Insulin resistance, not hepatic histological features, is the dominant correlate of insulin clearance in class 3 obesity.

AIMS: The liver is the primary site of insulin clearance (CLINS), and hepatic lipid content has been associated with impaired CLINS in class 1-2 obesity. Whether the full histological spectrum of metabolic dysfunction-associated steatotic liver disease (MASLD), including inflammation, ballooning and fibrosis, is independently associated with CLINS in class 3 obesity is unknown. We investigated the relationships between insulin kinetics and liver histology in class 3 obesity.

METHODS

This cross-sectional analysis within the BARIA_DDZ cohort included 69 adults without diabetes (57 % prediabetes; 81 % female; median age 40 years; BMI 46 kg/m2) undergoing bariatric surgery. Participants underwent a 75-g oral glucose tolerance test and intraoperative liver biopsy. Systemic CLINS was calculated from C-peptide-deconvolution-derived insulin secretion rates.

RESULTS

By histology, 33 % had no MASLD, 23 % MASL and 44 % MASH. No histological parameter correlated with CLINS (hepatic lipid content, steatosis grade, lobular inflammation, ballooning, fibrosis stage, NAFLD activity score, all P > 0.15). In multivariable regression adjusted for hepatic lipid content, glucose tolerance status, beta-cell glucose sensitivity, only HOMA-IR or oral glucose insulin sensitivity independently predicted CLINS (B =  - 0.101, P = 0.005 and B=+0.0070, P = 0.001, respectively).

CONCLUSIONS

In class 3 obesity, insulin resistance rather than hepatic histological features was the strongest independent correlate of systemic insulin clearance.

TRIAL REGISTRATION: ClinicalTrials.gov: NCT01477957.