Adipose Tissue Insulin Resistance Predicts the Severity of Liver Fibrosis in Patients With Type 2 Diabetes and NAFLD

Abstract Context Although type 2 diabetes (T2D) is a risk factor for liver fibrosis in nonalcoholic fatty liver disease (NAFLD), the specific contribution of insulin resistance (IR) relative to other factors is unknown. Objective Assess the impact on liver fibrosis in NAFLD of adipose tissue (adipos...

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Published in:	The journal of clinical endocrinology and metabolism Vol. 108; no. 5; pp. 1192 - 1201
Main Authors:	Kalavalapalli, Srilaxmi, Leiva, Eddison Godinez, Lomonaco, Romina, Chi, Xiaofei, Shrestha, Sulav, Dillard, Rachel, Budd, Jeffery, Romero, Jessica Portillo, Li, Christina, Bril, Fernando, Samraj, George, Pennington, John, Townsend, Petra, Orlando, Frank, Shetty, Shwetha, Mansour, Lydia, Silva-Sombra, Lorena Rodrigues, Bedossa, Pierre, Malaty, John, Barb, Diana, Gurka, Matthew J, Cusi, Kenneth
Format:	Journal Article
Language:	English
Published:	US Oxford University Press 01-05-2023
Subjects:	Adiponectin Adipose tissue Adipose Tissue - metabolism Adipose tissues Alanine transaminase Apoptosis Aspartate Aspartate aminotransferase Body fat Body mass index Clinics Cytokeratin Diabetes Diabetes mellitus (non-insulin dependent) Diabetes Mellitus, Type 2 - metabolism Fatty liver Fibrosis Humans Insulin - metabolism Insulin Resistance Keratin Keratin-18 - metabolism Liver Liver - metabolism Liver cirrhosis Liver Cirrhosis - pathology Liver diseases Metabolic syndrome Metabolism Metabolites Non-alcoholic Fatty Liver Disease - pathology Risk factors Steatosis Type 2 diabetes France type 2 diabetes mellitus (T2D) liver fibrosis adipose tissue insulin resistance index (Adipo-IR) vibration controlled transient elastography (VCTE) nonalcoholic steatohepatitis (NASH) nonalcoholic fatty liver disease (NAFLD) obesity
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Summary:	Abstract Context Although type 2 diabetes (T2D) is a risk factor for liver fibrosis in nonalcoholic fatty liver disease (NAFLD), the specific contribution of insulin resistance (IR) relative to other factors is unknown. Objective Assess the impact on liver fibrosis in NAFLD of adipose tissue (adipose tissue insulin resistance index [adipo-IR]) and liver (Homeostatic Model Assessment of Insulin Resistance [HOMA-IR]) IR in people with T2D and NAFLD. Design Participants were screened by elastography in the outpatient clinics for hepatic steatosis and fibrosis, including routine metabolites, cytokeratin-18 (a marker of hepatocyte apoptosis/steatohepatitis), and HOMA-IR/adipo-IR. Setting University ambulatory care practice. Participants A total of 483 participants with T2D. Intervention Screening for steatosis and fibrosis with elastography. Main outcome measures Liver steatosis (controlled attenuation parameter), fibrosis (liver stiffness measurement), and measurements of IR (adipo-IR, HOMA-IR) and fibrosis (cytokeratin-18). Results Clinically significant liver fibrosis (stage F ≥ 2 = liver stiffness measurement ≥8.0 kPa) was found in 11%, having more features of the metabolic syndrome, lower adiponectin, and higher aspartate aminotransferase (AST), alanine aminotransferase, liver fat, and cytokeratin-18 (P < 0.05-0.01). In multivariable analysis including just clinical variables (model 1), obesity (body mass index [BMI]) had the strongest association with fibrosis (odds ratio, 2.56; CI, 1.87-3.50; P < 0.01). When metabolic measurements and cytokeratin-18 were included (model 2), only BMI, AST, and liver fat remained significant. When fibrosis stage was adjusted for BMI, AST, and steatosis (model 3), only Adipo-IR remained strongly associated with fibrosis (OR, 1.51; CI, 1.05-2.16; P = 0.03), but not BMI, hepatic IR, or steatosis. Conclusions These findings pinpoint to the central role of dysfunctional, insulin-resistant adipose tissue to advanced fibrosis in T2D, beyond simply BMI or steatosis. The clinical implication is that targeting adipose tissue should be the priority of treatment in NAFLD.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0021-972X 1945-7197
DOI:	10.1210/clinem/dgac660