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Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis.

ABSTRACT: Previous studies have shown familial aggregation of insulin resistance and nonalcoholic fatty liver disease (NAFLD). Therefore, we aimed to examine whether family history of diabetes mellitus (DM) is associated with nonalcoholic steatohepatitis (NASH) and fibrosis in patients with NAFLD. This was a cross-sectional analysis in participants of the NAFLD Database study and PIVENS trial who had available data on family history of DM. One thousand and sixty-nine patients (63% women), with mean age of 49.6 (± 11.8) years and body mass index (BMI) of 34.2 (± 6.4) kg/m(2) , were included. Thirty percent had DM, and 56% had a family history of DM. Both personal history of DM and family history of DM were significantly associated with NASH, with an odds ratio (OR) of 1.93 (95% confidence interval [CI]: 1.37-2.73; P <0.001) and 1.48 (95% CI: 1.11-1.97; P = 0.01) and any fibrosis with an OR of 3.31 (95% CI: 2.26-4.85; P < 0.001) and 1.66 (95% CI: 1.25-2.20; P < 0.001), respectively. When the models were adjusted for age, sex, BMI, ethnicity, and metabolic traits, the association between diabetes and family history of DM with NASH showed an increased adjusted OR of 1.76 (95% CI: 1.13-2.72; P < 0.001) and 1.34 (95% CI: 0.99-1.81; P = 0.06), respectively, and with any fibrosis with a significant adjusted OR of 2.57 (95% CI: 1.61-4.11; P < 0.0001) and 1.38 (95% CI: 1.02-1.87; P = 0.04), respectively. After excluding patients with personal history of diabetes, family history of DM was significantly associated with the presence of NASH and any fibrosis with an adjusted OR of 1.51 (95% CI: 1.01-2.25; P = 0.04) and 1.49 (95% CI: 1.01-2.20; P = 0.04), respectively.Diabetes is strongly associated with risk of NASH, fibrosis, and advanced fibrosis. Family history of diabetes, especially among nondiabetics, is associated with NASH and fibrosis in NAFLD.

SUBMITTER: Loomba R

PROVIDER: S-EPMC3407289 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis.

Loomba Rohit R Abraham Maria M Unalp Aynur A Wilson Laura L Lavine Joel J Doo Ed E Bass Nathan M NM

Hepatology (Baltimore, Md.) 20120726 3

<h4>Unlabelled</h4>Previous studies have shown familial aggregation of insulin resistance and nonalcoholic fatty liver disease (NAFLD). Therefore, we aimed to examine whether family history of diabetes mellitus (DM) is associated with nonalcoholic steatohepatitis (NASH) and fibrosis in patients with NAFLD. This was a cross-sectional analysis in participants of the NAFLD Database study and PIVENS trial who had available data on family history of DM. One thousand and sixty-nine patients (63% women ...[more]

PMID: 22505194

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Project description:Hyperglycemia is an independent risk factor for the rapid progression of nonalcoholic steatohepatitis (NASH) to liver fibrosis with an incompletely defined mechanism. Ferroptosis is a novel form of programmed cell death that has been identified as a pathogenic mechanism in various diseases. However, the role of ferroptosis in the development of liver fibrosis in NASH with type 2 diabetes mellitus (T2DM) is unclear. Here, we observed the histopathological features of the progression of NASH to liver fibrosis as well as hepatocyte epithelial-mesenchymal transition (EMT) in a mouse model of NASH with T2DM and high-glucose-cultured steatotic human normal liver (LO2) cells. The distinctive features of ferroptosis, including iron overload, decreased antioxidant capacity, the accumulation of reactive oxygen species, and elevated lipid peroxidation products, were confirmed in vivo and in vitro. Liver fibrosis and hepatocyte EMT were markedly alleviated after treatment with the ferroptosis inhibitor ferrostatin-1. Furthermore, a decrease in the gene and protein levels of AGE receptor 1 (AGER1) was detected in the transition from NASH to liver fibrosis. Overexpression of AGER1 dramatically reversed hepatocyte EMT in high-glucose-cultured steatotic LO2 cells, whereas the knockdown of AGER1 had the opposite effect. The mechanisms underlying the phenotype appear to be associated with the inhibitory effects of AGER1 on ferroptosis, which is dependent on the regulation of sirtuin 4. Finally, in vivo adeno-associated virus-mediated AGER1 overexpression effectively relieved liver fibrosis in a murine model. Collectively, these findings suggest that ferroptosis participates in the pathogenesis of liver fibrosis in NASH with T2DM by promoting hepatocyte EMT. AGER1 could reverse hepatocyte EMT to ameliorate liver fibrosis by inhibiting ferroptosis. The results also suggest that AGER1 may be a potential therapeutic target for the treatment of liver fibrosis in patients with NASH with T2DM. Chronic hyperglycemia is associated with increased advanced glycation end products, resulting in the downregulation of AGER1. AGER1 deficiency downregulates Sirt4, which disturbs key regulators of ferroptosis (TFR-1, FTH, GPX4, and SLC7A11). These lead to increased iron uptake, decreasing the antioxidative capacity and enhanced lipid ROS production, ultimately leading to ferroptosis, which further promotes hepatocyte epithelial-mesenchymal transition and fibrosis progression in NASH with T2DM.

Project description:Aims/hypothesisThe aim of this work was to examine the relationship between family history of type 1 diabetes, birthweight, growth during the first 2 years and development of multiple beta cell autoantibodies in children with a first-degree relative with type 1 diabetes and HLA-conferred disease susceptibility.MethodsIn a secondary analysis of the Trial to Reduce IDDM in the Genetically at Risk (TRIGR), clinical characteristics and development of beta cell autoantibodies were compared in relation to family history of type 1 diabetes (mother vs father vs sibling) in 2074 children from families with a single affected family member.ResultsMultiple autoantibodies (≥2 of 5 measured) developed in 277 (13%) children: 107 (10%), 114 (16%) and 56 (18%) born with a mother, father or sibling with type 1 diabetes, respectively (p < 0.001). The HR for time to multiple autoimmunity was 0.54 (95% CI 0.39, 0.75) in offspring of affected mothers (n = 107/1046, p < 0.001) and 0.81 (95% CI 0.59, 1.11) (n = 114/722, p = 0.19) in offspring of affected fathers, compared with participants with a sibling with type 1 diabetes (comparator group n = 56/306). The time to the first autoantibody present (to insulin, GAD, tyrosine phosphatase-related insulinoma-associated 2 molecules, islet cell or zinc transporter 8) was similar in the three groups. Height velocity (z score/year) in the first 24 months was independently associated with developing multiple antibodies in the total cohort (HR 1.31 [95% CI 1.01, 1.70], p = 0.04). A higher birthweight in children born to an affected mother vs affected father or an affected sibling was not related to the risk of multiple autoimmunity.Conclusions/interpretationThe risk of developing multiple autoantibodies was lower in children with maternal type 1 diabetes. For the whole group, this risk of developing multiple autoantibodies was independent of birthweight but was greater in those with increased height velocity during the first 2 years of life. However, the risk associated with paternal type 1 diabetes was not linked to differences in birthweight or early growth.Trial registrationClinicalTrials.gov NCT00179777 Graphical abstract.

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Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis.

Publications

Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis.

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