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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
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) if 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 129 elastography (VCTE)-validated thresholds were used to assess liver fibrosis. Regression modelling, receiver 130 operator characteristic curve analysis and Sobel test statistics were used to test associations, risk predictors 131 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): 133 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.
2044-4052
Bilson, Josh
1132faa9-9276-48c7-8d44-ad38dbf1a63a
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
1132faa9-9276-48c7-8d44-ad38dbf1a63a
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).

Record type: Article

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) if 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 129 elastography (VCTE)-validated thresholds were used to assess liver fibrosis. Regression modelling, receiver 130 operator characteristic curve analysis and Sobel test statistics were used to test associations, risk predictors 131 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): 133 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: This research was funded in whole, or 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 licence to any Author Accepted Manuscript version arising from this submission”.

Identifiers

Local EPrints ID: 450976
URI: http://eprints.soton.ac.uk/id/eprint/450976
ISSN: 2044-4052
PURE UUID: 74ed6de5-bb50-4658-9fb9-d3dbd1e79d20
ORCID for Paul Afolabi: ORCID iD orcid.org/0000-0002-0553-1578
ORCID for Philip Calder: ORCID iD orcid.org/0000-0002-6038-710X
ORCID for Jaswinder K. Sethi: ORCID iD orcid.org/0000-0003-4157-0475
ORCID for Christopher Byrne: ORCID iD orcid.org/0000-0001-6322-7753

Catalogue record

Date deposited: 31 Aug 2021 16:30
Last modified: 24 Nov 2021 05:01

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Contributors

Author: Josh Bilson
Author: Eleonora Scorletti
Author: Laure B. Bindels
Author: Paul Afolabi ORCID iD
Author: Giovanni Targher
Author: Philip Calder ORCID iD

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