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

描述（由申请人提供）：越来越多的常见遗传变异与2型糖尿病（T2D）有可靠且可重复的关联。尽管取得了这些进展，但与增加T2D风险有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。通过在二甲双胍存在的情况下使用磺脲类药物或葡萄糖对人类受试者进行挑战，我们希望：1)根据与T2D或相关血糖特征相关位点的基因型或影响任一药物代谢的基因型区分反应；2)通过使用380种代谢物（包括脂质代谢物）的更大样本来检测人体对葡萄糖负荷的反应，确认并扩展胰岛素抵抗的新代谢组学特征；3)通过区分葡萄糖反应与胰岛素促分泌剂反应的代谢组学特征来区分胰岛素和葡萄糖反应的成分；4)评估精制代谢组学特征与预测胰岛素抵抗的遗传位点的相关性。如果成功，这一建议将有助于阐明遗传变异增加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药物的预期作用，或者是否可以通过药物克服，都将是临床关注的问题。此外，这项研究应该为长期的基于结果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. PUBLIC HEALTH RELEVANCE: Recent studies have identified a growing number of common genetic variants that are reproducibly associated with type 2 diabetes. Despite these advances, the precise identity of the genes involved in increasing diabetes risk has not yet been established, because in most cases the association signals detected merely signal genomic regions that are overrepresented in cases versus controls. We propose to use pharmacogenetic (describing the human response to a pharmacologic perturbation based on the genetic background of the individual) and metabolomic (describing the various metabolites that appear in serum in response to a perturbation) approaches to inform the searches for causal variants and better define the molecular pathways involved.