Plasma proteomic risk markers of incident type 2 diabetes reflect physiologically distinct components of glucose-insulin homeostasis

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.