Introduction and Objective: Type 2 diabetes (T2D) is often associated with metabolic dysfunction-associated steatotic liver disease (MASLD) which may lead to clinically significant fibrosis (defined as moderate-to-severe fibrosis stage ≥F2 or “at-risk” MASLD≥F2) and eventually cirrhosis. The role of insulin resistance (IR) in the development of MASLD≥F2 remains unclear. We examined the relationship of IR to the severity of MASLD in people with T2D.Methods: We studied 190 participants with T2DM (age: 59±10; BMI: 32±7 kg/m2, A1c: 6.6±1.0%) who were divided by into IR (HOMA-IR of ≥2.5) or insulin sensitive (IS). We used transient elastography (VCTE; Fibroscan®) to establish the presence of steatosis/MASLD (CAP ≥274 dB/m). Fibrosis (any stage) was defined as LSM ≥7.0 kPa (≥F1) and clinically significant fibrosis (MASLD≥F2) as LSM ≥8.2 kPa.Results: Having T2DM and IR (n=135), compared to those IS (n=55), was often associated with obesity (69% vs. 32%), higher triglycerides (TG), lower HDL-C, and adipose tissue dysfunction (higher adipo-IR and lower adiponectin). Also, the prevalence of steatosis (IR: 75% vs. IS: 31%) and liver fibrosis ≥F1 (IR: 13% vs. IS: 4%) or ≥F2 (IR: 7% vs. IS: 2%) was 2- to 3-fold higher (all p<0.01). Of interest, 25% of IR did not have steatosis (or fibrosis). In IS individuals with T2D, only 32% had steatosis and none developed MASLD≥F2. In people with steatosis, being IR vs. IS was associated with worse CV risk factors: A1c: 6.8±1.1 vs. 6.3±0.7%; sBP: 133±13 vs. 125±14 mmHg; dBP: 81±8 vs. 76±9 mmHg, TG: 148±78 vs. 101±40 mg/dL; HDL-C: 45±11 vs. 48±12; apoB: 94±23 vs. 83±19 mg/dL (all p<0.05). If IS, having steatosis played a minimal role on CV risk factors.Conclusion: In people with T2D who are insulin-sensitive, steatosis and clinically significant fibrosis are rare. In contrast, IR is a strong driver of both steatosis and MASLD≥F2. Measurement of IR (HOMA-IR) may assist in the risk stratification and prevention of cirrhosis in T2D.
N. Cuervo-Pardo: None. S. Kalavalapalli: None. E. Godinez Leiva: None. A. Ortiz Rocha: None. A. Sharma: None. D. Barb: Other Relationship; Inventiva Pharma, Boehringer-Ingelheim. T. Nguyen: None. E. Valdez Saenz: None. R. Lomonaco: None. M.A. Connelly: Employee; LabCorp. Stock/Shareholder; LabCorp. K. Cusi: Research Support; Boehringer-Ingelheim, Echosens, Inventiva, Perspectum Ltd, LabCorp. Consultant; Arrowhead Pharmaceuticals, Inc, AstraZeneca, TERNS Pharmaceuticals, 89bio, Inc, Boehringer-Ingelheim, Eli Lilly and Company, Novo Nordisk A/S, Sagimet Biosciences.
NIH/NIDDK (R01DK120331) PI: Kenneth Cusi.
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