Serum biomarker correlates of insulin secretion in individuals at risk of type 1 diabetes

Abstract

Type 1 diabetes mellitus (T1D) is characterised by b-cell dysfunction in the prediabetes phase. These abnormalities, along with islet antibody (AB) positivity determine risk of progression to diabetes, however there is considerable variation in the rate of b-cell decline. Progression to diabetes is associated with reduction in total insulin secretion (ISR AUC) derived from the oral glucose tolerance test. This reduction is associated with an increase in beta-cell death Additional biomarkers are needed to more accurately predict disease progression, elucidate heterogeneous mechanisms of disease and identify potential response to immunotherapy. In a Brisbane cohort of first-degree relatives (FDR) at risk of T1D, we profiled serum for potential discriminatory biomarkers. We identified three typical signatures, comprising a group of inflammatory cytokines/chemokines demethylated insulin DNA, and metabolic factors. To determine the relationship of these serum markers to diabetes progression, we profiled serum from at-risk FDR from the Trialnet Natural History Study comprising 30 AB-, 30 AB1+, 30 AB2+ and 30 children who progressed to T1D. ISR AUC was significantly lower in progressors than the non-progressor groups (ANOVA, p = 0.0008), however there was considerable variation amongst those who progressed to T1D. We found significant correlations between AUC insulin and twenty serum markers. Using a multiple linear regression model, we identified three inflammatory cytokines/chemokines and three clinical parameters which explained AUC insulin (R = 0.85, p = 2 × 10-16). Our findings demonstrate that a combination of inflammatory and metabolic factors contribute to reduced insulin secretion in the pre-diabetic phase, however there is significant variation in the rate of beta cell functional decline.L720733352015-11-20 <br />