Tissue-Specific Fructose Metabolism in Obesity and Diabetes.

PURPOSE OF REVIEW: The objective of this review is to provide up-to-date and comprehensive discussion of tissue-specific fructose metabolism in the context of diabetes, dyslipidemia, and nonalcoholic fatty liver disease (NAFLD). RECENT FINDINGS: Increased intake of dietary fructose is a risk factor for a myriad of metabolic complications. Tissue-specific fructose metabolism has not been well delineated in terms of its contribution to detrimental health effects associated with fructose intake. Since inhibitors targeting fructose metabolism are being developed for the management of NAFLD and diabetes, it is essential to recognize how inability of one tissue to metabolize fructose may affect metabolism in the other tissues. The primary sites of fructose metabolism are the liver, intestine, and kidney. Skeletal muscle and adipose tissue can also metabolize a large portion of fructose load, especially in the setting of ketohexokinase deficiency, the rate-limiting enzyme of fructose metabolism. Fructose can also be sensed by the pancreas and the brain, where it can influence essential functions involved in energy homeostasis. Lastly, fructose is metabolized by the testes, red blood cells, and lens of the eye where it may contribute to infertility, advanced glycation end products, and cataracts, respectively. An increase in sugar intake, particularly fructose, has been associated with the development of obesity and its complications. Inhibition of fructose utilization in tissues primary responsible for its metabolism alters consumption in other tissues, which have not been traditionally regarded as important depots of fructose metabolism.

Cardiac remodeling and dysfunction in childhood obesity: a cardiovascular magnetic resonance study.

BACKGROUND: Obesity affects nearly one in five children and is associated with increased risk of premature death. Obesity-related heart disease contributes to premature death. We aimed to use cardiovascular magnetic resonance (CMR) to comprehensively characterize the changes in cardiac geometry and function in obese children. METHODS AND RESULTS: Forty-one obese/overweight (age 12 ± 3 years, 56 % female) and 29 healthy weight children (age 14 ± 3 years, 41 % female) underwent CMR, including both standard cine imaging and displacement encoded imaging, for a complete assessment of left ventricular (LV) structure and function. After adjusting for age, LV mass index was 23 % greater (27 ± 4 g/m(2.7) vs 22 ± 3 g/m(2.7), p <0.001) and the LV myocardium was 10 % thicker (5.6 ± 0.8 mm vs 5.1 ± 0.8 mm, p <0.001) in the obese/overweight children. This evidence of cardiac remodeling was present in obese children as young as age 8. Twenty four percent of obese/overweight children had concentric hypertrophy, 59 % had normal geometry and 17 % had either eccentric hypertrophy or concentric remodeling. LV mass index, thickness, ejection fraction and peak longitudinal and circumferential strains all correlated with epicardial adipose tissue after adjusting for height and gender (all p <0.05). Peak longitudinal and circumferential strains showed a significant relationship with the type of LV remodeling, and were most impaired in children with concentric hypertrophy (p <0.001 and p = 0.003, respectively). CONCLUSIONS: Obese children show evidence of significant cardiac remodeling and dysfunction, which begins as young as age 8. Obese children with concentric hypertrophy and impaired strain may represent a particularly high risk subgroup that demands further investigation.

Impact of obesity on the risk of venous thromboembolism in an inpatient pediatric population.

INTRODUCTION: The incidence of venous thromboembolism in children has increased significantly over the past 20 years. Over the same period of time, there was an increase in the prevalence of obesity in the pediatric population. Obesity is a known risk factor for VTE in adults, but little information is available in children. METHODS: This study evaluates the relation between obesity and VTE using a retrospective, case-control design, comparing the body mass index (BMI) of patients admitted with a diagnosis of VTE versus patients admitted with other diagnoses, at a single institution, between 2007 and 2011. RESULTS: We studied 48 inpatients diagnosed with deep venous thrombosis or pulmonary embolism and a control group of 274 age and gender matched patients admitted with other diagnoses. We found obese patients (BMI > 95th percentile) to have significantly higher risk of VTE (odds ratio 2.1, with 95% CI 1.1-4.2) than patients of normal weight (BMI < 85th percentile). Overweight patients (BMI 85th-95th percentile) did not demonstrate a significant change in risk. Most of the VTE patients were adolescents and the majority of them had other identifiable risk factors for thrombosis. CONCLUSION: This study establishes a correlation between obesity and VTE in a group of hospitalized children, showing a risk for VTE in obese children similar to the one described in much larger adult cohorts.

The combined pioglitazone and topiramate therapy for management of pediatric patients with severe MASLD.

BACKGROUND: Metabolic dysfunction associated steatotic liver disease (MASLD) is the most common cause of chronic hepatitis in adult and pediatric patients. Adolescents with severe MASLD can demonstrate a more aggressive disease phenotype as they more commonly develop liver fibrosis than BMI matched adults. Therefore, MASLD is the fastest growing indication for liver transplants in young adults. METHODS: Pioglitazone has been shown to improve liver histology in adult patients with MASLD, and in some studies, it attenuated liver fibrosis. Despite its perceived efficacy, pioglitazone is not widely used, likely due to its side effect profile, specifically increased weight gain. Topiramate lowers body weight in adolescents and in combination with phentermine, is one of the few FDA-approved medications for the management of obesity in children over 12 years of age. We performed a retrospective review of the outcomes in pediatric patients with severe MASLD, treated with the combined pioglitazone and topiramate therapy. RESULTS: Here, we report a case series of seven adolescents with severe MASLD and ≥F2 liver fibrosis treated with the combined pioglitazone and topiramate therapy. The combined therapy improved mean serum ALT from 165 ± 80 U/L to 89 ± 62 U/L after 12 months mean duration of treatment. One patient who completed 24 months of the combined therapy demonstrated a decrease in liver stiffness from 8.9 kPa to 5.6 kPa, as assessed by FibroScan elastography. There was a significant increase in body weight during this time, however, body mass index as a percentage of the 95 th percentile adjusted for age and gender did not increase significantly, 151 ± 29% vs. 152 ± 28%. Moreover, waist circumference, mid-upper arm circumference, percent body fat, and muscle mass were not significantly different before and after treatment. Serum lipid levels and hemoglobin A1c also did not change with the treatment. CONCLUSION: In summary, this case series provides encouraging results about the efficacy of the combined pioglitazone and topiramate therapy for the management of adolescents with severe MASLD, which should be further explored in clinical studies.

Cardiometabolic risk factors in South American children: A systematic review and meta-analysis.

BACKGROUND: Cardiometabolic risk factors (impaired fasting glucose, abdominal obesity, high blood pressure, dyslipidemia) cluster in children, may predict adult disease burden, and are inadequately characterized in South American children. OBJECTIVES: To quantify the burden of cardiometabolic risk factors in South American children (0-21 years) and identify knowledge gaps. METHODS: We systematically searched PubMed, Google Scholar, and the Latin American and Caribbean Health Sciences Literature via Virtual Health Library from 2000-2021 in any language. Two independent reviewers screened and extracted all data. RESULTS: 179 studies of 2,181 screened were included representing 10 countries (n = 2,975,261). 12.2% of South American children experienced obesity, 21.9% elevated waist circumference, 3.0% elevated fasting glucose, 18.1% high triglycerides, 29.6% low HDL cholesterol, and 8.6% high blood pressure. Cardiometabolic risk factor definitions varied widely. Chile exhibited the highest prevalence of obesity/overweight, low HDL, and impaired fasting glucose. Ecuador exhibited the highest prevalence of elevated blood pressure. Rural setting (vs. urban or mixed) and indigenous origin protected against most cardiometabolic risk factors. CONCLUSIONS: South American children experience high rates of obesity, overweight, and dyslipidemia. International consensus on cardiometabolic risk factor definitions for children will lead to improved diagnosis of cardiometabolic risk factors in this population, and future research should ensure inclusion of unreported countries and increased representation of indigenous populations.

Dietary Counseling Aimed at Reducing Sugar Intake Yields the Greatest Improvement in Management of Weight and Metabolic Dysfunction in Children with Obesity.

Pediatric obesity is a significant public health problem, the negative outcomes of which will challenge individual well-being and societal resources for decades to come. The objective of this study was to determine the effects of dietary counseling on weight management and metabolic abnormalities in children with obesity. One hundred and sixty-five patients aged 2−18 years old were studied over a two and a half year period. Data collected included demographic information, anthropometric assessment, laboratory measurements, and self-reported eating behaviors. Dietary counseling was provided at each visit. The data was analyzed from the first and last visits and the subjects were retrospectively divided into responders and non-responders based on a decrease in their BMI. After receiving dietary guidance, BMI decreased in 44% of the children, and these participants were classified as responders (BMI-R; n = 72). However, BMI did not improve in 56% of the participants, and these were classified as non-responders (BMI-NR; n = 93). At the initial visit, anthropometric measurements and dietary habits were similar between the groups. At the time of the last visit, mean change in BMI was −1.47 (SD 1.31) for BMI-R and +2.40 (SD 9.79) for BMI-NR. Analysis of food intake revealed that BMI-R significantly improved their dietary habits (p = 0.002) by reducing the intake of sugar-sweetened beverages (p = 0.019), processed foods (p = 0.002), sweets (p < 0.001), and unhealthy snacks (p = 0.009), as compared with BMI-NR. There was no change in the intake of second helpings, portion sizes, skipping meals, frequency of meals eaten at school, condiment use, intake of fruits and vegetables and consumption of whole grains between the groups. BMI-R also achieved an improvement in fasted glucose (p = 0.021), triglycerides (p < 0.001), and total cholesterol (p = 0.023), as compared to BMI-NR. In conclusion, children with obesity who were able to decrease their BMI implemented a significant reduction in consumption of foods with high sugar content. Focusing on reducing sugar intake may yield the biggest impact in terms of weight management and the improvement of metabolic abnormalities.

Stratification by obesity class, rather than age, can identify a higher percent of children at risk for non-alcoholic fatty liver disease and metabolic dysfunction.

BACKGROUND: An increasing number of clinical practice guidelines recommend screening children with obesity for non-alcoholic fatty liver disease (NAFLD). However, there is limited evidence regarding what parameters should be used to initiate the screening. OBJECTIVE: The objective of this study was to determine whether obesity class rather than age group can identify a higher percent of children at risk of NAFLD as assessed by abnormal alanine aminotransferase (ALT). METHODS: This is a cross-sectional study in a regional referral clinic for evaluation of obesity. Children were stratified by age group or by obesity class, and data obtained at first visit were analysed. RESULTS: Of the 784 children, 482 were ≥10, 209 were 6 to 9 and 93 were 2 to 5 years of age. Abnormal ALT was observed in 32.1%, 46.9% and 61.0% of children with class I, II or III obesity, respectively (p < 0.001), while the risk of abnormal ALT did not differ in very young (2-5), young (6-9), or children older than 10 years. A multivariable analysis showed that class II and class III obesity were associated with 2.1-fold (1.27-3.72) and 4-fold (2.41-6.96) greater odds of abnormal ALT compared with class I obesity. African-American children had lower risk of abnormal ALT (0.27), whereas Hispanic children had higher risk (2.37). Obesity class was a better predictor of abnormal ALT than age, especially in girls. Furthermore, 66.7% of boys (p = 0.009) and 69% of girls (p < 0.001) with abnormal ALT exhibited additional signs of metabolic dysfunction. CONCLUSION: Obesity class is more strongly associated with abnormal ALT than age.