Marc J. Weigensberg

Increased hepatic fat in overweight Hispanic youth influenced by interaction between genetic variation in PNPLA3 and high dietary carbohydrate and sugar consumption.

BACKGROUND Recently, a genetic variant (rs738409; C→G) of the PNPLA3 gene was identified to be associated with increased hepatic fat deposition, and the effect was more pronounced in Hispanics. Animal models have also shown that PNPLA3 expression can be regulated by dietary carbohydrate. OBJECTIVE The aim of this study was to examine whether the influence of PNPLA3 genotype on hepatic fat is modulated by dietary factors in Hispanic children. DESIGN PNPLA3 was genotyped in 153 Hispanic children (75% female, ages 8-18 y) by using the TaqMan method. Dietary intake was assessed by using three 24-h dietary recalls or diet records. Visceral adipose tissue (VAT), subcutaneous abdominal adipose tissue (SAAT), and hepatic fat fraction (HFF) were assessed in multiple abdominal slices by magnetic resonance imaging. Analysis of covariance was used to assess the diet × genotype interaction in liver fat, with the following a priori covariates: sex, age, energy, VAT, and SAAT. RESULTS HFF was influenced by a significant interaction between genotype and diet (genotype × carbohydrate, P = 0.04; genotype × total sugar, P = 0.01). HFF was positively related to carbohydrate (r = 0.31, P = 0.04) and total sugar (r = 0.34, P = 0.02) intakes but only in the GG group, independent of covariates. Dietary variables were not related to HFF in the CC or CG group or to other fat depots in all genotype groups. CONCLUSIONS These findings suggest that Hispanic children carrying the GG genotype are susceptible to increased hepatic fat when dietary carbohydrate intake, specifically sugar, is high. Specific dietary interventions based on genetic predisposition in this population may lead to more effective therapeutic outcomes for fatty liver. This trial was registered at clinicaltrials.gov as NCT00697580, 195-1642394A1, and NCT00693511.

Association between the Metabolic Syndrome and Serum Cortisol in Overweight Latino Youth

OBJECTIVE The purpose of this report is to investigate the associations between metabolic syndrome (MS) and levels of morning serum cortisol in a cohort of overweight Latino youth. DESIGN Subjects were 205 overweight, Latino youth (age 8-13 yr, body mass index percentile > 85, family history positive for type 2 diabetes). Measures included body composition by dual-energy x-ray absorptiometry, intraabdominal adipose tissue (IAAT) by magnetic resonance imaging, insulin sensitivity by frequently sampled iv glucose tolerance test/minimal model, fasting lipids, and serum cortisol. RESULTS Children with MS had higher body mass index percentile, total body fat mass, and IAAT and lower insulin sensitivity than those without MS. Children with MS had higher morning serum cortisol levels, whether unadjusted (10.1 +/- 3.7 vs. 9.0 +/- 2.8 microg/dl, P < 0.05) or after adjusting for age, gender, total body fat and lean tissue mass, and insulin sensitivity (10.4 +/- 0.4 vs. 8.9 +/- 0.3 microg/dl, P < 0.01). Increasing number of features of MS was associated with higher cortisol levels, after adjusting for covariates (P = 0.001). Among individual features of MS, systolic blood pressure had the strongest relationship with adjusted cortisol level (r = 0.34; P < 0.001), followed by diastolic blood pressure and fasting plasma glucose (both r = 0.23; P < 0.01). IAAT was associated with cortisol (r = 0.16; P < 0.05), whereas high-density lipoprotein, triglycerides, and waist circumference were not. CONCLUSIONS In overweight, Latino youth, MS is associated with higher morning serum cortisol levels, independent of body fat and insulin sensitivity. More studies are needed to investigate the role of relative hypercortisolism and chronic stress in obesity-related metabolic disorders in children.

Randomized control trial to improve adiposity and insulin resistance in overweight Latino adolescents.

Few randomized trials attempt to improve insulin sensitivity and associated metabolic risks in overweight Latino youth. The purpose of this study is to examine the effects of a modified carbohydrate nutrition program combined with strength training on insulin sensitivity, adiposity, and other type 2 diabetes risk factors in overweight Latino adolescents. In a 16‐week randomized trial, 54 overweight Latino adolescents (15.5 ± 1.0 years) were randomly assigned to: (i) Control (C; n = 16), (ii) Nutrition (N; n = 21), or (iii) Nutrition + Strength training (N+ST; n = 17). The N group received modified carbohydrate nutrition classes (once per week), while the N+ST received the same nutrition classes plus strength training (twice per week). The following were measured at pre‐ and postintervention: strength by 1‐repetition maximum, dietary intake by 3‐day records, body composition by dual‐energy X‐ray absorptiometry, glucose/insulin indices by oral glucose tolerance test (OGTT) and intravenous glucose tolerance test with minimal modeling. Across intervention group effects were tested using analysis of covariance with post hoc pairwise comparisons. A significant overall intervention effect was found for improvement in bench press (P < 0.001) and reductions in energy (P = 0.05), carbohydrate (P = 0.04) and fat intake (P = 0.03). There were no significant intervention effects on insulin sensitivity, body composition, or most glucose/insulin indices with the exception of glucose incremental area under the curve (IAUC) (P = 0.05), which decreased in the N and N+ST group by 18 and 6.3% compared to a 32% increase in the C group. In conclusion, this intense, culturally tailored intervention resulted in no significant intervention effects on measured risk factors with the exception of a beneficial effect on glycemic response to oral glucose.

Effects of PNPLA3 on Liver Fat and Metabolic Profile in Hispanic Children and Adolescents

OBJECTIVE A genome-wide study of adults identified a variant of PNPLA3 (rs738409) associated with ∼twofold higher liver fat. The purpose of this study was to examine the influence of PNPLA3 genotype on liver fat and other related metabolic outcomes in obese Hispanic children and adolescents. RESEARCH DESIGN AND METHODS Three hundred and twenty-seven Hispanics aged 8–18 years were genotyped for rs738409. One hundred and eighty-eight subjects had measures of visceral (VAT) and subcutaneous (SAT) adipose tissue volume and hepatic (HFF) and pancreatic (PFF) fat fraction by magnetic resonance imaging. One hundred and thirty-nine subjects did not have HFF measures but had extensive measures of insulin sensitivity and fasting lipids. RESULTS Liver fat in GG subjects was 1.7 and 2.4 times higher than GC and CC (11.1 ± 0.8% in GG vs. 6.6 ± 0.7% in GC and 4.7 ± 0.9% in CC; P < 0.0001), and this effect was observed even in the youngest children (8–10 years of age). The variant was not associated with VAT, SAT, PFF, or insulin sensitivity or other glucose/insulin indexes. However, Hispanic children carrying the GG genotype had significantly lower HDL cholesterol (40.9 ± 10.9 in CC vs. 37.0 ± 8.3 in CG vs. 35.7 ± 7.4 in GG; P = 0.03) and a tendency toward lower free fatty acid levels (P = 0.06). CONCLUSIONS These results provide new evidence that the effect of the PNPLA3 variant is apparent in Hispanic children and adolescents, is unique to fat deposition in liver as compared with other ectopic depots examined, and is associated with lower HDL cholesterol.

Persistence of Pre-Diabetes in Overweight and Obese Hispanic Children: Association With Progressive Insulin Resistance, Poor β-Cell Function, and Increasing Visceral Fat

OBJECTIVE—To examine changes in risk factors in overweight and obese Hispanic children at high risk of developing type 2 diabetes. RESEARCH DESIGN AND METHODS—We recruited 128 overweight/obese Hispanic children with a family history of type 2 diabetes primarily from clinics in East Los Angeles. Children were evaluated annually for 4 years with an oral glucose tolerance test, applying American Diabetes Association criteria to define diabetes and pre-diabetes. Insulin sensitivity (Si), acute insulin response (AIR) to glucose, and β-cell function (BCF) were determined from frequently sampled intravenous glucose tolerance tests, and total body fat by dual-energy X-ray absorptiometry and intra-abdominal and subcutaneous abdominal adipose tissue (IAAT and SAAT) by magnetic resonance imaging were assessed in years 1, 2, and 4. RESULTS—No subjects developed type 2 diabetes, 40% never had pre-diabetes, 47% had intermittent pre-diabetes with no clear pattern over time, and 13% had persistent pre-diabetes. At baseline, those with persistent pre-diabetes had lower BCF and higher IAAT. In repeated measures, Si deteriorated regardless of pre-diabetes, and there was a significant effect of pre-diabetes on AIR (42% lower in pre-diabetes; P = 0.01) and disposition index (34% lower in pre-diabetes; P = 0.021) and a significant interaction of pre-diabetes and time on IAAT (greater increase over time in those with pre-diabetes; P = 0.034). CONCLUSIONS—In this group of Hispanic children at high risk of type 2 diabetes, 1) pre-diabetes is highly variable from year to year; 2) the prevalence of persistent pre-diabetes over 3 years is 13%; and 3) children with persistent pre-diabetes have lower BCF, due to a lower AIR, and increasing visceral fat over time.

Association of breakfast skipping with visceral fat and insulin indices in overweight Latino youth.

Few studies have investigated the relationship between breakfast consumption and specific adiposity or insulin dynamics measures in children. The goal of this study is to determine whether breakfast consumption is associated with adiposity, specifically intra‐abdominal adipose tissue (IAAT), and insulin dynamics in overweight Latino youth. Participants were a cross‐sectional sample of 93 overweight (≥85th percentile BMI) Latino youth (10–17 years) with a positive family history of type 2 diabetes. Dietary intake was assessed by two 24‐h recalls, IAAT, and subcutaneous abdominal adipose tissue (SAAT) by magnetic resonance imaging, body composition by dual energy X‐ray absorptiometry, and insulin dynamics by a frequently sampled intravenous glucose tolerance test and minimal modeling. Participants were divided into three breakfast consumption categories: those who reported not eating breakfast on either day (breakfast skippers; n = 20), those who reported eating breakfast on one of two days (occasional breakfast eaters; n = 39) and those who ate breakfast on both days (breakfast eaters; n = 34). Using analyses of covariance, breakfast omission was associated with increased IAAT (P = 0.003) independent of age, Tanner, sex, total body fat, total body lean tissue mass, and daily energy intake. There were no significant differences in any other adiposity measure or in insulin dynamics between breakfast categories. Eating breakfast is associated with lower visceral adiposity in overweight Latino youth. Interventions focused on increasing breakfast consumption are warranted.

Aerobic and strength training reduces adiposity in overweight Latina adolescents.

PURPOSE To date, no study has examined the synergistic effects of a nutrition and combination of aerobic and strength training (CAST) on both adiposity and metabolic parameters in overweight Latina adolescent females. The goal was to assess if a 16-wk nutrition plus CAST pilot study had stronger effects on reducing adiposity and on improving glucose/insulin indices compared with control (C), nutrition only (N), and a nutrition plus strength training (N + ST) groups. METHODS In a 16-wk randomized trial, 41 overweight Latina girls (15.2 +/- 1.1 yr) were randomly assigned to C (n = 7), N (n = 10), N + ST (n = 9), or N + CAST (n = 15). All intervention groups received modified carbohydrate nutrition classes (once a week), whereas the N + ST also received strength training (twice a week) and the N + CAST received a combination of strength and aerobic training (twice a week). The following were measured before and after intervention: strength by one repetition maximum, physical activity by the 7-d accelerometry and the 3-d physical activity recall, dietary intake by 3-d records, body composition by dual-energy x-ray absorptiometry (DEXA), glucose/insulin indices by oral glucose tolerance test, and intravenous glucose tolerance test with minimal modeling. Across intervention group, effects were tested using ANCOVA with post hoc pairwise comparisons. RESULTS There were significant overall intervention effects for all adiposity measures (weight, body mass index [BMI], BMI z-scores, and DEXA total body fat), with a decrease of 3% in the N + CAST group compared with a 3% increase in the N + ST group (P < or = 0.05). There was also an intervention effect for fasting glucose with the N group increasing by 3% and the N + CAST group decreasing by 4% (P < or = 0.05). CONCLUSION The CAST was more effective than nutrition alone or nutrition plus strength training for reducing multiple adiposity outcomes and fasting glucose in overweight Latina girls. However, further research investigating and identifying intervention approaches that improve both adiposity and insulin indices, particularly in high-risk populations, are warranted.

Reduction in Risk Factors for Type 2 Diabetes Mellitus in Response to a Low-Sugar, High-Fiber Dietary Intervention in Overweight Latino Adolescents

OBJECTIVE To examine if reductions in added sugar intake or increases in fiber intake in response to a 16-week intervention were related to improvements in metabolic outcomes related to type 2 diabetes mellitus risk. DESIGN Secondary analysis of a randomized control trial. SETTING Intervention classes at a lifestyle laboratory and metabolic measures at the General Clinical Research Center. PARTICIPANTS Fifty-four overweight Latino adolescents (mean [SD] age, 15.5 [1] years). Intervention Sixteen-week study with 3 groups: control, nutrition, or nutrition plus strength training. MAIN OUTCOME MEASURES Body composition by dual-energy x-ray absorptiometry; visceral adipose tissue by magnetic resonance imaging; glucose and insulin incremental area under the curve by oral glucose tolerance test; insulin sensitivity, acute insulin response, and disposition index by intravenous glucose tolerance test; and dietary intake by 3-day records. RESULTS Fifty-five percent of all participants decreased added sugar intake (mean decrease, 47 g/d) and 59% increased fiber intake (mean increase, 5 g/d), and percentages were similar in all intervention groups, including controls. Those who decreased added sugar intake had an improvement in glucose incremental area under the curve (-15% vs +3%; P = .049) and insulin incremental area under the curve (-33% vs -9%; P = .02). Those who increased fiber intake had an improvement in body mass index (-2% vs +2%; P = .01) and visceral adipose tissue (-10% vs no change; P = .03). CONCLUSIONS Individuals who reduced added sugar intake by the equivalent of 1 can of soda per day or increased fiber intake by the equivalent of a cup of beans showed improvements in key risk factors for type 2 diabetes, specifically in insulin secretion and visceral fat. Improvements occurred independent of group assignment and were equally likely to occur in control group participants.

Dietary Intake and the Metabolic Syndrome in Overweight Latino Children

Little is known about the relationship between diet and metabolic health in Latino children, a population at increased risk for diabetes. The present study evaluates diet composition and the metabolic syndrome in a cross-sectional sample of 109 overweight Latino children aged 10 to 17 years with a family history of type 2 diabetes. Dietary intake was assessed by two 24-hour recalls. Associations between nutrients and features of the metabolic syndrome were examined using multiple linear regression and analysis of covariance. Log cholesterol intake was positively associated with log systolic blood pressure (beta=0.034, P=0.017) and log soluble dietary fiber intake was inversely associated with log waist circumference (beta=-0.069, P=0.036). Log soluble fiber intake was significantly higher in participants with 0 features compared to those with 3+ features of the metabolic syndrome (P=0.046), which translates to 5.2 g vs 4.1 g soluble fiber daily. No other significant associations were found between dietary variables and either the individual features of the metabolic syndrome or the clustering of metabolic syndrome components. Increases in soluble fiber through the daily consumption of fruits, vegetables, and beans may improve metabolic health in Latino children.

Ethnic Differences in Pancreatic Fat Accumulation and Its Relationship With Other Fat Depots and Inflammatory Markers

OBJECTIVE Visceral adipose tissue (VAT) and hepatic fat are associated with insulin resistance and vary by sex and ethnicity. Recently, pancreatic fat fraction (PFF) has also been linked with increasing obesity. Our aim was to assess ethnic and sex differences in PFF and its relationship to other fat depots, circulating free fatty acids (FFA), insulin secretion and sensitivity, and inflammation in obese adolescents and young adults. RESEARCH DESIGN AND METHODS We examined 138 (40 males, 98 females) obese Hispanics and African Americans (13–25 years). Subcutaneous adipose tissue and VAT volumes, hepatic fat fraction (HFF), and PFF were determined by magnetic resonance imaging. Insulin sensitivity and β-cell function were assessed during an intravenous glucose tolerance test. RESULTS Hispanics had higher PFF than African Americans (7.3 ± 3.8 vs. 6.2 ± 2.6%, P = 0.03); this ethnic difference was higher in young adults compared with children and adolescents (ethnicity × age: P = 0.01). Males had higher PFF than females (P < 0.0001). PFF was positively correlated with VAT (r = 0.45, P < 0.0001), HFF (r = 0.29, P < 0.0001), and FFA (r = 0.32, P = 0.001). PFF positively correlated with inflammatory markers but lost significance when adjusted for VAT. In multiple stepwise regression analysis, VAT and FFA were the best predictors of PFF (adjusted R2 = 0.40). There were no significant correlations between PFF and markers of insulin sensitivity or β-cell function. CONCLUSIONS PFF is higher in Hispanics than African Americans, and this difference increases with age. In young obese individuals, PFF is related to VAT, HFF, and circulating FFA, thus possibly contributing to their increased risk for type 2 diabetes and related metabolic disorders.