Growth differentiation factor-15 and the association between type 2 diabetes and liver fibrosis in NAFLD
Growth differentiation factor-15 and the association between type 2 diabetes and liver fibrosis in NAFLD
Background: Type 2 diabetes mellitus (T2DM) is a strong risk factor for liver fibrosis in non-alcoholic fatty liver disease (NAFLD). It remains uncertain why T2DM increases the risk of liver fibrosis. It has been suggested that growth differentiation factor-15 (GDF-15) concentrations increase the risk of liver fibrosis. We aimed to investigate (a) whether GDF-15 concentrations were associated with liver fibrosis and involved in the relationship between T2DM and liver fibrosis and (b) what factors linked with T2DM are associated with increased GDF-15 concentrations. Methods: Ninety-nine patients with NAFLD (61% men, 42.4% T2DM) were studied. Serum GDF-15 concentrations were measured by electro-chemiluminescence immunoassay. Vibration-controlled transient elastography (VCTE)-validated thresholds were used to assess liver fibrosis. Regression modelling, receiver operator characteristic curve analysis and Sobel test statistics were used to test associations, risk predictors and the involvement of GDF-15 in the relationship between T2DM and liver fibrosis, respectively. Results: Patients with NAFLD and T2DM (n = 42) had higher serum GDF-15 concentrations [mean (SD): 1271.0 (902.1) vs. 640.3 (332.5) pg/ml, p < 0.0001], and a higher proportion had VCTE assessed ≥F2 fibrosis (48.8 vs. 23.2%, p = 0.01) than those without T2DM. GDF-15 was independently associated with liver fibrosis (p = 0.001), and GDF-15 was the most important single factor predicting ≥F2 or ≥F3 fibrosis (≥F2 fibrosis AUROC 0.75, (95% CI 0.63–0.86), p < 0.001, with sensitivity, specificity, positive predictive (PPV) and negative predictive (NPV) values of 56.3%, 86.9%, 69.2% and 79.1%, respectively). GDF-15 was involved in the association between T2DM and ≥F2 fibrosis (Sobel test statistic 2.90, p = 0.004). Other factors associated with T2DM explained 60% of the variance in GDF-15 concentrations (p < 0.0001). HbA1c concentrations alone explained 30% of the variance (p < 0.0001). Conclusions: GDF-15 concentrations are a predictor of liver fibrosis and potentially involved in the association between T2DM and liver fibrosis in NAFLD. HbA1c concentrations explain a large proportion of the variance in GDF-15 concentrations.
Bilson, Josh
a99f9320-335c-47c8-bf30-07df48a5467d
Scorletti, Eleonora
42bb0659-ac67-4a73-bf36-a881fe6c1563
Bindels, Laure B.
9993bc5b-9730-4e4c-b812-761c67349047
Afolabi, Paul
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Targher, Giovanni
043e0811-b389-4922-974e-22e650212c5f
Calder, Philip
1797e54f-378e-4dcb-80a4-3e30018f07a6
Sethi, Jaswinder K.
923f1a81-91e4-46cd-8853-bb4a979f5a85
Byrne, Christopher
1370b997-cead-4229-83a7-53301ed2a43c
18 October 2021
Bilson, Josh
a99f9320-335c-47c8-bf30-07df48a5467d
Scorletti, Eleonora
42bb0659-ac67-4a73-bf36-a881fe6c1563
Bindels, Laure B.
9993bc5b-9730-4e4c-b812-761c67349047
Afolabi, Paul
757e7f01-664c-493e-bc51-c6a2c933dc22
Targher, Giovanni
043e0811-b389-4922-974e-22e650212c5f
Calder, Philip
1797e54f-378e-4dcb-80a4-3e30018f07a6
Sethi, Jaswinder K.
923f1a81-91e4-46cd-8853-bb4a979f5a85
Byrne, Christopher
1370b997-cead-4229-83a7-53301ed2a43c
Bilson, Josh, Scorletti, Eleonora, Bindels, Laure B., Afolabi, Paul, Targher, Giovanni, Calder, Philip, Sethi, Jaswinder K. and Byrne, Christopher
(2021)
Growth differentiation factor-15 and the association between type 2 diabetes and liver fibrosis in NAFLD.
Nutrition & Diabetes, 11 (1), [32].
(doi:10.1038/s41387-021-00170-3).
Abstract
Background: Type 2 diabetes mellitus (T2DM) is a strong risk factor for liver fibrosis in non-alcoholic fatty liver disease (NAFLD). It remains uncertain why T2DM increases the risk of liver fibrosis. It has been suggested that growth differentiation factor-15 (GDF-15) concentrations increase the risk of liver fibrosis. We aimed to investigate (a) whether GDF-15 concentrations were associated with liver fibrosis and involved in the relationship between T2DM and liver fibrosis and (b) what factors linked with T2DM are associated with increased GDF-15 concentrations. Methods: Ninety-nine patients with NAFLD (61% men, 42.4% T2DM) were studied. Serum GDF-15 concentrations were measured by electro-chemiluminescence immunoassay. Vibration-controlled transient elastography (VCTE)-validated thresholds were used to assess liver fibrosis. Regression modelling, receiver operator characteristic curve analysis and Sobel test statistics were used to test associations, risk predictors and the involvement of GDF-15 in the relationship between T2DM and liver fibrosis, respectively. Results: Patients with NAFLD and T2DM (n = 42) had higher serum GDF-15 concentrations [mean (SD): 1271.0 (902.1) vs. 640.3 (332.5) pg/ml, p < 0.0001], and a higher proportion had VCTE assessed ≥F2 fibrosis (48.8 vs. 23.2%, p = 0.01) than those without T2DM. GDF-15 was independently associated with liver fibrosis (p = 0.001), and GDF-15 was the most important single factor predicting ≥F2 or ≥F3 fibrosis (≥F2 fibrosis AUROC 0.75, (95% CI 0.63–0.86), p < 0.001, with sensitivity, specificity, positive predictive (PPV) and negative predictive (NPV) values of 56.3%, 86.9%, 69.2% and 79.1%, respectively). GDF-15 was involved in the association between T2DM and ≥F2 fibrosis (Sobel test statistic 2.90, p = 0.004). Other factors associated with T2DM explained 60% of the variance in GDF-15 concentrations (p < 0.0001). HbA1c concentrations alone explained 30% of the variance (p < 0.0001). Conclusions: GDF-15 concentrations are a predictor of liver fibrosis and potentially involved in the association between T2DM and liver fibrosis in NAFLD. HbA1c concentrations explain a large proportion of the variance in GDF-15 concentrations.
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Accepted/In Press date: 10 August 2021
Published date: 18 October 2021
Additional Information:
Funding Information:
JB, PRA, PCC, JKS and CDB are supported by the National Institute for Health Research through the NIHR Southampton Biomedical Research Centre (Grant Number IS-BRC-20004). This research was funded in part by the Wellcome Trust [Grant number 206453/Z/17/Z to JKS]. For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.
Funding Information:
We would like to thank the National Institute for Health Research Southampton Biomedical Research Centre for funding this study and supporting the authors throughout the study. We also thank Debbie Smith, Sanchia Triggs, Gemma Rood and Jennifer Hedges without whose help this study would not have been possible and Lucinda England for research governance administration. Finally, we thank all the study volunteers for their invaluable contribution towards furthering knowledge about NAFLD. The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Publisher Copyright:
© 2021, The Author(s).
Identifiers
Local EPrints ID: 450976
URI: http://eprints.soton.ac.uk/id/eprint/450976
ISSN: 2044-4052
PURE UUID: 74ed6de5-bb50-4658-9fb9-d3dbd1e79d20
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Date deposited: 31 Aug 2021 16:30
Last modified: 10 Apr 2024 04:06
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Author:
Josh Bilson
Author:
Eleonora Scorletti
Author:
Laure B. Bindels
Author:
Paul Afolabi
Author:
Giovanni Targher
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