Grace Kim

The Triglyceride-to-HDL Cholesterol Ratio Association with insulin resistance in obese youths of different ethnic backgrounds

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.

Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents

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. (Hepatology 2012)

Effect of Pramlintide on Prandial Glycemic Excursions During Closed-Loop Control in Adolescents and Young Adults With Type 1 Diabetes

OBJECTIVE Even under closed-loop (CL) conditions, meal-related blood glucose (BG) excursions frequently exceed target levels as a result of delays in absorption of insulin from the subcutaneous site of infusion. We hypothesized that delaying gastric emptying with preprandial injections of pramlintide would improve postprandial glycemia by allowing a better match between carbohydrate and insulin absorptions. RESEARCH DESIGN AND METHODS Eight subjects (4 female; age, 15–28 years; A1C, 7.5 ± 0.7%) were studied for 48 h on a CL insulin-delivery system with a proportional integral derivative algorithm with insulin feedback: 24 h on CL control alone (CL) and 24 h on CL control plus 30-μg premeal injections of pramlintide (CLP). Target glucose was set at 120 mg/dL; timing and contents of meals were identical on both study days. No premeal manual boluses were given. Differences in reference BG excursions, defined as the incremental glucose rise from premeal to peak, were compared between conditions for each meal. RESULTS CLP was associated with overall delayed time to peak BG (2.5 ± 0.9 vs. 1.5 ± 0.5 h; P < 0.0001) and reduced magnitude of glycemic excursion (88 ± 42 vs. 113 ± 32 mg/dL; P = 0.006) compared with CL alone. Pramlintide effects on glycemic excursions were particularly evident at lunch and dinner, in association with higher premeal insulin concentrations at those mealtimes. CONCLUSIONS Pramlintide delayed the time to peak postprandial BG and reduced the magnitude of prandial BG excursions. Beneficial effects of pramlintide on CL may in part be related to higher premeal insulin levels at lunch and dinner compared with breakfast.

Hepatic fat accumulation is modulated by the interaction between the rs738409 variant in the PNPLA3 gene and the dietary omega6/omega3 PUFA intake.

Background A single nucleotide polymorphism (SNP), the rs738409, in the patatin like phospholipase 3 gene (PNPLA3) has been recently associated with increased hepatic steatosis and ALT levels in adults and children. Given the potential role of PNPLA3 in fatty liver development, we aimed to explore whether the influence of PNPLA3 genotype on hepatic fat in obese youth might be modulated by dietary factors such as essential omega polyunsaturated fatty acids (PUFA) intake. Materials and Methods We studied 127 children and adolescents (56 boys, 71 girls; 58 Caucasians; 30 African Americans and 39 Hispanics; mean age 14.7±3.3; mean BMI 30.7±7.2). The dietary composition was assessed by the Nutrition Data System for Research (NDS-R version 2011). The patients underwent a MRI study to assess the liver fat content (HFF%), ALT measurement and the genotyping of the rs738409 SNP by automatic sequencing. Results As previously observed, HFF% and ALT levels varied according to the genotype in each ethnicity. ALT levels and HFF% were significantly influenced by the interaction between genotype and omega-6/omega-3 PUFA ratio (n-6/n-3), p = 0.003 and p = 0.002, respectively. HFF% and ALT levels were, in fact, related to the n-6/n-3 consumption only in subjects homozygote for the G allele of the rs738409 (r2 = 0.45, p =  0.001 and r2 = 0.40, p = 0.006, respectively). Conclusions These findings suggest that the association of a high dietary n-6/n-3 PUFA with fatty liver and liver damage in obese youths may be driven by a predisposing genotype.

Reversal of Early Abnormalities in Glucose Metabolism in Obese Youth: Results of an Intensive Lifestyle Randomized Controlled Trial

OBJECTIVE The childhood obesity epidemic has been accompanied by an increasing prevalence of type 2 diabetes (T2D), particularly in minority children. Twenty to thirty percent of obese youth have “prediabetes,” a precursor to diabetes marked by insulin resistance, β-cell dysfunction, and impaired glucose tolerance. The Diabetes Prevention Program demonstrated that T2D could be prevented/delayed by intensive lifestyle modification in adults with prediabetes, but efficacy of similar interventions in youth has not been established. Therefore, we evaluated the effects of the Bright Bodies (BB) Healthy Lifestyle Program on 2-h oral glucose tolerance test (OGTT) glucose in comparison with adolescents receiving standard of care. RESEARCH DESIGN AND METHODS A parallel-group randomized controlled trial comparing BB with standard clinical care (CC) in obese adolescents (10–16 years old, Tanner stage >2) with elevated OGTT 2-h blood glucose (130–199 mg/dL) from a racially/ethnically diverse population. OGTTs, including cardiovascular and anthropometric assessments, were conducted at baseline and 6 months. Children attended BB twice per week for exercise and nutrition/behavior modification, and the CC group received CC from their pediatrician. Primary outcome was change in 2-h OGTT glucose and percentage conversion from elevated 2-h blood glucose to nonelevated (<130 mg/dL) 2-h blood glucose. Changes in outcomes were compared between groups using an ANCOVA, with adjustment for baseline outcome and multiple imputation for missing data. RESULTS Reductions in 2-h glucose were more favorable in BB compared with CC (−27.2 vs. −10.1 mg/dL; difference = −17.1, 95% CI; P = 0.005). Moreover, greater conversion to <130 mg/dL 2-h glucose occurred in BB than CC (P = 0.003), and other insulin sensitivity indices were significantly improved. CONCLUSIONS Compared with standard of care, the Yale BB Program is a more effective means of reducing the risk of T2D in obese adolescents with elevated 2-h glucose levels.

Circulating Levels of FGF-21 in Obese Youth: Associations With Liver Fat Content and Markers of Liver Damage

OBJECTIVE Fibroblast growth factor (FGF)-21 is highly expressed in the liver and regulates glucose and lipid metabolism in rodents. The effects of obesity and fatty liver on circulating FGF-21 levels have been described mainly in adults. Herein, we measured plasma FGF-21 levels in lean and obese adolescents with low and high hepatic fat content (HFF% <5.5% and HFF% ≥ 5.5%, respectively) and explored their relationship with hepatic fat content, measures of hepatic apoptosis, and insulin sensitivity. METHODS A total of 217 lean and obese adolescents with both low and high HFF% (lean = 31; obese low HFF% = 107; and obese high HFF% = 79) underwent an oral glucose tolerance test, a fast gradient magnetic resonance imaging to measure the %HFF and abdominal fat distribution. Cytokeratin 18 levels were measured as a biomarker of liver apoptosis. A subset of adolescents underwent a 2-step hyperinsulinemic-euglycemic clamp, and a liver biopsy (N = 14), to assess insulin sensitivity and steatohepatitis, respectively. RESULTS Compared to controls, FGF-21 levels were higher in obese youth, especially in those with high HFF (P < .001). FGF-21 significantly correlated with adiposity indexes (P < .001), visceral fat (r² = 0.240, P < .001), hepatic fat content (r² = 0.278, P < .001), cytokeratin 18 (r² = 0.217, P < .001), and alanine aminotransferase (r² = .164, P < .001). In subjects with steatoheaptitis, FGF-21 levels significantly correlated with the nonalcoholic fatty liver disease activity score (r² = 0.27, P = .04). Stepwise regression analysis indicated that these relationships are independent of body mass index, visceral fat, and insulin sensitivity. An inverse correlation was documented with insulin, hepatic resistance indexes, and adipose resistance indexes, which disappeared after adjusting for hepatic fat content. CONCLUSIONS Plasma FGF-21 levels are increased in obese adolescents, particularly in those with fatty liver. FGF-21 concentrations significantly and independently correlate with hepatic fat content and markers of hepatic apoptosis in obese youths.

Demographic, dietary, and biochemical determinants of vitamin D status in inner-city children

BACKGROUND Reports of clinical rickets are particularly evident in minority infants and children, but only limited analyses of vitamin D are available in this demographic group. OBJECTIVE We sought to characterize circulating 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)(2)D], and their determinants, including circulating parathyroid hormone (PTH), total alkaline phosphatase activity (ALP), calcium, and phosphorus, in minority infants and children. DESIGN We obtained demographic information and blood samples for measurement of PTH, ALP, 25(OH)D, and 1,25(OH)(2)D in >750 6-mo- to 3-y-old children. Dietary intake data were obtained and analyzed. RESULTS The mean (±SD) 25(OH)D concentration was 66 ± 22 nmol/L (26.3 ± 8.7 ng/dL). A total of 15% of children had 25(OH)D concentrations less than the recommended target threshold of 50 nmol/L. Combined elevations of PTH and ALP occurred in only 2.5% of children. Determinants of 25(OH)D included vitamin D intake, age (decreasing with age), skin type (greater concentrations in lighter-skinned children than in darker-skinned children), formula use (higher intakes), season (greater concentrations in the summer and fall than in the winter and spring), and, inversely, PTH. The mean 1,25(OH)(2)D concentration was 158 ± 58 pmol/L (60.6 ± 22.5 pg/mL), which was consistent with a reference range of 41-274 pmol/L or 15.7-105.5 pg/mL. Determinants for 1,25(OH)(2)D were age (decreasing with age), sex (greater concentrations in girls than in boys), skin type (greater concentrations in lighter-skinned children than in darker-skinned children), and, inversely, serum calcium and phosphorus. CONCLUSIONS Although 15% of subjects were vitamin D insufficient, only 2.5% of subjects had elevations of both PTH and ALP. The greater 25(OH)D concentrations observed with formula use confirm that dietary vitamin D fortification is effective in this demographic group. Circulating 1,25(OH)(2)D is higher in infants than in older children and adults and, in contrast to 25(OH)D, is not directly correlated with nutrient intakes.

Diabetes and Insulin Resistance in Pediatric Obesity

Over the past 2 decades, the prevalence of obesity and type 2 diabetes mellitus (T2DM) in children and adolescents has risen to epidemic proportions and disproportionately affects racial and ethnic minorities, who are at greater risk. The pathophysiology of T2DM is complex and involves insulin resistance, pancreatic β-cell dysfunction, and visceral adiposity. Current treatments of T2DM are limited to lifestyle intervention, metformin, and insulin therapy; use of these strategies in combination is often most effective. The role of research is to uncover simple biomarkers for insulin sensitivity and optimal and innovative treatment of insulin resistance and T2DM.

The Association Between Hepatic Fat Content and Liver Injury in Obese Children and Adolescents: Effects of ethnicity, insulin resistance, and common gene variants

OBJECTIVE Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH) are highly prevalent in obese youth. Herein, we aimed to study the association between hepatic fat accumulation as assessed by magnetic resonance imaging and circulating levels of cytokeratin-18 (CK-18) fragments, a robust NASH biomarker, and to explore the impact on this association of ethnicity, insulin resistance, and single nucleotide polymorphisms (SNPs) associated with steatosis (rs738409 in the PNPLA3, rs1260326 in the GCKR) or NASH severity (rs2645424 in the FDFT1). RESEARCH DESIGN AND METHODS Two-hundred twenty-nine obese youths (87 Caucasians, 61 African Americans, and 81 Hispanics; mean age, 12.8 ± 2.9 years; mean BMI, 31.4 ± 7.4) underwent magnetic resonance imaging, oral glucose tolerance test, and CK-18 levels measurement; 12 subjects underwent liver biopsy. RESULTS African Americans showed lower CK-18 levels than Hispanics (P < 0.001) and Caucasians (P = 0.004). Hepatic fat content (HFF%) and whole body insulin sensitivity index (WBISI) modulated CK-18 levels in Caucasians and Hispanics (P = 0.02 and P = 0.011), but not in African Americans; in fact, CK-18 was associated with HFF% and WBISI in Caucasians (P = 0.0018 and P < 0.0001) and Hispanics (P < 0.0001 and P = 0.02), but not in African Americans (both P = 0.5). The PNPLA3 SNP showed association in Caucasians (P = 0.02) and Hispanics (P = 0.05), and FDFT1 SNP showed an association in Caucasians (P = 0.05) and Hispanics (P = 0.02), with the same trend in African Americans (P = 0.07). CONCLUSIONS African Americans have lower levels of CK-18 than Caucasians and Hispanics irrespective of HFF% and insulin resistance. Moreover, SNPs in the PNPLA3 and FDFT1 may drive the individual predisposition to development of hepatic injury.

Oxidized fatty acids: A potential pathogenic link between fatty liver and type 2 diabetes in obese adolescents?

In this study, we sought to investigate the putative association of the oxidized metabolites derived from linoleic acid (OXFAs) with pediatric nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). We studied 80 obese adolescents (age 13.3 ± 3.31 years; body mass index 33.0 ± 6.79 kg/m(2)), who underwent an oral glucose tolerance test, a magnetic resonance imaging (MRI) to measure the hepatic fat content, and the measurement of OXFAs and caspase-cleaved Citokeratin18 fragment (CK-18), a robust biomarker of liver injury. In this study, we show that only in subjects with hepatic steatosis, the OXFAs are associated with the CK-18 and that this association is modulated by the PNPLA3 rs738409 variant. We also show that most of the OXFAs are associated with a lower insulin secretion and that adolescents with T2D have higher levels of OXFAs than subjects with impaired or normal glucose tolerance. These observations lead to the hypothesis that the OXFAs may be the pathogenic link between liver injury and T2D and that the novel therapeutic opportunities targeting the OXFAs are possible in adolescents with early-onset NAFLD and T2D.