Intrahepatic fat, irrespective of ethnicity, is associated with reduced endogenous insulin clearance and hepatic insulin resistance in obese youths: A cross‐sectional and longitudinal study from the Yale Pediatric NAFLD cohort

Abstract

AimTo evaluate whether intrahepatic fat accumulation contributes to impaired insulin clearance and hepatic insulin resistance across different ethnic groups.MethodsThe intrahepatic fat content (HFF%) was quantified by magnetic resonance imaging in a multi‐ethnic cohort of 632 obese youths aged 7‐18 years at baseline and after a 2‐year follow‐up. Insulin secretion rate (ISR), endogenous insulin clearance (EIC) and hepatic insulin resistance index (HIRI) were estimated by modelling glucose, insulin and C‐peptide data during 3‐hour, 9‐point oral glucose tolerance tests.ResultsAfrican American youths exhibited the lowest HFF% and a prevalence of non‐alcoholic fatty liver disease (NAFLD) less than half of that shown by Caucasians and Hispanics. Furthermore, African Americans had lower EIC and glucose‐stimulated ISR, despite similar HIRI and plasma insulin levels, compared with Caucasians and Hispanics. EIC and HIRI were markedly reduced in individuals with NAFLD and declined across group‐specific HFF% tertiles in all ethnic groups. Consistently, the HFF% correlated with EIC and HIRI, irrespective of the ethnic background, after adjustment for age, sex, ethnicity, adiposity, waist‐hip ratio, pubertal status and plasma glucose levels. An increased HFF% at follow‐up was associated with decreased EIC and increased HIRI across all groups.ConclusionsIntrahepatic lipid accumulation is associated with reduced insulin clearance and hepatic insulin sensitivity in obese youths, irrespective of their ethnic background.

The Role of Hepatic Fat Accumulation in Glucose and Insulin Homeostasis—Dysregulation by the Liver

“…Moreover, postprandial hyperinsulinemia during an OGTT in obese NAFLD individuals has been shown to strongly correlate with reduced hepatic insulin clearance but not insulin secretion [68]. In a large cross-sectional study including 532 obese young individuals, it was shown that insulin clearance and the hepatic insulin resistance index calculated during an OGTT was~50% lower in individuals with steatosis [69].…”

Exploring the determinants of ethnic differences in insulin clearance between men of Black African and White European ethnicity

“…While low adiponectin concentrations appear to be an important factor, they do not entirely explain the low insulin clearance of the BA men. Low insulin clearance has been demonstrated in a wide variety of BA subjects, including healthy men [27] and women [36], obese adolescents [37] and adults with T2D [38]. The highly conserved nature of this trait is well illustrated by Osei et al who demonstrated that while African-Americans, native Ghanaians and Ghanaian immigrants to the USA have similar rates of insulin clearance to each other, all three BA groups have lower insulin clearance compared with White Americans [39].…”

Type 2 diabetes: one disease, many pathways

“…The model as presented here is oversimplified in that it only considers glucotoxicity and neglects other factors that are likely to play a role, such as lipotoxicity (48). We are thus unable at present to address the possible role of hyperinsulinemia to promote hepatic fat accumulation (76). If prolonged, this could lead to liver damage and thus to a worsening of insulin resistance that could outlast the induced resistance we have modeled here (Eqs.…”