Proinsulin as a Biomarker for Beta-Cell Function in a Diverse Cohort

Declining beta-cell function is a key component in the development of type 2 diabetes (T2D). Early in disease progression, first-phase insulin secretion deteriorates, precipitating impaired glucose tolerance. Markers for early beta-cell decline could assist in identifying individuals at risk for disease progression, particularly among demographic groups at elevated risk for T2D. This study was designed to test the hypothesis that proinsulin concentrations would be inversely associated with first-phase beta-cell function, as reflected in the Disposition Index (DI), in a diverse cohort of young individuals without T2D. Participants were 117 men and women of African-American and European-American descent aged 19-45 years with normal glucose tolerance. An oral-glucose tolerance test (OGTT) was used to measure proinsulin concentrations and assess beta-cell function. Mathematical modeling was used to estimate insulin sensitivity (Si) and indices of beta-cell function specific to basal, first-phase, second-phase, and total insulin secretion (PhiB, PhiD, PhiS, PhiTot, respectively). First-phase DI (DId) was calculated as Si x PhiD and second-phase DI (DIs) as Si x PhiS. Proinsulin concentrations were normalized for C-peptide. Fasting and 2-h proinsulin concentrations were inversely associated with DId (r=-0.21, p=0.02 and r=-0.22, p=0.01, respectively). Neither fasting nor 2-h proinsulin concentrations were significantly associated with DIs. African-Americans, who as a group have an elevated prevalence of T2D, had 25% higher concentrations of fasting proinsulin and 18% higher concentrations of 2-h proinsulin compared to EA (p=0.001 and p=0.01, respectively). Proinsulin may be a practical biomarker for first-phase beta-cell function that could assist in identification of individuals at risk for T2D who would benefit from interventions to prevent deterioration of glucose metabolism. Disclosure C. Couch: None. B. Gower: Advisory Panel; Self; Abbott. F. Piccinini: Employee; Self; Medtronic. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK096388); Nutrition Obesity Research Center (P30DK056336); Diabetes Research Center (P30DK079626); National Heart, Lung, and Blood Institute (T32HL105349)