Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome; its rising prevalence parallels the rise in obesity and diabetes. Historically thought to result from ...overnutrition and a sedentary lifestyle, recent evidence suggests that diets high in sugar (from sucrose and/or high-fructose corn syrup HFCS) not only increase the risk of NAFLD, but also non-alcoholic steatohepatitis (NASH). Herein, we review the experimental and clinical evidence that fructose precipitates fat accumulation in the liver, due to both increased lipogenesis and impaired fat oxidation. Recent evidence suggests that the predisposition to fatty liver is linked to the metabolism of fructose by fructokinase C, which results in ATP consumption, nucleotide turnover and uric acid generation that mediate fat accumulation. Alterations to gut permeability, the microbiome, and associated endotoxemia contribute to the risk of NAFLD and NASH. Early clinical studies suggest that reducing sugary beverages and total fructose intake, especially from added sugars, may have a significant benefit on reducing hepatic fat accumulation. We suggest larger, more definitive trials to determine if lowering sugar/HFCS intake, and/or blocking uric acid generation, may help reduce NAFLD and its downstream complications of cirrhosis and chronic liver disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The severity and frequency of childhood obesity has increased significantly over the past three to four decades. The health effects of increased body mass index as a child may significantly impact ...obese youth as they age. However, many of the long-term outcomes of childhood obesity have yet to be studied. This article examines the currently available longitudinal data evaluating the effects of childhood obesity on adult outcomes. Consequences of obesity include an increased risk of developing the metabolic syndrome, cardiovascular disease, type 2 diabetes and its associated retinal and renal complications, nonalcoholic fatty liver disease, obstructive sleep apnea, polycystic ovarian syndrome, infertility, asthma, orthopedic complications, psychiatric disease, and increased rates of cancer, among others. These disorders can start as early as childhood, and such early onset increases the likelihood of early morbidity and mortality. Being obese as a child also increases the likelihood of being obese as an adult, and obesity in adulthood also leads to obesity-related complications. This review outlines the evidence for childhood obesity as a predictor of adult obesity and obesity-related disorders, thereby emphasizing the importance of early intervention to prevent the onset of obesity in childhood.
Elevated serum uric acid (SUA) is increasingly recognized as a risk factor for kidney disease in adults with diabetes, but data in youth are limited. We hypothesized that elevated SUA predicts ...development of elevated urinary albumin excretion (UAE) and hypertension over time in teens with type 2 diabetes (T2D).
Serum creatinine, cystatin C, SUA, and the urine albumin-to-creatinine ratio (UACR) were assessed in 539 obese youth, ages 12-17 years, with T2D duration <2 years at baseline in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Estimated glomerular filtration rate (eGFR) was calculated using creatinine and cystatin C. Hypertension was defined as systolic or diastolic blood pressure ≥130/80 mmHg and elevated UAE as UACR ≥30 mg/g. Cox proportional hazards models evaluated the relationship between SUA and outcome variables longitudinally over an average follow-up of 5.7 years, adjusting for age, sex, race/ethnicity, BMI, HbA
, eGFR, ACE inhibitor/angiotensin receptor blocker use, and TODAY treatment group assignment.
At baseline, hyperuricemia (≥6.8 mg/dL) was present in 25.6% of participants, hypertension in 18.7%, and elevated UAE in 6.1%. During follow-up of up to 7 years, hypertension developed in 37.4% and UAE in 18.0%. Higher baseline SUA increased the risk of incident hypertension (hazard ratio HR 1.19, 95% CI 1.03-1.38, per 1 mg/dL increase in SUA) and elevated UAE (HR 1.24, 95% CI 1.03-1.48) in adjusted models.
Hyperuricemia was common in youth with T2D. Higher baseline SUA independently increased the risk for onset of hypertension and elevated UAE. Research is needed to determine whether SUA-lowering therapies can impede development of diabetic kidney disease and hypertension in T2D youth.
Hepatic steatosis (HS) is common in adolescents with obesity and polycystic ovary syndrome (PCOS). Gut microbiota are altered in adults with obesity, HS, and PCOS, which may worsen metabolic ...outcomes, but similar data is lacking in youth.
Thirty-four adolescents with PCOS and obesity underwent stool and fasting blood collection, oral glucose tolerance testing, and MRI for hepatic fat fraction (HFF). Fecal bacteria were profiled by high-throughput 16S rRNA gene sequencing.
50% had HS (N = 17, age 16.2±1.5 years, BMI 38±7 kg/m2, HFF 9.86.5, 20.7%) and 50% did not (N = 17, age 15.8±2.2 years, BMI 35±4 kg/m2, HFF 3.82.6, 4.4%). The groups showed no difference in bacterial α-diversity (richness p = 0.202; evenness p = 0.087; and diversity p = 0.069) or global difference in microbiota (β-diversity). Those with HS had lower % relative abundance (%RA) of Bacteroidetes (p = 0.013), Bacteroidaceae (p = 0.009), Porphyromonadaceae (p = 0.011), and Ruminococcaceae (p = 0.008), and higher Firmicutes:Bacteroidetes (F:B) ratio (47.8% vs. 4.3%, p = 0.018) and Streptococcaceae (p = 0.034). Bacterial taxa including phyla F:B ratio, Bacteroidetes, and family Bacteroidaceae, Ruminococcaceae and Porphyromonadaceae correlated with metabolic markers.
Obese adolescents with PCOS and HS have differences in composition of gut microbiota, which correlate with metabolic markers, suggesting a modifying role of gut microbiota in HS and PCOS.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Context
Alterations in gut microbiota relate to the metabolic syndrome, but have not been examined in at-risk obese youth with polycystic ovary syndrome (PCOS).
Objective
Compare the ...composition and diversity of the gut microbiota and associations with metabolic and hormonal measures between 2 groups of female adolescents with equal obesity with or without PCOS.
Design
Prospective, case-control cross-sectional study.
Setting
Tertiary-care center.
Participants
A total of 58 obese female adolescents (n = 37 with PCOS; 16.1 ± 0.3 years of age; body mass index BMI 98.5th percentile) and (n = 21 without PCOS; 14.5 ± 0.4 years of age; BMI 98.7th percentile).
Outcomes
Bacterial diversity, percent relative abundance (%RA), and correlations with hormonal and metabolic measures.
Results
Participants with PCOS had decreased α-diversity compared with the non-PCOS group (Shannon diversity P = 0.045 and evenness P = 0.0052). β-diversity, reflecting overall microbial composition, differed between groups (P < 0.001). PCOS had higher %RA of phyla Actinobacteria (P = 0.027), lower Bacteroidetes (P = 0.004), and similar Firmicutes and Proteobacteria. PCOS had lower %RA of families Bacteroidaceae (P < 0.001) and Porphyromonadaceae (P = 0.024) and higher Streptococcaceae (P = 0.047). Lower bacterial α-diversity was strongly associated with higher testosterone concentrations. Several individual taxa correlated with testosterone and metabolic measures within PCOS and across the entire cohort. Receiver operative curve analysis showed 6 taxa for which the %RA related to PCOS status and lower Bacteroidaceae conferred a 4.4-fold likelihood ratio for PCOS.
Conclusion
Alterations in the gut microbiota exist in obese adolescents with PCOS versus obese adolescents without PCOS and these changes relate to markers of metabolic disease and testosterone. Further work is needed to determine if microbiota changes are reflective of, or influencing, hormonal metabolism.
The purpose of this review is to provide an update on the changing face of paediatric type 1 diabetes and type 2 diabetes. Paediatric diabetes is on the rise, with extensive research dedicated to ...understanding its pathophysiology, comorbidities and complications. As obesity continues to increase among all youth, differentiating between type 1 diabetes and type 2 diabetes has become increasingly difficult but remains important for optimising treatment, anticipating complications and predicting disease risk. Novel treatments are emerging, with the ultimate goal being to achieve glycaemic control, limit weight gain, improve quality of life and reduce comorbidities. In this review, we focus on updates regarding the epidemiology, clinical presentation, comorbidities and complications of paediatric type 1 diabetes and type 2 diabetes and conclude with current and emerging treatments.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Type 2 diabetes is a significant and increasing burden in adolescents and young adults. Clear strategies for research, prevention, and treatment of the disease in these vulnerable patients are ...needed. Evidence suggests that type 2 diabetes in children is different not only from type 1 but also from type 2 diabetes in adults. Understanding the unique pathophysiology of type 2 diabetes in youth, as well as the risk of complications and the psychosocial impact, will enable industry, academia, funding agencies, advocacy groups, and regulators to collectively evaluate both current and future research, treatment, and prevention approaches. This Consensus Report characterizes type 2 diabetes in children, evaluates the fundamental differences between childhood and adult disease, describes the current therapeutic options, and discusses challenges to and approaches for developing new treatments.
Several factors, including genetics, family history, diet, physical activity, obesity, and insulin resistance in puberty, appear to increase the risk of type 2 diabetes in youth. Youth-onset type 2 ...diabetes is often thought of as a single entity but rather exists as a spectrum of disease with differences in presentation, metabolic characteristics, clinical progression, and complication rates. We review what is currently known regarding the risks associated with developing type 2 diabetes in youth. Additionally, we focus on the spectrum of phenotypes of pediatric type 2 diabetes, discuss the pathogenic underpinnings and potential therapeutic relevance of this heterogeneity, and compare youth-onset type 2 diabetes with type 1 diabetes and adult-onset type 2 diabetes. Finally, we highlight knowledge gaps in prediction and prevention of youth-onset type 2 diabetes.
Previous research has documented racial/ethnic disparities in diabetes treatments and outcomes. It remains controversial whether these disparities result from differences in socioeconomic status ...(SES) or other factors. We examined racial/ethnic disparities in therapeutic modalities and diabetes outcomes among the large number of pediatric participants in the T1D Exchange Clinic Registry.
The cohort included 10 704 participants aged <18 years with type 1 diabetes for ≥1 year (48% female; mean age: 11.9 ± 3.6 years; diabetes duration: 5.2 ± 3.5 years). Diabetes management and clinical outcomes were compared among 8841 non-Hispanic white (white) (83%), 697 non-Hispanic black (black) (7%), and 1166 Hispanic (11%) participants. The population included 214 high-income black and Hispanic families.
Insulin pump use was higher in white participants than in black or Hispanic participants (61% vs 26% and 39%, respectively) after adjusting for gender, age, diabetes duration, and SES (P < .001). Mean hemoglobin A1c was higher (adjusted P < .001) in black participants than in white or Hispanic participants (9.6%, 8.4%, and 8.7%). More black participants experienced diabetic ketoacidosis and severe hypoglycemic events in the previous year than white or Hispanic participants (both, P < .001). There were no significant differences in hemoglobin A1c, diabetic ketoacidosis, or severe hypoglycemia between white and Hispanic participants after adjustment for SES.
Even after SES adjustment, marked disparities in insulin treatment method and treatment outcomes existed between black versus Hispanic and white children within this large pediatric cohort. Barriers to insulin pump use and optimal glycemic control beyond SES should be explored in all ethnic groups.
The objective of this study was to compare the ratio of renal oxygen availability (RO
) to glomerular filtration rate (GFR), a measure of relative renal hypoxia, in adolescents with and without type ...1 diabetes (T1D) and relate the ratio to albuminuria, renal plasma flow (RPF), fat mass, and insulin sensitivity (
). RO
was estimated by blood oxygen level-dependent MRI; fat mass was estimated by DXA; GFR and RPF were estimated by iohexol and
-aminohippurate clearance; albuminuria was estimated by urine albumin-to-creatinine ratio (UACR); and
was estimated from steady-state glucose infusion rate/insulin (mg/kg/min) by hyperglycemic clamp in 50 adolescents with T1D (age 16.1 ± 3.0 years, HbA
8.6 ± 1.2%) and 20 control patients of similar BMI (age 16.1 ± 2.9 years, HbA
5.2 ± 0.2%). The RO
:GFR (ms/mL/min) was calculated as RO
(T2*, ms) divided by GFR (mL/min). Whole-kidney RO
:GFR was 25% lower in adolescents with T1D versus control patients (
< 0.0001). In adolescents with T1D, lower whole-kidney RO
:GFR was associated with higher UACR (
= -0.31,
= 0.03), RPF (
= -0.52,
= 0.0009), and fat mass (
= -0.33,
= 0.02). Lower medullary RO
:GFR was associated with lower
(
= 0.31,
= 0.03). In conclusion, adolescents with T1D exhibited relative renal hypoxia that was associated with albuminuria and with increased RPF, fat mass, and insulin resistance. These data suggest a potential role of renal hypoxia in the development of diabetic kidney disease.
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