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

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posted on 2023-02-07, 21:12 authored by Héléne T. Cronjé, Michael Y. Mi, Thomas R. Austin, Mary L. Biggs, David S. Siscovick, Rozenn N. Lemaitre, Bruce M. Psaty, Russell P. Tracy, Luc Djoussé, Jorge R. Kizer, Joachim H. Ix, Prashant Rao, Jeremy M. Robbins, Jacob L. Barber, Mark A. Sarzynski, Clary B. Clish, Claude Bouchard, Kenneth J. Mukamal, Robert E. Gerszten, Majken K. Jensen

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.

Funding

The Cardiovascular Health Study was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and 75N92021D00006, and grants U01HL080295, U01HL130114, and R01HL144483 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). The HERITAGE Family Study was initially funded by the NHLBI through the following grants: HL45670 (C. Bouchard, PI) from 1992 to 2010, HL47317 (D. C. Rao, PI) from 1992 to 2010, HL47321 (J.H. Wilmore, PI) from 1992 to 2003, HL47323 (A. S. Leon, PI) from 1992 to 2003, and HL47327 (J.S. Skinner, PI) from 1992 to 2003. Current funding for HERITAGE is provided to Dr. Sarzynski (R01HL146462) and to Drs. Gerszten and Sarzynski (R01NR019628). H.T.C. and M.K.J. are supported by grants from the Novo Nordic Foundation Challenge Programme: Harnessing the Power of Big Data to Address the Societal Challenge of Aging (NNF17OC0027812). M.Y.M. is supported by NIH 5T32HL007208. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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