OBJECTIVE We evaluated whether the triglyceride-to-HDL cholesterol (TG/HDL-C) ratio is associated with insulin resistance (IR) in a large multiethnic cohort of obese youths. RESEARCH DESIGN AND METHODS Obese youths (1,452) had an oral glucose tolerance test and a fasting lipid profile. Insulin sensitivity was estimated using the whole body insulin sensitivity index (WBISI) and homeostasis model assessment (HOMA)-IR and evaluated, in a subgroup of 146 obese youths, by the hyperinsulinemic-euglycemic clamp. The cohort was divided by ethnicity (612 whites, 357 Hispanics, and 483 African Americans) and then stratified into ethnicity-specific tertiles of TG/HDL-C ratio. Differences across tertiles were evaluated, and the association between the TG/HDL-C ratio and insulin sensitivity (WBISI) was defined by a multiple stepwise linear regression analysis. The area under the receiver operating characteristic (ROC) curve (AUC) was determined to calculate the TG/HDL-C ratio cutoff to identify insulin-resistant subjects by ethnicity. RESULTS In each ethnic group and across rising tertiles of TG/HDL-C ratio, insulin sensitivity (WBISI) progressively decreased, whereas 2-h glucose and the AUC-glucose progressively increased. The cutoff for TG/HDL-C ratio was 2.27, and the odds of presenting with IR, in youths with TG/HDL-C ratio higher than the cutoff, was 6.023 (95% CI 2.798–12.964; P < 0.001) in white girls and boys, whereas for both Hispanics and African Americans the AUC-ROCs were not significant, thus not allowing the calculation of an optimal cutoff TG/HDL-C value. CONCLUSIONS The TG/HDL-C ratio is associated with IR mainly in white obese boys and girls and thus may be used with other risk factors to identify subjects at increased risk of IR-driven morbidity.

Recently, the single nucleotide polymorphism (SNP) identified as rs1260326, in the glucokinase regulatory protein ( GCKR ), was associated with hypertriglyceridemia in adults. Because accumulation of triglycerides in hepatocytes represents the hallmark of steatosis, we aimed to investigate whether this variant might be associated with fatty liver (hepatic fat content, HFF%). Moreover, because recently rs738409 in the PNPLA3 and rs2854116 in the APOC3 were associated with fatty liver, we explored how the GCKR SNP and these two variants jointly influence hepatosteatosis. We studied 455 obese children and adolescents (181 Caucasians, 139 African Americans, and 135 Hispanics). All underwent an oral glucose tolerance test and fasting lipoprotein subclasses measurement by proton nuclear magnetic resonance. A subset of 142 children underwent a fast gradient magnetic resonance imaging to measure the HFF%. The rs1260326 was associated with elevated triglycerides (Caucasians P = 0.00014; African Americans P = 0.00417), large very low-density lipoprotein (VLDL) (Caucasians P = 0.001; African Americans, P = 0.03), and with fatty liver (Caucasians P = 0.034; African Americans P = 0.00002; and Hispanics P = 0.016). The PNPLA3 , but not the APOC3 rs2854116 SNP, was associated with fatty liver but not with triglyceride levels. There was a joint effect between the PNPLA3 and GCKR SNPs, explaining 32% of HFF% variance in Caucasians ( P = 0.00161), 39.0% in African Americans ( P = 0.00000496), and 15% in Hispanics ( P = 0.00342). Conclusion : The rs1260326 in GCKR is associated with hepatic fat accumulation along with large VLDL and triglyceride levels. GCKR and PNPLA3 act together to convey susceptibility to fatty liver in obese youths.

OBJECTIVE We evaluated the role of fatty liver in the alteration of insulin sensitivity and β-cell function in two groups of obese adolescents, differing in hepatic fat content (hepatic fat fraction [HFF]) but with similar intrabdominal intramyocellular lipid content (IMCL) and overall degree of obesity. RESEARCH DESIGN AND METHODS We studied 23 obese adolescents with high HFF (HFF >5.5%) and 20 obese adolescents with low HFF (HFF <5.5%), matched for age, Tanner stage, BMI z score, and percentages of body fat, visceral fat, and IMCL. All subjects underwent an oral glucose tolerance test and a two-step hyperinsulinemic-euglycemic clamp, magnetic resonance imaging and ¹H nuclear magnetic resonance to assess abdominal fat distribution, HFF, and IMCL, respectively. RESULTS The high HFF group showed significantly lower whole-body insulin sensitivity index (P = 0.001) and estimates of insulin secretion (P = 0.03). The baseline hepatic glucose production (EGP) rate was not different between the two groups. Suppression of EGP was significantly lower (P = 0.04) in the high HFF group during low-dose insulin; no differences were observed during the second step. Baseline fatty acids, glycerol concentrations, and clamp suppression of glycerol turnover did not differ between the groups. During the second step, the glucose disposal rate was significantly lower (P = 0.01) in the high HFF group. CONCLUSIONS Fatty liver, independent of visceral fat and IMCL, plays a central role in the insulin-resistant state in obese adolescents.

The genetic factors associated with susceptibility to nonalcoholic fatty liver disease (NAFLD) in pediatric obesity remain largely unknown. Recently, a nonsynonymous single-nucleotide polymorphism (rs738409), in the patatin-like phospholipase 3 gene ( PNPLA3 ) has been associated with hepatic steatosis in adults. In a multiethnic group of 85 obese youths, we genotyped the PNLPA3 single-nucleotide polymorphism, measured hepatic fat content by magnetic resonance imaging and insulin sensitivity by the insulin clamp. Because PNPLA3 might affect adipogenesis/lipogenesis, we explored the putative association with the distribution of adipose cell size and the expression of some adipogenic/lipogenic genes in a subset of subjects who underwent a subcutaneous fat biopsy. Steatosis was present in 41% of Caucasians, 23% of African Americans, and 66% of Hispanics. The frequency of PNPLA3 (rs738409) G allele was 0.324 in Caucasians, 0.183 in African Americans, and 0.483 in Hispanics. The prevalence of the G allele was higher in subjects showing hepatic steatosis. Surprisingly, subjects carrying the G allele showed comparable hepatic glucose production rates, peripheral glucose disposal rate, and glycerol turnover as the CC homozygotes. Carriers of the G allele showed smaller adipocytes than those with CC genotype ( P = 0.005). Although the expression of PNPLA3, PNPLA2, PPARγ2 (peroxisome proliferator-activated receptor gamma 2), SREBP1c (sterol regulatory element binding protein 1c), and ACACA (acetyl coenzyme A carboxylase) was not different between genotypes, carriers of the G allele showed lower leptin ( LEP )( P = 0.03) and sirtuin 1 ( SIRT1 ) expression ( P = 0.04). Conclusion: A common variant of the PNPLA3 gene confers susceptibility to hepatic steatosis in obese youths without increasing the level of hepatic and peripheral insulin resistance. The rs738409 PNPLA3 G allele is associated with morphological changes in adipocyte cell size. (Hepatology 2010.)