MON-606 - Systemic Insulin Resistance, Not Hepatic Histology, Determines Insulin Clearance in Class 3 Obesity

Introduction:
Metabolic dysfunction-associated steatotic liver disease (MASLD) is tightly related to insulin resistance and abnormal glucose homeostasis. We previously showed liver lipid content is not only associated with insulin resistance, but also with impaired insulin clearance (IC), thereby contributing to hyperinsulinemia in individuals with class 1 obesity, with or without diabetes (Zaharia OP et al. Diabetes Care. 2023;46:2232-2239.). Since the liver accounts for the majority of IC, we hypothesized that hepatic steatosis (MASL) and steatohepatitis (MASH) would lead to worsening of IC. Thus, we investigated the relationships between insulin kinetics and liver histological features in a cohort of class 3 obesity.

Methods:
This cross-sectional study comprised of 69 Caucasian adults without diabetes (median age 40 [33-48] years; 56 female [81.2%]; median BMI 46.2 [42.3-51.9] kg/m²; median HbA1c 5.4 [5.2-5.7%]; 30 with normal glucose tolerance, 39 with prediabetes), of whom 23 had no MASL, 16 had MASL, and 30 had MASH, all scheduled for bariatric surgery within the BARIA-DDZ study (NCT01477957). Participants underwent a 75-g oral glucose tolerance test and an intraoperative liver biopsy. Insulin secretion rates (ISR) were assessed from C-peptide deconvolution. Total IC was calculated as the ratio of the area under the curve (AUC) of ISR to the AUC of insulin concentrations. Beta-cell glucose sensitivity (β-GS) was calculated as the incremental slope relating ISR to plasma glucose concentrations using a mathematical model. Liver histology (steatosis, ballooning, lobular inflammation, fibrosis and NAS score) was evaluated according to international guidelines.

Results:
As expected, total IC was inversely correlated with insulin resistance (HOMA-IR; ρ = -0.51, p< 0.0001). This association explained 26% of the variance in total IC (ρ²=0.26). However, total IC neither associated with any of the parameters of hepatic histology (hepatic lipid content: p=0.17; steatosis grade: p=0.15; NAS score: p=0.32; fibrosis stage: p=0.28; ballooning: p=0.84; lobular inflammation: p=0.21) nor with β-GS (p=0.14). ISR demonstrated a negative correlation with IC (ρ = -0.28, p=0.020). A multiple linear regression analysis adjusted for age, sex, NAS score and β-GS, showed that HOMA-IR emerged as the sole independent determinant of IC (p=0.0002).

Conclusion:
In individuals with class 3 obesity, fasting insulin resistance rather than features of progressing steatotic liver disease determine insulin clearance.

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