A proteomic signature that reflects pancreatic beta-cell function

Aoife M Curran,Marie Pier Scott-Boyer,Miriam F Ryan,Lorraine Brennan,Michael J Gibney,Eileen R Gibney,Elaine Drummond,Jim Kaput,Helen M Roche,Corentin Cras-Méneur

doi:10.1371/journal.pone.0202727

Abstract

AimProteomics has the potential to enhance early identification of beta-cell dysfunction, in conjunction with monitoring the various stages of type 2 diabetes onset. The most routine method of assessing pancreatic beta-cell function is an oral glucose tolerance test, however this method is time consuming and carries a participant burden. The objectives of this research were to identify protein signatures and pathways related to pancreatic beta-cell function in fasting blood samples.MethodsBeta-cell function measures were calculated for MECHE study participants who completed an oral glucose tolerance test and had proteomic data (n = 100). Information on 1,129 protein levels was obtained using the SOMAscan assay. Receiver operating characteristic curves were used to assess discriminatory ability of proteins of interest. Subsequent in vitro experiments were performed using the BRIN-BD11 pancreatic beta-cell line. Replication of findings were achieved in a second human cohort where possible.ResultsTwenty-two proteins measured by aptamer technology were significantly associated with beta-cell function/HOMA-IR while 17 proteins were significantly associated with the disposition index (p ≤ 0.01). Receiver operator characteristic curves determined the protein panels to have excellent discrimination between low and high beta-cell function. Linear regression analysis determined that beta-endorphin and IL-17F have strong associations with beta-cell function/HOMA-IR, β = 0.039 (p = 0.005) and β = -0.027 (p = 0.013) respectively. Calcineurin and CRTAM were strongly associated with the disposition index (β = 0.005 and β = 0.005 respectively, p = 0.012). In vitro experiments confirmed that IL-17F modulated insulin secretion in the BRIN-BD11 cell line, with the lower concentration of 10 ng/mL significantly increasing glucose stimulated insulin secretion (p = 0.043).ConclusionsEarly detection of compromised beta-cell function could allow for implementation of nutritional and lifestyle interventions before progression to type 2 diabetes.

Highlights

The prevalence of obesity has escalated dramatically in recent decades, throughout most of the Western world and much of the developing world [1] with a concomitant increase globally of the incidence of type 2 diabetes (T2D) [2]
Detection of compromised beta-cell function could allow for implementation of nutritional and lifestyle interventions before progression to type 2 diabetes
Poor insulin sensitivity with increasing obesity typically leads to impaired glucose tolerance and pre-diabetes, which is estimated to affect 37% of the U.S population [3]

Summary

Introduction

The prevalence of obesity has escalated dramatically in recent decades, throughout most of the Western world and much of the developing world [1] with a concomitant increase globally of the incidence of type 2 diabetes (T2D) [2]. Poor insulin sensitivity with increasing obesity typically leads to impaired glucose tolerance and pre-diabetes, which is estimated to affect 37% of the U.S population [3]. Cathepsin D, leptin, interleukin 1 receptor antagonist, tissue plasminogen activator, renin, hepatocyte growth factor and fatty acid binding protein 4 have been identified as biomarkers of insulin resistance (HOMA-IR) in two non-diabetic community cohorts (n = 1367) [11]. Retinol binding protein (RBP4) was increased in fasting plasma samples of individuals with impaired glucose tolerance (n = 11) compared to healthy controls (n = 44) [12]. Plasminogen activator inhibitor-1 (PAI1) was linked to T2D in a number of observational studies, with increased levels of PAI-1 in individuals with T2D [13, 14]

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