Dysglycemia and liver lipid content determine the relationship of insulin resistance with hepatic OXPHOS capacity in obesity

Background & aims: Hepatic mitochondrial respiration is higher in steatosis, but lower in overt type 2 diabetes. We hypothesized that hepatic oxidative phosphorylation (OXPHOS) capacity increases with a greater degree of insulin resistance in obesity, independent of other metabolic diseases.

Methods: We analyzed 65 humans without diabetes (BMI 50 ± 7 kg/m², hemoglobin A1c 5.5 ± 0.4%) undergoing bariatric surgery. Metabolic dysfunction-associated steatotic liver disease (MASLD) stages were assessed by histology, whole-body insulin sensitivity (PREDIcted-M index) by oral glucose tolerance tests, and maximal ADP-stimulated mitochondrial OXPHOS capacity by high-resolution respirometry of liver samples.

Results: Prediabetes was present in 30 participants and MASLD in 46 participants, of whom 25 had metabolic dysfunction-associated steatohepatitis, and seven had F2-F3 fibrosis. While simple regression did not detect an association of insulin sensitivity with hepatic OXPHOS capacity, interaction analyses revealed that the regression coefficient of OXPHOS capacity depended on fasting plasma glucose (FPG) and liver lipid content. Interestingly, the respective slopes were negative for FPG ≤100 mg/dl, but positive for FPG >100 mg/dl. Liver lipid content displayed similar behavior, with a threshold value of 24%. Post-challenge glycemia affected the association between insulin sensitivity and OXPHOS capacity normalized for citrate synthase activity. Presence of prediabetes affected hepatic insulin signaling, mitochondrial dynamics and fibrosis prevalence, while the presence of MASLD was associated with increases in biomarkers of hepatic inflammation, cell damage and lipid peroxidation in people with normal glucose tolerance.

Conclusions: Increasing liver lipid contents and plasma glucose concentrations, even in the non-diabetic range, are associated with a progressive decline of hepatic mitochondrial adaptation in people with obesity and insulin resistance.

Impact and implications: Mechanisms underlying the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) are still unclear, but a better understanding of the pathogenesis of MASLD is essential for the development of targeted treatments. Adaptation of liver oxidative capacity was found to be impaired in people with diabetes and MASLD or liver fibrosis. Glycemia and liver lipid content affect the adaptation of hepatic oxidative capacity to insulin resistance in obesity. These results highlight the relevance of metabolically active drugs in individuals with grade 3 obesity and early MASLD. CLINTRIALS.

Gov identifier: NCT01477957.