Adipose tissue insulin resistance in children and adolescents: linking glucose and free fatty acid metabolism to hepatic injury markers

Obesity is one of the leading causes of the development of insulin resistance, diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD) in children. With the progression of insulin resistance, both glucose and free fatty acid (FFA) plasma levels are elevated, leading to cardiometabolic complications such as impaired glucose tolerance (IGT), type 2 diabetes, and liver fat accumulation. In this study, oral minimal models were used to estimate insulin sensitivity indexes (SI and SI_FFA) in 375 adolescents with obesity. Differences between normal glucose tolerance (NGT) and IGT were assessed by using Mann-Whitney <i>U</i> test, while the relationship between insulin sensitivities and plasma alanine transaminase (ALT) was assessed using Spearman correlation and linear regression model of the log-transformed variables. Also, 48 youths repeated the oral glucose tolerance test and the measurement of liver function test after ∼1.3 yr of follow-up. SI was statistically different between NGT and IGT (<i>P</i> < 10^-6) and correlated with each other (ρ = 0.7, <i>P</i> < 10^-6). Lipolysis was completely suppressed after 30 min in NGT, compared with 120 min in IGT. SI and SI_FFA were both statistically correlated with ALT (ρ = -0.19, <i>P</i> < 10^-3). Also, the percentages of variation of SI_FFA and ALT between the first and second visits correlated significantly (ρ = -0.47, <i>P</i> = 0.002). FFA minimal model can be used to estimate adipose tissue lipolysis in youths with obesity. The relationship of SI and SI_FFA with ALT, along with the progression of the impairment of adipose tissue insulin sensitivity, shows that systemic insulin resistance underlies the relationship of glucose and FFA metabolism with hepatic damage.<b>NEW & NOTEWORTHY</b> In this study, we applied glucose, Cpeptide, and FFA minimal models to assess insulin sensitivities, insulin secretion, and lipolytic flux in NGT and IGT in adolescents with obesity. The results show that glucose and adipose tissue insulin sensitivities are strongly correlated with each other and with ALT plasma level. The longitudinal results show that changes in FFA insulin sensitivity are inversely associated with changes of beta cell secretion and with biomarkers of metabolic dysfunction-associated steatohepatitis.