Fida Bacha

Childhood obesity may have a negative impact on bone mineral properties, with unclear underlying mechanisms. We investigated the relationship of adipocytokine imbalance to bone mineral properties in adolescence, and sex related differences. A cohort of 501 pubertal Hispanic youth (47% male), 10-19 years of age underwent assessment of body composition, bone mineral content (BMC) and density (BMD) by DXA; fasting glucose, insulin, estradiol, testosterone, leptin, and adiponectin concentrations. HOMA-IR and leptin to adiponectin ratio (LAR) were calculated. Cardiorespiratory fitness (CRF) as reflected by VO₂ max was measured using a treadmill ramp protocol. LAR was higher in youth with obesity and with overweight compared with normal weight. LAR negatively contributed to the variance in BMC (β = -0.096, p = 0.001) (R² = 0.887, p < 0.001) together and independently of HOMA-IR, sex steroids, and CRF. This relationship persisted in males but weakened in females when the 2 sexes were examined separately. Similar findings were seen with BMD as the dependent variable. LAR has a negative relationship with BMC and BMD in pubertal youth, with a more notable adverse relationship in males. This suggests that adipocytokine dysregulation may contribute to the adverse effects of childhood obesity on bone mineral properties, with sex-differences related to body fat topography. Childhood obesity associated adipokine imbalance, as reflected by leptin to adiponectin ratio, has a negative relationship with bone mineral content and density in adolescence. This adverse relationship is more notable in males compared with females. These findings contribute to our understanding of the complex effects of obesity on bone mineral content and density in children and adolescents. The findings emphasize the importance of prevention and management of youth-onset obesity to prevent metabolic complications and their impact on skeletal health.

Context The relationship between obesity, type 2 diabetes (T2D), and bone health in youth is not clear. Objective; To examine the relationship of adiposity and glucose metabolism with bone mineral content (BMC) and quality (microarchitecture and strength) in youth across the glycemia spectrum, and evaluate sex-related differences. Design Cross-sectional study. Setting Research Center. Participants 92 adolescents (56 females); 32% normal weight (NW), 29% overweight-normal glucose tolerance (OW-NGT), 39% OW-impaired glucose regulation (OW-IGR), including prediabetes (n=9) or T2D (n=27). Main Outcome Measures Bone quality (HRpQCT), body composition and BMC (DXA), anthropometrics, OGTT with glucose and insulin indices, vitamin D and calcium metabolism. Results BMC and distal tibia bone microarchitecture and strength (modulus) measures were worse in OW-IGR and OW-NGT compared with NW in males but not in females. In multivariable models, accounting for age, Tanner stage and sex, age and lean mass (β=3.9, p2=0.45, p<0.001). Similar relationships were found with radial vBMD and with whole bone modulus at the tibia and radius independent of sex. Fasting glucose was inversely related to trabecular thickness at the tibia and radius. Conclusions There is a negative relationship between adiposity and insulin resistance with bone microarchitecture and strength in youth after accounting for age, sex, height and lean mass. There appears to be sexual dimorphism in these relationships, with more negative effect of adiposity and dysglycemia on bone quality in males.

Volumetric bone density, microarchitecture, and strength measures using HR-pQCT are valuable measures of bone health in pediatrics. Our cross-sectional study evaluated bone measure reproducibility in pediatric participants using repeat HR-pQCT (XtremeCT II, Scanco Medical) scans of non-dominant distal tibia and radius of 30 healthy children and adolescents (7-17 yr, 47% female) by 2 technicians. Additionally, we examined HR-pQCT and micro-CT of 26 cadaveric distal tibia specimens to evaluate agreement between the modalities. All HR-pQCT scans were analyzed using manufacturer-provided software (Image Processing Language, Scanco Medical) and a fully automated, previously validated, in-house algorithm, offering measures of bone microstructure (eg, trabecular plate-rod distribution, transverse trabeculae, trabecular bone strength) currently unavailable in the manufacturer-provided software. Root-mean-squared percent coefficient of variation (RMS-%CV) assessed precision and least significant change. Intraclass correlation coefficients (ICCs) using absolute-agreement, 2-way random-effects models assessed reliability. Pearson’s correlation coefficients and ICC assessed linear relationships and agreements between HR-pQCT and micro-CT, respectively. In children and adolescents, RMS-%CV of HR-pQCT-derived trabecular bone measures at distal tibia and radius ranged from 0.8-4.4 to 0.8-6.0, respectively. Most cortical bone results were in a similar range. Both computational algorithms showed ICC > 0.90. RMS-%CV and least significant change values were lower for tibia than radius. ICCs were lower for cortical than trabecular outcomes. Most cadaveric results showed ICC > 0.83, other than trabecular bone thickness and modulus (ICC = 0.7). Pearson’s r (>0.86) suggested strong correlations for almost all parameters. HR-pQCT and micro-CT results using in-house algorithm did not differ significantly, while manufacturer-provided algorithm results showed lower yet still moderate reliability (ICC > 0.55). Reliability of the second-generation HR-pQCT in pediatric participants is excellent—better in tibia vs radius. Our results support the high reproducibility of XtremeCT II scans and thus the use of this clinical imaging modality in studies of pediatric bone health.

Objective: Despite β‐cell failure in youth with dysglycemia (i.e., impaired glucose tolerance [IGT] and type 2 diabetes), fasting insulin (FI) concentrations are elevated. Herein, we examined the following: 1) metabolic clearance rate of insulin (MCRI) in youth with obesity and normal glucose tolerance (NGT) versus those with IGT versus those with type 2 diabetes; 2) racial and ethnic differences in insulin dynamics; and 3) metabolic/adiposity correlates of MCRI.Methods: A total of 206 youth underwent assessment of fasting glucose, FI, MCRI and peripheral insulin sensitivity (PIS), first‐phase insulin secretion, disposition index, body composition, and abdominal adiposity.Results: In type 2 diabetes versus NGT, MCRI was lower (p < 0.001), and FI was higher (p < 0.001). In Black versus White youth, MCRI was lower (p < 0.001), driven by lower MCRI in youth with dysglycemia (p < 0.001) and not with NGT. MCRI correlated inversely with FI, as well as adiposity measures, and correlated directly with PIS and disposition index. Lower PIS, lower MCRI, and higher first‐phase insulin secretion were characteristics of Black versus White youth with dysglycemia.Conclusions: Higher FI concentrations in the presence of dysglycemia despite β‐cell failure could be explained by decreased MCRI. Racial and ethnic contrast in insulin dynamics differs by glycemic status and is more pronounced in dysglycemia manifested by lower MCRI and heightened first‐phase insulin secretion in Black versus White youth.

Key Points: Proteomics analyses identified seven proteins predictive of time to development of albuminuria among youth with type 2 diabetes in the Treatment Options for Type 2 Diabetes in Adolescents and Youth cohort, 118 proteins predictive of time to development of hyperfiltration, and three proteins predictive of time to rapid eGFR decline. Seven proteins were predictive of all three outcomes (SEM4A, PSB3, dihydroxyphenylalanine decarboxylase, C1RL1, T132A, pyruvate carboxylase, and C1-esterase inhibitor) and have been implicated in immune regulatory mechanisms, metabolic dysregulation, proteostasis, and cellular signaling pathways. Elastic net Cox proportional hazards model identified distinct multiprotein signatures (38–68 proteins) of time to albuminuria, hyperfiltration, and rapid eGFR decline with concordance for models with clinical covariates and selected proteins between 0.81 and 0.96, whereas the concordance for models with clinical covariates only was between 0.56 and 0.63. Background: The onset of diabetic kidney disease (DKD) in youth with type 2 diabetes (T2D) mellitus often occurs early, leading to complications in young adulthood. Risk biomarkers associated with the early onset of DKD are urgently needed in youth with T2D. Methods: We conducted an in-depth analysis of 6596 proteins (SomaScan 7K) in 374 baseline plasma samples from the Treatment Options for Type 2 Diabetes in Adolescents and Youth study to identify multiprotein signatures associated with the onset of albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g), a rapid decline in eGFR (annual eGFR decline >3 ml/min per 1.73 m ² and/or ≥3.3% at two consecutive visits), and hyperfiltration (≥135 ml/min per 1.73 m ² at two consecutive visits). Elastic net Cox regression with ten-fold cross-validation was applied to the top 100 proteins (ranked by P value) to identify multiprotein signatures of time to development of DKD outcomes. Results: Participants in the Treatment Options for Type 2 Diabetes in Adolescents and Youth study (14±2 years, 63% female, 7±6 months diabetes duration) experienced high rates of early DKD: 43% developed albuminuria, 48% hyperfiltration, and 16% rapid eGFR decline. Increased levels of seven and three proteins were predictive of shorter time to develop albuminuria and rapid eGFR decline, respectively; 118 proteins predicted time to development of hyperfiltration. Elastic net Cox proportional hazards models identified multiprotein signatures of time to incident early DKD with concordance for models with clinical covariates and selected proteins between 0.81 and 0.96, whereas the concordance for models with clinical covariates only was between 0.56 and 0.63. Conclusions: Our research sheds new light on proteomic changes early in the course of youth-onset T2D that associate with DKD. Proteomic analyses identified promising risk factors that predict DKD risk in youth with T2D and could deepen our understanding of DKD mechanisms and potential interventions. Clinical Trial registry name and registration number: NCT00081328.

Youth-onset type 2 diabetes is a heterogeneous disease with increasing prevalence in relation to increased rates of obesity in children. It has genetic, epigenetic, social, and environmental determinants. Youth-onset type 2 diabetes is alarming given a rapidly progressive course compared with the course of adult-onset disease, early-onset vascular complications, and long-term exposure to hyperglycemia and associated complications. It is often preceded by prediabetes, a disease phase where defects in β-cell function relative to insulin sensitivity emerge. Herein, we review the current understanding of the pathophysiology of prediabetes and type 2 diabetes in youth. We describe the mechanisms underlying insulin resistance, the precipitous decline of β-cell function, and the role of other hormonal abnormalities in the pathogenesis of the disease. We discuss the critical importance of social determinants of health in the predisposition and progression of these conditions and present current management strategies and the advances in therapeutic approaches. These must adapt to meet the unique needs of the individual patient and family. Significant knowledge gaps remain that need to be addressed in future research.

The prevalence of type 2 diabetes in youth is increasing at an alarming rate. Identifying potentially modifiable factors modulating glycemic control is critically important to reduce micro and macrovascular complications. In a large cohort of youth-onset type 2 diabetes, self-reported late bedtime on work/school days was independently associated with loss of glycemic control in this longitudinal cohort of young adults with youth-onset type 2 diabetes.

Branched-chain amino acids (BCAAs) and aromatic AAs (AAAs) are associated with increased risk for type 2 diabetes in adults. Studies in youth show conflicting results. We hypothesized that an AA metabolomic signature can be defined to identify youth at risk for β-cell failure and the development of type 2 diabetes. We performed targeted AA metabolomics analysis on 127 adolescents (65 girls; 15.5 [SD ±1.9] years old, Tanner stage II–V) with normal weight or obesity across the spectrum of glycemia, with assessment of AA concentrations by mass spectrometry, at fasting, and steady state of a hyperinsulinemic-euglycemic clamp, with determination of insulin sensitivity (IS) per fat-free mass (FFM). We measured insulin secretion during a 2-h hyperglycemic clamp and calculated the disposition index per FFM (DIFFM), a measure of β-cell function. Our results showed that concentration of glycine (Gly) and the glutamine (Gln)-to-glutamate (Glu) ratio were lower, whereas BCAA, tyrosine, and lysine (Lys) concentrations were higher in the groups with obesity and dysglycemia compared with those with normal weight. Gly and Gln-to-Glu ratio were positively related to IS and DIFFM, with opposite relationships observed for BCAAs, AAAs, and Lys. We conclude that a metabolic signature of low Gly concentration and low Gln-to-Glu ratio, and elevated BCAAs, AAAs, and Lys concentrations may constitute a biomarker to identify youth at risk for β-cell failure. Article Highlights: