Identification of novel biomarkers to monitor β-cell function and enable early detection of type 2 diabetes risk

Aug 2017

A decline in β-cell function is a prerequisite for the development of type 2 diabetes, yet the level of β-cell function in individuals at risk of the condition is rarely measured. This is due, in part, to the fact that current methods for assessing β-cell function are inaccurate, prone to error, labor-intensive, or affected by glucose-lowering therapy. The aim of the current study was to identify novel circulating biomarkers to monitor β-cell function and to identify individuals at high risk of developing β-cell dysfunction. In a nested case-control study from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) cohort (n = 1157), proteomics and miRNA profiling were performed on fasting plasma samples from 43 individuals who progressed to impaired glucose tolerance (IGT) and 43 controls who maintained normal glucose tolerance (NGT) over three years. Groups were matched at baseline for age, gender, body mass index (BMI), insulin sensitivity (euglycemic clamp) and β-cell glucose sensitivity (mathematical modeling). Proteomic profiling was performed using the SomaLogic platform (Colorado, USA); miRNA expression was performed using a modified RT-PCR protocol (Regulus Therapeutics, California, USA). Results showed differentially expressed proteins and miRNAs including some with known links to type 2 diabetes, such as adiponectin, but also novel biomarkers and pathways. In cross sectional analysis at year 3, the top differentially expressed biomarkers in people with IGT/ reduced β-cell glucose sensitivity were adiponectin, alpha1-antitrypsin (known to regulate adiponectin levels), endocan, miR-181a, miR-342, and miR-323. At baseline, adiponectin, cathepsin D and NCAM.L1 (proteins expressed by pancreatic β-cells) were significantly lower in those that progressed to IGT. Many of the novel prognostic biomarker candidates were within the epithelial-mesenchymal transition (EMT) pathway: for example, Noggin, DLL4 and miR-181a. Further validation studies are required in additional clinical cohorts and in patients with type 2 diabetes, but these results identify novel pathways and biomarkers that may have utility in monitoring β-cell function and/ or predicting future decline, allowing more targeted efforts to prevent and intercept type 2 diabetes.

Article PDF cannot be displayed. You can download it here:

https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0182932&type=printable

Identification of novel biomarkers to monitor β-cell function and enable early detection of type 2 diabetes risk

RESEARCH ARTICLE Identification of novel biomarkers to monitor β-cell function and enable early detection of type 2 diabetes risk Kirstine J. Belongie1, Ele Ferrannini2, Kjell Johnson3, Patricia Andrade-Gordon1, Michael K. Hansen1‡, John R. Petrie4‡* a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 1 Cardiovascular and Metabolic Disease Research, Janssen Research & Development, Spring House, Pennsylvania, United States of America, 2 CNR Institute of Clinical Physiology, Pisa, Italy, 3 Arbor Analytics, Ann Arbor, Michigan, United States of America, 4 Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom ‡ These authors are joint senior authors on this work. * Abstract OPEN ACCESS Citation: Belongie KJ, Ferrannini E, Johnson K, Andrade-Gordon P, Hansen MK, Petrie JR (2017) Identification of novel biomarkers to monitor β-cell function and enable early detection of type 2 diabetes risk. PLoS ONE 12(8): e0182932. https:// doi.org/10.1371/journal.pone.0182932 Editor: Bridget Wagner, Broad Institute, UNITED STATES Received: December 22, 2016 Accepted: July 26, 2017 Published: August 28, 2017 Copyright: © 2017 Belongie et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: This work was funded by an unrestricted grant from Janssen Pharmaceuticals. The Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study was partly supported by EU Framework V Program Grant QLG1-CT-2001-01252 with additional funding from AstraZeneca (Sweden). RISC is run by the European Group for the study of Insulin Resistance A decline in β-cell function is a prerequisite for the development of type 2 diabetes, yet the level of β-cell function in individuals at risk of the condition is rarely measured. This is due, in part, to the fact that current methods for assessing β-cell function are inaccurate, prone to error, labor-intensive, or affected by glucose-lowering therapy. The aim of the current study was to identify novel circulating biomarkers to monitor β-cell function and to identify individuals at high risk of developing β-cell dysfunction. In a nested case-control study from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) cohort (n = 1157), proteomics and miRNA profiling were performed on fasting plasma samples from 43 individuals who progressed to impaired glucose tolerance (IGT) and 43 controls who maintained normal glucose tolerance (NGT) over three years. Groups were matched at baseline for age, gender, body mass index (BMI), insulin sensitivity (euglycemic clamp) and β-cell glucose sensitivity (mathematical modeling). Proteomic profiling was performed using the SomaLogic platform (Colorado, USA); miRNA expression was performed using a modified RT-PCR protocol (Regulus Therapeutics, California, USA). Results showed differentially expressed proteins and miRNAs including some with known links to type 2 diabetes, such as adiponectin, but also novel biomarkers and pathways. In cross sectional analysis at year 3, the top differentially expressed biomarkers in people with IGT/ reduced β-cell glucose sensitivity were adiponectin, alpha1-antitrypsin (known to regulate adiponectin levels), endocan, miR-181a, miR-342, and miR-323. At baseline, adiponectin, cathepsin D and NCAM.L1 (proteins expressed by pancreatic β-cells) were significantly lower in those that progressed to IGT. Many of the novel prognostic biomarker candidates were within the epithelial-mesenchymal transition (EMT) pathway: for example, Noggin, DLL4 and miR-181a. Further validation studies are required in additional clinical cohorts and in patients with type 2 diabetes, but these results identify novel pathways and biomarkers that may have utility in monitoring β-cell function and/ or predicting future decline, allowing more targeted efforts to prevent and intercept type 2 diabetes. PLOS ONE | https://doi.org/10.1371/journal.pone.0182932 August 28, 2017 1 / 18 Novel biomarkers of β-cell function (EGIR) which at the time of this manuscript submission was supported by Novo Nordisk (Europe). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Janssen Research & Development (KJB, PAG, MKH) and Arbor Analytics (KJ) provided support in the form of salaries for authors (as per initials) but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of each author is articulated in the ‘author contributions’ section. Competing interests: Dr. Petrie reports personal fees via his employer the University of Glasgow from Novo Nordisk; grants, personal fees and nonfinancial support from Sanofi Aventis via his employer; non-financial support from Merck (Germany); personal fees from Lilly, non-financial support from Itamar Medical, grants from JDRF (US Charity), grants and personal fees from Quintiles, personal fees from Janssen, personal fees from Boehringer Ingelheim. MKH, PAG, and KJB are employees of Janssen Research & Development, LLC. Dr. Ferrannini reports consulting/speaker fee from Boehringer-Ingelheim/ Lilly, MSD, Sanofi, Janssen, and Mitsubishi, and grant support from Boehringer-Ingelheim/Lilly. Funding support was received from Janssen Pharmaceuticals, Novo Nordisk (Europe) and AstraZeneca (Sweden). Kjell Johnson is employed by Arbor Analytics LLC. Kirstine J. Belongie, Patricia Andrade-Gordon, and Michael K. Hansen are employed by Janssen Research & Development LLC. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors. Introduction Type 2 Diabetes is a heterogeneous disease caused by insulin resistance, β-cell insufficiency or a combination of both but the specific pathophysiology of the disease in the individual patient is usually unknown. Currently, methods of measuring β-cell function are inaccurate, prone to error, laborintensive, or affected by glucose-lowering therapy. For example, in the ADOPT study, the βcell function parameter HOMA-B was biased by the acute effects of glyburide, a sulfonylurea that increases insulin secretion, in that a large apparent “improvement” in β-cell function in the first year was followed by a sharp decline. During years 4 and 5 of the study, overall HbA1c deteriorated much faster with glyburide than with metformin or rosiglitazone therapy while HOMA-B remained stable [1]. Progression to type 2 diabetes is associated with a decline in β-cell function usually (...truncated)


This is a preview of a remote PDF: https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0182932&type=printable
Article home page: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0182932

Kirstine J. Belongie, Ele Ferrannini, Kjell Johnson, Patricia Andrade-Gordon, Michael K. Hansen, John R. Petrie. Identification of novel biomarkers to monitor β-cell function and enable early detection of type 2 diabetes risk, 2017, Volume 12, Issue 8, DOI: 10.1371/journal.pone.0182932