High-throughput proteomics allow researchers to simultaneously explore the roles of thousands of biomarkers in the pathophysiology of diabetes. We conducted proteomic association studies of incident type 2 diabetes and physiologic responses to an intravenous glucose tolerance test (IVGTT) to identify novel protein contributors to glucose homeostasis and diabetes risk. We tested 4,776 SomaScan® proteins measured in relation to 18-year incident diabetes risk in participants from the Cardiovascular Health Study (CHS, N=2,631), and IVGTT-derived measures in participants from the HERITAGE Family Study (N=752). We characterize 51 proteins that were associated with longitudinal diabetes risk, using their respective 39, 9, and 8 concurrent associations with insulin sensitivity (SI), acute insulin response to glucose (AIRG), and glucose effectiveness (SG). Twelve of the 51 diabetes associations were novel, including beta-glucuronidase, which associated with increased diabetes risk and lower SG, suggesting an alternative pathway to insulin for glucose disposal; and plexin-B2 which also associated with increased diabetes risk, but with lower AIRG, and not with SI, indicating a mechanism related instead to pancreatic dysfunction. Other novel protein associations included alcohol dehydrogenase-1C, fructose-bisphosphate aldolase-B, and sorbitol dehydrogenase with elevated type 2 diabetes risk, and leucine rich repeat containing protein-15 and myocilin with decreased risk.

中文翻译：

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2 型糖尿病的血浆蛋白质组风险标志物反映了葡萄糖-胰岛素稳态的生理上不同的组成部分

高通量蛋白质组学使研究人员能够同时探索数千种生物标志物在糖尿病病理生理学中的作用。我们对 2 型糖尿病事件和静脉葡萄糖耐量试验 (IVGTT) 的生理反应进行了蛋白质组学关联研究，以确定导致葡萄糖稳态和糖尿病风险的新蛋白质。我们测试了 4,776 种 SomaScan® 蛋白，这些蛋白与心血管健康研究 (CHS，N=2,631) 参与者的 18 年糖尿病风险相关，以及 HERITAGE 家庭研究 (N=752) 参与者的 IVGTT 衍生测量值。我们利用它们各自与胰岛素敏感性 (SI)、对葡萄糖的急性胰岛素反应 (AIRG) 和葡萄糖有效性 (SG) 的 39、9 和 8 个并发关联，描述了与纵向糖尿病风险相关的 51 种蛋白质。51 种糖尿病关联中有 12 种是新的，其中包括 β-葡萄糖醛酸酶，它与糖尿病风险增加和 SG 降低相关，这表明胰岛素处理葡萄糖的另一种途径；plexin-B2 也与糖尿病风险增加相关，但与较低的 AIRG 相关，而不与 SI 相关，表明与胰腺功能障碍相关的机制。其他新的蛋白质关联包括与 2 型糖尿病风险升高的乙醇脱氢酶-1C、果糖二磷酸醛缩酶-B 和山梨糖醇脱氢酶，以及与风险降低的蛋白 15 和肌纤蛋白富含亮氨酸重复序列。