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（T2 D）密切相关。尽管取得了这些进展，但尚未确定增加T2 D风险的基因的确切身份。 我们建议使用药物遗传学和代谢组学的方法，通知搜索的因果变异，并更好地定义所涉及的分子途径。通过在二甲双胍存在下用磺酰脲类或葡萄糖激发人类受试者，我们希望1）根据与T2 D或相关血糖性状相关的基因座或影响任一药物代谢的基因座的基因型来区分应答; 2）通过用380种代谢物的更大组检查人对葡萄糖负荷的响应，确认和扩展胰岛素抵抗的新兴代谢组学特征（包括脂质代谢物），3）通过区分响应于葡萄糖的代谢组学谱与响应于胰岛素促分泌素的代谢组学谱来区分这种响应的胰岛素和葡萄糖组分;和4）评估精确的代谢组学特征与预测胰岛素抗性的遗传基因座相关的程度。 如果成功的话，这一提议将有助于阐明遗传变异增加T2 D风险的机制，并评估其对常用疗法的影响。基因缺陷是否足以阻止任何一种药物的预期作用，或者它是否可以被克服，都将是临床感兴趣的。此外，这项研究应该为更长时间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.