Plasma Proteomic Risk Markers of Incident Type 2 Diabetes Reflect Physiologically Distinct Components of Glucose-Insulin Homeostasis

Abstract

High-throughput proteomics allows researchers to simulta-neously explore the roles of thousands of biomarkers in the pathophysiology of diabetes. We conducted proteomic association studies of incident type 2 diabetes and physio-logic responses to an intravenous glucose tolerance test (IVGTT) to identify novel protein contributors to glucose ho-meostasis 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 (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 index (SI), acute insulin response to glucose (AIRG), and glucose effectiveness (SG). Twelve of the 51 diabetes associations appear to be novel, including b-glucuronidase, which was associated with increased diabetes risk and lower SG, suggesting an alternative path-way to insulin for glucose disposal; and plexin-B2, which also was 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, sorbitol dehydrogenase with elevated type 2 diabetes risk, and a leucine-rich repeat containing protein-15 and myocilin with decreased risk.