Introduction and Objective: Insulin resistance (IR) and higher BMI are associated with the development of MASLD. However, their independent association with “at-risk” MASLD (i.e., steatohepatitis with clinically significant fibrosis or stage ≥F2; MASLD≥F2) is unclear. We investigated how IR and obesity interact to impact MASLD severity.Methods: We divided 283 individuals without diabetes into having overweight (OW) or obesity (OB), further stratified by either having insulin resistance (IR, HOMA-IR ≥ 2.5) or not (IS). Transient elastography (VCTE; Fibroscan®) was used to diagnose steatosis (CAP ≥ 274 dB/m) and “at-risk” MASLD with ≥F2 fibrosis stage (≥8.2 kPa).Results: Among individuals who were OW (n=118), OW-IS or OW-IR had similar rates of steatosis (37% vs. 44%, p=0.47) and none developed MASLD≥F2. However, those with OW-IR had worse plasma TG, HDL-C, AST, and ALT levels (p<0.05-0.01) but no differences in LDL-C, Apo B, or LDL particle number, A1c or BP. In the OB group (n=165), having IR was associated with a higher prevalence of steatosis (OB-IR: 77% vs. OB-IS: 52%) and of MASLD≥F2 (OB-IR: 6% vs. OB-IS: 0%; both p<0.05). These differences were linked to “sick fat” as reflected by lower adiponectin (4.9 vs. 7.9 μg/ml) and higher adipo-IR (7.6 vs. 2.9, both p<0.0001). The OB-IR vs. OB-IS group also had higher BP, TG, ALT and AST levels, and lower HDL-C, but no differences in A1c, LDL-C, apo B, LDL particle and size (p<0.05). Among individuals with OB-IS (n=71), having prediabetes did not increase the risk of steatosis or fibrosis, but it did increase fibrosis risk in OB-IR.Conclusion: In middle-aged subjects with overweight, IR has a modest impact on the development of MASLD or CV risk factors (except TG/HDL-C). In contrast, IR in obesity increases the prevalence of steatosis and fibrosis, as well as worsens CV risk factors (BP and lipid profile). Screening for MASLD should focus especially on people with obesity with IR or having CV risk factors.
N. Cuervo-Pardo: None. T. Nguyen: None. S. Kalavalapalli: None. E. Godinez Leiva: None. A. Ortiz Rocha: None. A. Sharma: None. E. Valdez Saenz: None. R. Lomonaco: None. D. Barb: Other Relationship; Inventiva Pharma, Boehringer-Ingelheim. 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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