Liraglutide in Children and Adolescents with Type 2 Diabetes.

BACKGROUND: Metformin is the regulatory-approved treatment of choice for most youth with type 2 diabetes early in the disease. However, early loss of glycemic control has been observed with metformin monotherapy. Whether liraglutide added to metformin (with or without basal insulin treatment) is safe and effective in youth with type 2 diabetes is unknown. METHODS: Patients who were 10 to less than 17 years of age were randomly assigned, in a 1:1 ratio, to receive subcutaneous liraglutide (up to 1.8 mg per day) or placebo for a 26-week double-blind period, followed by a 26-week open-label extension period. Inclusion criteria were a body-mass index greater than the 85th percentile and a glycated hemoglobin level between 7.0 and 11.0% if the patients were being treated with diet and exercise alone or between 6.5 and 11.0% if they were being treated with metformin (with or without insulin). All the patients received metformin during the trial. The primary end point was the change from baseline in the glycated hemoglobin level after 26 weeks. Secondary end points included the change in fasting plasma glucose level. Safety was assessed throughout the course of the trial. RESULTS: Of 135 patients who underwent randomization, 134 received at least one dose of liraglutide (66 patients) or placebo (68 patients). Demographic characteristics were similar in the two groups (mean age, 14.6 years). At the 26-week analysis of the primary efficacy end point, the mean glycated hemoglobin level had decreased by 0.64 percentage points with liraglutide and increased by 0.42 percentage points with placebo, for an estimated treatment difference of -1.06 percentage points (P<0.001); the difference increased to -1.30 percentage points by 52 weeks. The fasting plasma glucose level had decreased at both time points in the liraglutide group but had increased in the placebo group. The number of patients who reported adverse events was similar in the two groups (56 [84.8%] with liraglutide and 55 [80.9%] with placebo), but the overall rates of adverse events and gastrointestinal adverse events were higher with liraglutide. CONCLUSIONS: In children and adolescents with type 2 diabetes, liraglutide, at a dose of up to 1.8 mg per day (added to metformin, with or without basal insulin), was efficacious in improving glycemic control over 52 weeks. This efficacy came at the cost of an increased frequency of gastrointestinal adverse events. (Funded by Novo Nordisk; Ellipse ClinicalTrials.gov number, NCT01541215.).

Country-Specific Prevalence and Incidence of Youth-Onset Type 2 Diabetes: A Narrative Literature Review.

BACKGROUND: With increased awareness of type 2 diabetes (T2D) in children and adolescents, an overview of country-specific differences in epidemiology data is needed to develop a global picture of the disease development. SUMMARY: This study examined country-specific prevalence and incidence data of youth-onset T2D published between 2008 and 2019, and searched for national guidelines to expand the understanding of country-specific similarities and differences. Of the 1,190 articles and 17 congress abstracts identified, 58 were included in this review. Our search found the highest reported prevalence rates of youth-onset T2D in China (520 cases/100,000 people) and the USA (212 cases/100,000) and lowest in Denmark (0.6 cases/100,000) and Ireland (1.2 cases/100,000). However, the highest incidence rates were reported in Taiwan (63 cases/100,000) and the UK (33.2 cases/100,000), with the lowest in Fiji (0.43 cases/100,000) and Austria (0.6 cases/100,000). These differences in epidemiology data may be partly explained by variations in the diagnostic criteria used within studies, screening recommendations within national guidelines and race/ethnicity within countries. Key Messages: Our study suggests that published country-specific epidemiology data for youth-onset T2D are varied and scant, and often with reporting inconsistencies. Finding optimal diagnostic criteria and screening strategies for this disease should be of high interest to every country. TRIAL REGISTRATION: Not applicable.

Genetic and environmental (physical fitness and sedentary activity) interaction effects on cardiometabolic risk factors in Mexican American children and adolescents.

Knowledge on genetic and environmental (G × E) interaction effects on cardiometabolic risk factors (CMRFs) in children is limited.  The purpose of this study was to examine the impact of G × E interaction effects on CMRFs in Mexican American (MA) children (n = 617, ages 6-17 years). The environments examined were sedentary activity (SA), assessed by recalls from "yesterday" (SAy) and "usually" (SAu) and physical fitness (PF) assessed by Harvard PF scores (HPFS). CMRF data included body mass index (BMI), waist circumference (WC), fat mass (FM), fasting insulin (FI), homeostasis model of assessment-insulin resistance (HOMA-IR), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), systolic (SBP) and diastolic (DBP) blood pressure, and number of metabolic syndrome components (MSC). We examined potential G × E interaction in the phenotypic expression of CMRFs using variance component models and likelihood-based statistical inference. Significant G × SA interactions were identified for six CMRFs: BMI, WC, FI, HOMA-IR, MSC, and HDL, and significant G × HPFS interactions were observed for four CMRFs: BMI, WC, FM, and HOMA-IR. However, after correcting for multiple hypothesis testing, only WC × SAy, FM × SAy, and FI × SAu interactions became marginally significant. After correcting for multiple testing, most of CMRFs exhibited significant G × E interactions (Reduced G × E model vs. Constrained model). These findings provide evidence that genetic factors interact with SA and PF to influence variation in CMRFs, and underscore the need for better understanding of these relationships to develop strategies and interventions to effectively reduce or prevent cardiometabolic risk in children.

Prevalence of Suspected Nonalcoholic Fatty Liver Disease in Lean Adolescents in the United States.

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) can develop in lean subjects referred to as lean NAFLD. We aim to evaluate the prevalence and risk factors of NAFLD in lean adolescents in the United States (US). METHODS: Cross sectional data from 1482 lean subjects (body mass index <85th percentile) ages between 12 and 18 years, who were enrolled in the National Health and Examination Survey during the 2005 to 2014 cycles were included. We defined suspected NAFLD as alanine aminotransferase >25.8 U/L for boys and >22.1 U/L for girls; hypertriglyceridemia as triglycerides ≥150 mg/dL; low HDL as HDL <40 mg/dL and insulin resistance (IR) as homeostatic model assessment of IR ≥3. RESULTS: The mean weighted prevalence of suspected NAFLD among lean adolescents during 2005 to 2014 cycles was 8% (95% CI 6.2-9.9). Lean subjects with suspected NAFLD were significantly older compared with lean non-NAFLD subjects (15.5 vs 15 years, P value <0.05). Low HDL (15.5% vs 6.8%; P value 0.016) and hypertriglyceridemia (10% vs 3.9%; P value 0.028) were also found to be more common among lean NAFLD subjects compared with their non-NAFLD counterparts. Presence of IR increased the risk of having suspected NAFLD by 4-fold among lean adolescents. Non-Hispanic black lean adolescents were less likely to have suspected NAFLD compared with non-Hispanic white lean adolescents. CONCLUSIONS: The estimated prevalence of suspected NAFLD among lean adolescents in the US was found to be 8% with evidence of metabolic derangements such as low HDL, hypertriglyceridemia, and IR.

Nephropathy in youth and young adults with type 2 diabetes.

The occurrence and progression of nephropathy associated with early onset type 2 diabetes (T2D) is a consequence of the ongoing epidemic of childhood obesity. Minimal evidence regarding treatment effectiveness of renovascular comorbidities in youth with early onset T2D is available, due to the relatively recent emergence of T2D in youth and young adults. Extrapolation of adult therapy guidelines is not an ideal approach to making therapeutic decisions in this population. Evolving management and intervention strategies are based on accumulating longitudinal data from cohorts of well characterized youth and young adults with T2D. The degree of similarity in histologic findings and disease specific characteristics of kidney disease in patients with early onset T2D and albuminuria compared with affected adults is not well characterized. Early aggressive therapies to minimize the impact of nephropathy are indicated as the evidence for best therapies in youth with T2D are further explored.

Genetic epidemiology of cardiometabolic risk factors and their clustering patterns in Mexican American children and adolescents: the SAFARI Study.

Pediatric metabolic syndrome (MS) and its cardiometabolic components (MSCs) have become increasingly prevalent, yet little is known about the genetics underlying MS risk in children. We examined the prevalence and genetics of MS-related traits among 670 non-diabetic Mexican American (MA) children and adolescents, aged 6-17 years (49 % female), who were participants in the San Antonio Family Assessment of Metabolic Risk Indicators in Youth study. These children are offspring or biological relatives of adult participants from three well-established Mexican American family studies in San Antonio, TX, at increased risk of type 2 diabetes. MS was defined as ≥3 abnormalities among 6 MSC measures: waist circumference, systolic and/or diastolic blood pressure, fasting insulin, triglycerides, HDL-cholesterol, and fasting and/or 2-h OGTT glucose. Genetic analyses of MS, number of MSCs (MSC-N), MS factors, and bivariate MS traits were performed. Overweight/obesity (53 %), pre-diabetes (13 %), acanthosis nigricans (33 %), and MS (19 %) were strikingly prevalent, as were MS components, including abdominal adiposity (32 %) and low HDL-cholesterol (32 %). Factor analysis of MS traits yielded three constructs: adipo-insulin-lipid, blood pressure, and glucose factors, and their factor scores were highly heritable. MS itself exhibited 68 % heritability. MSC-N showed strong positive genetic correlations with obesity, insulin resistance, inflammation, and acanthosis nigricans, and negative genetic correlation with physical fitness. MS trait pairs exhibited strong genetic and/or environmental correlations. These findings highlight the complex genetic architecture of MS/MSCs in MA children, and underscore the need for early screening and intervention to prevent chronic sequelae in this vulnerable pediatric population.

LRG1 is an adipokine that mediates obesity-induced hepatosteatosis and insulin resistance.

Dysregulation in adipokine biosynthesis and function contributes to obesity-induced metabolic diseases. However, the identities and functions of many of the obesity-induced secretory molecules remain unknown. Here, we report the identification of leucine-rich alpha-2-glycoprotein 1 (LRG1) as an obesity-associated adipokine that exacerbates high fat diet-induced hepatosteatosis and insulin resistance. Serum levels of LRG1 were markedly elevated in obese humans and mice compared with their respective controls. LRG1 deficiency in mice greatly alleviated diet-induced hepatosteatosis, obesity, and insulin resistance. Mechanistically, LRG1 bound with high selectivity to the liver and promoted hepatosteatosis by increasing de novo lipogenesis and suppressing fatty acid ß-oxidation. LRG1 also inhibited hepatic insulin signaling by downregulating insulin receptor substrates 1 and 2. Our study identified LRG1 as a key molecule that mediates the crosstalk between adipocytes and hepatocytes in diet-induced hepatosteatosis and insulin resistance. Suppressing LRG1 expression and function may be a promising strategy for the treatment of obesity-related metabolic diseases.

Serum carotenoids and Pediatric Metabolic Index predict insulin sensitivity in Mexican American children.

High concentrations of carotenoids are protective against cardiometabolic risk traits (CMTs) in adults and children. We recently showed in non-diabetic Mexican American (MA) children that serum α-carotene and ß-carotene are inversely correlated with obesity measures and triglycerides and positively with HDL cholesterol and that they were under strong genetic influences. Additionally, we previously described a Pediatric Metabolic Index (PMI) that helps in the identification of children who are at risk for cardiometabolic diseases. Here, we quantified serum lycopene and ß-cryptoxanthin concentrations in approximately 580 children from MA families using an ultraperformance liquid chromatography-photodiode array and determined their heritabilities and correlations with CMTs. Using response surface methodology (RSM), we determined two-way interactions of carotenoids and PMI on Matsuda insulin sensitivity index (ISI). The concentrations of lycopene and ß-cryptoxanthin were highly heritable [h2 = 0.98, P = 7 × 10-18 and h2 = 0.58, P = 1 × 10-7]. We found significant (P ≤ 0.05) negative phenotypic correlations between ß-cryptoxanthin and five CMTs: body mass index (- 0.22), waist circumference (- 0.25), triglycerides (- 0.18), fat mass (- 0.23), fasting glucose (- 0.09), and positive correlations with HDL cholesterol (0.29). In contrast, lycopene only showed a significant negative correlation with fasting glucose (- 0.08) and a positive correlation with HDL cholesterol (0.18). Importantly, we found that common genetic influences significantly contributed to the observed phenotypic correlations. RSM showed that increased serum concentrations of α- and ß-carotenoids rather than that of ß-cryptoxanthin or lycopene had maximal effects on ISI. In summary, our findings suggest that the serum carotenoids are under strong additive genetic influences and may have differential effects on susceptibility to CMTs in children.

Acanthosis nigricans as a composite marker of cardiometabolic risk and its complex association with obesity and insulin resistance in Mexican American children.

AIM: Acanthosis nigricans (AN) is a strong correlate of obesity and is considered a marker of insulin resistance (IR). AN is associated with various other cardiometabolic risk factors (CMRFs). However, the direct causal relationship of IR with AN in obesity has been debated. Therefore, we aimed to examine the complex causal relationships among the troika of AN, obesity, and IR in Mexican Americans (MAs). METHODS: We used data from 670 non-diabetic MA children, aged 6-17 years (49% girls). AN (prevalence 33%) severity scores (range 0-5) were used as a quasi-quantitative trait (AN-q) for analysis. We used the program SOLAR for determining phenotypic, genetic, and environmental correlations between AN-q and CMRFs (e.g., BMI, HOMA-IR, lipids, blood pressure, hs-C-reactive protein (CRP), and Harvard physical fitness score (PFS)). The genetic and environmental correlations were subsequently used in mediation analysis (AMOS program). Model comparisons were made using goodness-of-fit indexes. RESULTS: Heritability of AN-q was 0.75 (p<0.0001). It was positively/significantly (p<0.05) correlated with traits such as BMI, HOMA-IR, and CRP, and negatively with HDL-C and PFS. Of the models tested, indirect mediation analysis of BMI→HOMA-IR→AN-q yielded lower goodness-of-fit than a partial mediation model where BMI explained the relationship with both HOMA-IR and AN-q simultaneously. Using complex models, BMI was associated with AN-q and IR mediating most of the CMRFs; but no relationship between IR and AN-q. CONCLUSION: Our study suggests that obesity explains the association of IR with AN, but no causal relationship between IR and AN in Mexican American children.

Simultaneous Blood Glucose Monitoring During Gastric-Emptying Scintigraphy May Identify Unsuspected Abnormalities.

PURPOSE: A retrospective study of 197 patients was performed to evaluate utility of simultaneous fingerstick glucose monitoring during standardized solid meal gastric-emptying scintigraphy (GES). We hypothesized the unlabeled carbohydrate components of the standardized meal often empty at different rates than the labeled egg protein component and that simultaneous glucose monitoring may identify rapid carbohydrate gastric emptying. METHODS: Patients were classified as normal, rapid, or delayed gastric emptying from the standardized solid egg meal GES criteria. Further subcategorization was made based on postprandial glycemic excursions above baseline at 30/60 minutes and was delineated as elevated (>75 mg/>85 mg/dL), normal, or diminished (<30 mg/dL) glucose excursion. RESULTS: Of the 197 patients, solid gastric-emptying rates for 105 were normal, delayed in 54, and rapid in 25 patients, and 13 patients had initially delayed emptying 1 or 2 hours with normal emptying by 4 hours. Of the 105 patients with normal gastric emptying, 58 had elevated, 47 normal, and none had diminished glucose excursions. Of the 54 patients with delayed gastric emptying, 26 had elevated, 16 had normal, and 12 had diminished glucose excursions. Nine patients with normal or delayed gastric emptying but elevated glycemic excursions returned for a liquid glucose GES. In contrast to their standardized GES results, all 9 had rapid emptying with elevated glycemic excursions. CONCLUSIONS: Simultaneous blood glucose monitoring with standardized GES protocols may provide a marker for contradictory findings of rapid gastric emptying of the unlabeled carbohydrate component in the standardized meal and may contribute to unexplained postprandial gastrointestinal symptoms. The additional insights provided by fingerstick glucose monitoring are inexpensive, easy to perform and may provide for new approaches to management of patient's gastrointestinal symptoms.

Genetics of serum carotenoid concentrations and their correlation with obesity-related traits in Mexican American children.

Background: Dietary intake of phytonutrients present in fruits and vegetables, such as carotenoids, is associated with a lower risk of obesity and related traits, but the impact of genetic variation on these associations is poorly understood, especially in children.Objective: We estimated common genetic influences on serum carotenoid concentrations and obesity-related traits in Mexican American (MA) children.Design: Obesity-related data were obtained from 670 nondiabetic MA children, aged 6-17 y. Serum α- and ß-carotenoid concentrations were measured in ∼570 (α-carotene in 565 and ß-carotene in 572) of these children with the use of an ultraperformance liquid chromatography-photodiode array. We determined heritabilities for both carotenoids and examined their genetic relation with 10 obesity-related traits [body mass index (BMI), waist circumference (WC), high-density lipoprotein (HDL) cholesterol, triglycerides, fat mass (FM), systolic and diastolic blood pressure, fasting insulin and glucose, and homeostasis model assessment of insulin resistance] by using family data and a variance components approach. For these analyses, carotenoid values were inverse normalized, and all traits were adjusted for significant covariate effects of age and sex.Results: Carotenoid concentrations were highly heritable and significant [α-carotene: heritability (h2) = 0.81, P = 6.7 × 10-11; ß-carotene: h2 = 0.90, P = 3.5 × 10-15]. After adjusting for multiple comparisons, we found significant (P ≤ 0.05) negative phenotypic correlations between carotenoid concentrations and the following traits: BMI, WC, FM, and triglycerides (range: α-carotene = -0.19 to -0.12; ß-carotene = -0.24 to -0.13) and positive correlations with HDL cholesterol (α-carotene = 0.17; ß-carotene = 0.24). However, when the phenotypic correlations were partitioned into genetic and environmental correlations, we found marginally significant (P = 0.051) genetic correlations only between ß-carotene and BMI (-0.27), WC (-0.30), and HDL cholesterol (0.31) after accounting for multiple comparisons. None of the environmental correlations were significant.Conclusions: The findings from this study suggest that the serum carotenoid concentrations were under strong additive genetic influences based on variance components analyses, and that the common genetic factors may influence ß-carotene and obesity and lipid traits in MA children.

Youth-Onset Type 2 Diabetes Consensus Report: Current Status, Challenges, and Priorities.

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.

Pediatric obesity epidemiology.

PURPOSE OF REVIEW: To provide updated summary of recently published data regarding pediatric obesity epidemiology. RECENT FINDINGS: There is a burgeoning literature of pediatric obesity epidemiology, with type 2 diabetes trends serving as the harbinger for obesity related diseases in children. The National Health and Nutrition Examination Survey and Pediatric Nutrition Surveillance System report a tripling of the prevalence of BMI at least 95% (obesity) among US school-age children and adolescents over the past three decades. Recent updates provide insight into infants and toddler obesity and explore the impact of ethnicity, socioeconomic status, school setting and geographic variations. International data confirm similar upward shifts in pediatric BMI distribution, especially in countries undergoing economic transitions favoring industrialized, western urban lifestyles. SUMMARY: The health and financial consequences of this epidemic are a complex global public health dilemma. International efforts are underway to reverse these obesity trends. On-going analysis of obesity prevalence and exploration of potential causal associations are required to implement and assess the effectiveness of interventions and policies.