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

Abstract

High-throughput proteomics allows 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 (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 β-glucuronidase, which was associated with increased diabetes risk and lower SG, suggesting an alternative pathway 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.

Article highlights: Plasma proteins are associated with the risk of incident diabetes in older adults independent of various demographic, lifestyle, and biochemical risk factors. These same proteins are associated with subtle differences in measures of glucose homeostasis earlier in life. Proteins that are associated with lower insulin sensitivity in individuals without diabetes tend to be associated with appropriate compensatory mechanisms, such as a stronger acute insulin response or higher glucose effectiveness. Proteins that are associated with future diabetes risk, but not with insulin insensitivity, tend to be associated with lower glucose effectiveness and/or impaired acute insulin response.

Graphical abstract

Figure 1

Comparison of association plots of incident type 2 diabetes associations in the CHS cohort and S_I in the HERITAGE cohort. Proteins are labeled using their Entrez gene symbol. All proteins were associated with incident type 2 diabetes at P < 1.04 × 10⁻⁵ upon adjustment for age, sex, race, clinic site, and estimated glomerular filtration rate. Green indicates a protein associated with S_I at P < 0.05 upon adjustment for age, sex, race, family grouping, BMI, smoking status, and alcohol consumption status. Grey indicates a statistically nonsignificant protein–S_I association. Because of their strong effect sizes, IGFBP1, IGFBP2, and LEP are plotted off the axes in some of the panels to ensure that other proteins can be better visualized.

Figure 2

Comparison of association plots of AIR_G. A: Protein associations with AIR_G versus with S_I in the HERITAGE cohort. B: Protein associations with AIR_G in the HERITAGE cohort versus with incident type 2 diabetes associations in the CHS cohort. Proteins are labeled using their Entrez gene symbol. All proteins were associated with incident type 2 diabetes at P < 1.04 × 10⁻⁵ upon adjustment for age, sex, race, clinic site, and estimated glomerular filtration rate. Orange and green indicate a protein associated with AIR_G or S_I, respectively, at P < 0.05 upon adjustment for age, sex, race, family grouping, BMI, smoking status, and alcohol consumption status. Red and grey respectively indicate that both or neither association(s) were statistically significant. Because their strong effect sizes, IGFBP1, IGFBP2, and LEP are plotted off the axes in some of the panels to ensure that other proteins can be better visualized.

Figure 3

Comparison of association plots of S_G. A: Protein associations with S_G versus with S_I in the HERITAGE cohort. B: Protein associations with S_G in the HERITAGE cohort versus with incident type 2 diabetes associations in the CHS cohort. Proteins are labeled using their Entrez gene symbol. All proteins were associated with incident type 2 diabetes at P < 1.04 × 10⁻⁵ upon adjustment for age, sex, race, clinic site, and estimated glomerular filtration rate. Purple and green indicate a protein associated with S_G or S_I, respectively, at P < 0.05 upon adjustment for age, sex, race, family grouping, BMI, smoking status, and alcohol consumption status. Red and grey respectively indicate that both or neither association(s) were statistically significant. Because of their strong effect sizes, IGFBP1, IGFBP2, and LEP are plotted off the axes in some of the panels to ensure that other proteins can be better visualized.