Clinical features of the study population according to ethnicity and <i>PNPLA3</i> rs738409 genotype.

*<p> = log transformed and adjusted for age, gender, BMI, glucose tolerance. ** = Square root transformed and adjusted for age, gender, BMI, glucose tolerance. GT  =  glucose tolerance. NGT =  normal glucose tolerance, IGT =  impaired glucose tolerance, T2D  =  type 2 diabetes.</p

Interaction between <i>PNPLA3</i> rs738409 and n-6/n-3 PUFA in modulating ALT levels.

<p>The figure shows a different degree of regression between ALT (log10) and n-6/n-3 PUFA (log10) in the three genotypes. In the CC (Panel A) and CG (Panel B) group there was no association between ALT and n-6/n-3 PUFA (r2 = 0.0006, p = 0.91 and r2 = 0.015, p = 0.21 respectively). Only in the GG group (Panel C) there was a strong association between HFF% and n-6/n-3 PUFA (r2 =  0.40, p = 0.006).</p

Interaction between <i>PNPLA3</i> rs738409 and n-6/n-3 PUFA in modulating HFF%.

<p>The figure shows a different degree of regression between HFF% (square root) and n-6/n-3 PUFA (log10) in the three genotypes. In the CC (Panel A) and CG (Panel B) group there was no association between HFF% and n-6/n-3 PUFA (r2 = 0.0004, p = 0.86 and r2 = 0.018, p = 0.39, respectively). Only in the GG group (Panel C) there was a strong association between HFF% and n-6/n-3 PUFA (r2 =  0.45, p = 0.001).</p

Metabolic profile of the cohort, adjusted for age, gender and percent body fat.

<p>Metabolic profile of the cohort, adjusted for age, gender and percent body fat.</p

Anthropometric Characteristics (mean±SD)

<p>Anthropometric Characteristics (mean±SD)</p

Relationships between IMCL, Hepatic Fat Fraction (HFF), Visceral Fat, and insulin sensitivity (WBISI) in all 3 ethnic groups.

<p>Relationships between IMCL, Hepatic Fat Fraction (HFF), Visceral Fat, and insulin sensitivity (WBISI) in all 3 ethnic groups.</p

Representative abdominal MRI image, liver scans and ¹H-MRS of soleus muscle spectra from one Caucasian, one African American, and one Hispanic boy.

<p>Representative abdominal MRI image, liver scans and ¹H-MRS of soleus muscle spectra from one Caucasian, one African American, and one Hispanic boy.</p

Visceral fat, subcutaneous fat (total, deep, and superficial), intramyocellular lipid (IMCL), and hepatic fat fraction by ethnicity (mean±SEM, adjusted for age, gender, and percent fat).

<p>Visceral fat, subcutaneous fat (total, deep, and superficial), intramyocellular lipid (IMCL), and hepatic fat fraction by ethnicity (mean±SEM, adjusted for age, gender, and percent fat).</p

Alterations in adipose tissue distribution, cell morphology and function mark primary insulin hypersecretion in youths with obesity

Excessive insulin secretion independent of insulin resistance, defined as primary hypersecretion, is associated with obesity and an unfavorable metabolic phenotype. We examined the characteristics of the adipose tissue in youths with primary insulin hypersecretion and the longitudinal metabolic alterations influenced by the complex adipo-insular interplay. In a multiethnic cohort of non-diabetic adolescents with obesity, primary insulin hypersecretors had enhanced model-derived β-cell glucose sensitivity and rate sensitivity, but worse glucose tolerance, despite similar demographics, adiposity, and insulin resistance measured by both OGTT and euglycemic-hyperinsulinemic clamp. Hypersecretors had greater intrahepatic and visceral fat depots at abdominal MRI, hypertrophic abdominal subcutaneous adipocytes, higher FFA and leptin serum levels per fat mass, and faster in vivo lipid turnover assessed by a long-term 2H2O labeling protocol. At 2-year follow up, hypersecretors had greater fat accrual and 3-fold higher risk for abnormal glucose tolerance, while individuals with hypertrophic adipocytes or higher leptin levels showed enhanced β-cell glucose sensitivity. Primary insulin hypersecretion is associated with marked alterations in adipose tissue distribution, cellularity, and lipid dynamics, independent of whole-body adiposity and insulin resistance. Pathogenetic insight into the metabolic crosstalk between β-cell and adipocyte may help identify individuals at risk for chronic hyperinsulinemia, body weight gain, and glucose intolerance. </p