used therapies. Whether the genetic defect is sufficient to prevent the expected action of either drug, or whether it can be overcome pharmacologically, would both be of clinical interest. In addition, this study should lay the groundwork for a longer outcomes-based pharmacogenetic trial.