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Publications

Journal Article Ahead of print

PubMed: 42926238 DOI: 10.1007/s00125-026-06904-1

Prediabetes and diabetes as drivers of fibrosis in MASLD: roles of obesity, adipose tissue dysfunction and insulin resistance.

Diabetologia

Authors: Eddison Godinez Leiva, Diana Barb, Srilaxmi Kalavalapalli, Andrea Ortiz Rocha, Nathaly Cuervo-Pardo, Anu Sharma, Enrique Valdez Saenz, Romina Lomonaco, Stephen A Marangi, Shwetha S Shetty, Fernando Bril, Juan Pablo Perdomo, Lisa Porgesz, Marcos Lamas, Maria A Gonzalez, Jens T Rosenberg, Joseph R Grajo, Pierre Bedossa, Amy Sheer, Kenneth Cusi

Affiliations

  • Division of Endocrinology, Diabetes and Metabolism, University of Florida College of Medicine, Gainesville, FL, USA.
  • Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Alabama, Birmingham, AL, USA.
  • Advanced Magnetic Resonance Imaging and Spectroscopy Facility, McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
  • Department of Radiology, University of Florida College of Medicine, Gainesville, FL, USA.
  • Department of Pathology, Hôspital Beaujon, AP-HP Nord, Clichy, France.
  • Division of General Internal Medicine, Department of Medicine, University of Florida College of Medicine, Gainesville, FL, USA.
  • Division of Endocrinology, Diabetes and Metabolism, University of Florida College of Medicine, Gainesville, FL, USA.

Abstract

AIMS/HYPOTHESIS

Prediabetes and type 2 diabetes have been associated with more severe metabolic dysfunction-associated steatotic liver disease (MASLD), but not all individuals have the same risk and the metabolic drivers remain incompletely understood. To understand why, we examined the roles of obesity, adipose tissue dysfunction and insulin resistance in the development of significant liver fibrosis (fibrosis stage ≥F2) in adults across the glycaemic spectrum.

METHODS

We performed a prospective, cross-sectional study in a real-world setting of adults attending primary care or endocrinology/diabetes clinics. Transient elastography was used to diagnose steatosis (controlled attenuation parameter ≥274 dB/m) and clinically significant liver fibrosis (vibration-controlled transient elastography liver stiffness measurement ≥8.2 kPa). When ≥F2 was suspected, MR-based imaging or liver biopsy was used to improve stratification. MASLD and significant fibrosis were compared across glycaemic and BMI categories and severity of insulin resistance (HOMA-IR; predominantly hepatic) and adipose tissue insulin resistance (assessed by adipose tissue insulin resistance [Adipo-IR]).

RESULTS

Among the 1446 participants, the prevalence of MASLD increased across glycaemic categories from 39% in participants with normoglycaemia, to 55% in those with prediabetes and to 68% in type 2 diabetes. Clinically significant fibrosis also increased across groups, being 1%, 6% and 12%, respectively. In prediabetes, clinically significant fibrosis was rare in lean or overweight individuals even though most had associated cardiometabolic risk factors, but this increased fourfold in individuals with obesity, particularly when associated with severe adipose tissue and systemic insulin resistance. Having obesity and type 2 diabetes had the highest prevalence of clinically significant fibrosis (16%), and again, mostly if associated with insulin resistance. Most participants with clinically significant fibrosis were in the highest quintiles of Adipo-IR or HOMA-IR (Q4-Q5).

CONCLUSIONS/INTERPRETATION

In a real-world cohort from primary care/endocrinology clinics, the prevalence of MASLD increased in a stepwise manner with glycaemic and BMI categories, but the prevalence of fibrosis did not increase in the same stepwise manner and remained rare in the absence of obesity, or in obesity without significant insulin resistance. Prediabetes was a risk factor for significant fibrosis mainly in individuals with obesity and significant insulin resistance. In the context of current guidelines, MASLD risk-stratification may be improved in primary care by establishing the metabolic impact of obesity/diabetes (i.e. assessing insulin resistance by HOMA-IR).

MeSH

Diabetes Mellitus, Endocrinology, Insulin Resistance, Insulin, Fibrosis, Elasticity Imaging Techniques, Liver, Prediabetic State, Prevalence, Obesity, Risk Factors, Tissues, Adipose Tissue, Diabetes Mellitus, Type 2