Muscle-to-fat ratio in children and adolescents with type 1 diabetes in predicting glycaemic control and partial clinical remission.

BACKGROUND: Advances in treatment could mitigate the expected adverse changes in the body composition of children and adolescents with type 1 diabetes (T1D). OBJECTIVES: To examine the evolution of weight status and body composition and their association with glycaemic control and partial clinical remission in youth with T1D. METHODS: Ninety-nine participants with T1D (median age 9.5 years [interquartile range 7.3, 12.9], 59.6% boys) were longitudinally followed for 3 years since diagnosis. Data at seven pre-determined time points were extracted from medical files. Outcome measures included body mass index (BMI) z-scores, muscle-to-fat ratio (MFR) z-scores, haemoglobin A1c (HbA1c) levels, continuous glucose monitoring metrics, and insulin dose-adjusted HbA1c (IDAA1c) levels. RESULTS: The BMI z-scores increased significantly (p < 0.001) for both sexes, with no significant change in MFR z-scores over time. The girls had higher BMI z-scores (p < 0.001) and lower MFR z-scores than the boys (p = 0.016). The mean HbA1c levels decreased during the first month and at 3 months since diagnosis (p < 0.001), then plateaued and achieved a median overall HbA1c of 7.1% for the entire cohort. At 12 months, 37 participants (37.6%) were in partial clinical remission, as evidenced by IDAA1c ≤ 9. The odds of partial clinical remission at 2 years increased by 2.1-fold for each standard deviation increase in the MFR z-score (p < 0.001). Higher MFR z-scores were associated with better metabolic control. CONCLUSIONS: Integration of body composition assessments could mitigate adverse body changes in paediatric patients with T1D.

Glucagon-like peptide-1 analog therapy in rare genetic diseases: monogenic obesity, monogenic diabetes, and spinal muscular atrophy.

AIM: Implementing genetic analyses have unraveled rare alterations causing early-onset obesity and complications, in whom treatment is challenging. We aimed to report on the effects of adjuvant off-label therapy with liraglutide, glucagon-like peptide-1 analogue (GLP-1a), in rare genetic diagnoses. METHODS: Case scenarios and review of the literature. RESULTS: Case 1: Nine-year-old boy with early-onset severe obesity and nonalcoholic fatty liver disease (NAFLD) due to a homozygous mutation in the MC4R gene deteriorated under lifestyle change and metformin therapy [at 10.5 years: body mass index (BMI) 51.2kg/m2, 226% of the 95th percentile, fat percentage (FP) 65% and muscle-to-fat ratio (MFR) z-score of -2.41]. One year of liraglutide treatment halted progressive weight gain [BMI 50.3kg/m2, 212% of the 95th percentile, 63.7% FP and MFR z-score of -2.34], with biochemical improvement. Case 2: Twelve-year-old boy with obesity presented with diabetes and progressive NAFLD. Exome analysis revealed two heterozygous mutations compatible with monogenic diabetes (HNF1A) and familial hypercholesterolemia (LDLR). Lifestyle modifications resulted in clinical and laboratory improvement (BMI 87th percentile, 32.8% FP, MFR z-score of -1.63, HbA1c 5.5%) without the expected recovery in liver transaminases. Liraglutide treatment augmented the improvement in weight status (BMI 68th percentile, 22.6% FP, MFR z-score of -1.13) with normalization of liver transaminases. Case 3: Nineteen-year-old male with spinal muscular atrophy type 3 presented with sarcopenic obesity and comorbidities. Treatment strategy included dietary counseling and multiple drug therapies (metformin, anti-hypertensive and statins). Liraglutide therapy led to a gradual recovery of metabolic complications allowing tapering-down other medications. CONCLUSIONS: Considering the pleiotropic effects of GLP1-a beyond BMI reduction, this treatment modality may serve as a game changer in challenging cases.

Sex differences in body composition in youth with type 1 diabetes and its predictive value in cardiovascular disease risk assessment.

BACKGROUND: Women with type 1 diabetes (T1D) are more susceptible than men to cardiovascular disease (CVD). Signs of increased risk may already appear among adolescent girls. OBJECTIVES: We explored the contribution of body composition to the development of CVD risk factors among youth with T1D. METHODS: One hundred and eighty nine subjects with T1D (mean age 15.3 ± 5.1 years, 55% boys) followed between January 2018-January 2022 were included in this observational study. Sociodemographic and clinical data were extracted from medical files. Body composition was measured by bioelectrical impedance analysis, and muscle-to-fat ratio (MFR) z-scores were calculated. Logistic regression model assessed the association between body composition (MFR z-scores) and evidence of CVD risk factors. RESULTS: Females were characterised by higher median BMI z-scores (0.47 vs. 0.04, p = 0.012), higher fat and truncal fat percentage levels (p ≤ 0.001) and lower median MFR z-scores (-0.64 vs. -0.25, p ≤ 0.001), higher median triglyceride (TG) levels (71 vs. 61 mg/dl, p = 0.05), longer disease duration to initiation of insulin pump therapy (p = 0.041), and more time spent in marked hypoglycemia (1 vs. 0.2%, p = 0.007) than males. Males' MFR z-scores were associated with several diabetes-related parameters (age at diagnosis, CGM metrics, HbA1c and insulin dose), while the females'' MFR z-scores were linked to the atherogenic dyslipidemia index (TG:HDL ratio). The odds for CVD risk factors were doubled for every 1 SD decrease in MFR z-score (OR = 0.50, CI [0.30-0.84], p = 0.009) and also increased with age (OR = 1.07, CI [1.004-1.148], p = 0.038). CONCLUSIONS: Body composition measurement has a predictive value in CVD risk assessment in youth with T1D, with unique characteristics and influences in each sex.

Looking for the skeleton in the closet-rare genetic diagnoses in patients with diabetes and skeletal manifestations.

AIMS: The precision medicine approach of tailoring treatment to the individual characteristics of each patient has been a great success in monogenic diabetes subtypes, highlighting the importance of accurate clinical and genetic diagnoses of the type of diabetes. We sought to describe three unique cases of childhood-onset diabetes in whom skeletal manifestations led to the revelation of a rare type of diabetes. METHODS : Case-scenarios and review of the literature. RESULTS: Case 1: A homozygous mutation in TRMT10A, a tRNA methyltransferase, was identified in a 15-year-old boy with new-onset diabetes, developmental delay, microcephaly, dysmorphism, short stature and central obesity. The progressive apoptosis of pancreatic beta cells required insulin replacement therapy, with increased demand due to an unfavorable body composition. Case 2: Congenital generalized lipodystrophy type 1 was suspected in an adolescent male with an acromegaloid facial appearance, muscular habitus, and diabetes who presented with a pathological fracture in a cystic bone lesion. A homozygous mutation in AGPAT2, an acyl transferase which mediates the formation of phospholipid precursors, was identified. Leptin replacement therapy initiation resulted in a remarkable improvement in clinical parameters. Case 3: A 12-year-old boy with progressive lower limb weakness and pain was diagnosed with diabetic ketoacidosis. Diffuse diaphyseal osteosclerosis compatible with the diagnosis of Camurati-Engelmann disease and a heterozygous mutation in TGFß1 were identified. Preservation of euglycemia by insulin replacement relieved pain, suggesting that the diabetic milieu may have augmented TGFß1 overexpression. CONCLUSION: Unraveling the precise genetic cause for the clinical manifestations led to the prediction of phenotypic manifestations, and enhanced the clinical outcomes.

Glycaemic control in the paediatric and young adult population with type 1 diabetes following a single telehealth visit - what have we learned from the COVID-19 lockdown?

AIMS: Children with chronic diseases were unable to receive their usual care during COVID-19 lockdown. We assessed the feasibility and impact of telehealth visits on the time-in-range (TIR) of paediatric individuals with type 1 diabetes (T1D). METHODS: An observational multicentre real-life study. Patients scheduled for an in-clinic visit during the lockdown were offered to participate in a telehealth visit. Sociodemographic, clinical, continuous glucose monitor and pump data were recorded 2 weeks prior and 2 weeks after telehealth visit. The primary endpoint was change in relative-TIR, i.e. change in TIR divided by the percent of possible change (∆TIR/(100-TIRbefore)*100). RESULTS: The study group comprised 195 individuals with T1D (47.7% males), mean±SD age 14.6 ± 5.3 years, and diabetes duration 6.0 ± 4.6 years. Telehealth was accomplished with 121 patients and their parents (62.0%); 74 (38.0%) did not transfer complete data. Mean TIR was significantly higher for the two-week period after the telehealth visit than for the two-week period prior the visit (62.9 ± 16.0, p < 0.001 vs. 59.0 ± 17.2); the improvement in relative-TIR was 5.7±26.1%. Initial higher mean glucose level, lower TIR, less time spent at <54 mg/dl range, longer time spent at 180-250 mg/dl range, higher daily insulin dose, and single-parent household were associated with improved relative-TIR. Multiple regression logistic analysis demonstrated only initial lower TIR and single-parent household were significant, odds ratio: -0.506, (95%CI -0.99,-0.023), p=0.04 and 13.82, (95%CI 0.621, 27.016), p=0.04, respectively. CONCLUSIONS: Paediatric and young adult patients with T1D benefited from a telehealth visit during COVID-19. However, this modality is not yet suitable for a considerable proportion of patients.

Association between age at type 1 diabetes diagnosis and metabolic outcome at young adulthood: a real-life observational study.

BACKGROUND: Younger age at diagnosis of type 1 diabetes (T1D) may affect the clinical course and outcome. We examined whether age at diagnosis was associated with glycemic control and metabolic outcome in young adulthood. METHODS: This observational study included 105 young adults with T1D (current mean age: 21.2 ± 3.0 years, mean age at diagnosis 12.0 ± 4.0 years) followed during 2012 to 2019. Data on HbA1c, glucose variability, continuous glucose monitoring (CGM) metrics, body mass index (BMI), blood pressure (BP), and body composition were collected from medical records from age 18 years until last visit, and the association between age at diagnosis and outcomes was assessed. RESULTS: Age at T1D diagnosis was negatively associated with HbA1c levels (r = -0.368, P = .001), BMI (r = -0.218, P = .026), and diastolic BP (r = -0.215, P = .028). Younger age at diagnosis predicted poorer glycemic control after controlling for T1D duration, sex, socioeconomic status, BMI, and CGM use (r2 = 0.19, P = .002). There was a 0.1% greater HbA1c reduction for every yearly increase in age at diagnosis (ß = -0.090, P = .042). The mean metabolic age of females diagnosed at <10 years of age was older than their chronological age (P = .049). CONCLUSIONS: Younger age at T1D diagnosis predicts worse glycemic control at young adulthood, independent of recognized confounding risk factors (disease duration, sex, socioeconomic status, weight, and use of diabetes technology). Female patients diagnosed at a young age have an older metabolic age, indicating the need for lifestyle alteration to improve their basal metabolic rate.

Type 1 diabetes outcomes of children born in Israel of Eritrean asylum seekers.

AIMS: Disparities in health outcomes in pediatric type 1 diabetes (T1D) based on race/ethnicity and socioeconomic position (SEP) have been reported. We compared T1D characteristics between Eritrean status-less children living in Israel and native-born Israeli children. METHODS: This observational study compared 7 Eritrean and 28 Israeli children (< 8 years old at T1D diagnosis) who were diagnosed in a single diabetes center during 2015-2019. Sociodemographic and diabetes-related data from diagnosis until the last clinic visit were retrieved from their medical files. RESULTS: At diagnosis, the mean age was 4.8 ± 2.2 years, 17 (48.6%) had diabetic ketoacidosis with a mean HbA1c level of 10.5 ± 2.1% (91.3 mmol/mol) and 29 (82.9%) had ≥ 2 pancreatic autoantibodies. The mean T1D duration of follow-up was 2.7 ± 1.4 years. Overall glycemic control during follow-up (> 6 months from diagnosis, mean number of samples 10.6 ± 5.2) was good, with mean, best, and peak HbA1c levels of 7.4 ± 0.8% (57.4 mmol/mol), 6.7 ± 0.7% (49.7 mmol/mol), and 8.1 ± 1.1% (65 mmol/mol), respectively. Thirty-two children (91.4%) used continuous glucose monitoring devices (CGMs), and the mean time from diagnosis to CGM initiation was 10.8 ± 14.1 months. CGM metrics: time CGM active: 95.4 ± 3.8%, mean glucose level: 170.0 ± 27.0 mg/dl (9.4 mmol/L), time-in-range: 56.4 ± 14.7%, time-below-range: 5.5 ± 5.7%, and time-above-range: 38.6 ± 16.1%. Diabetes-related parameters at diagnosis and during follow-up were similar between groups. Eritrean children had significantly lower SEPs (P < 0.001) and parental education levels (P < 0.001). Correlations between SEP and diabetes parameters and SEP and growth parameters were not significant. CONCLUSIONS: Eritrean status-less children in Israel achieved glycemic targets similar to those of Israeli children, perhaps reflecting uniformity in the standard of care and CGM usage.

CHILDREN AND ADOLESCENTS WITH GENDER DYSPHORIA IN ISRAEL: INCREASING REFERRAL AND FERTILITY PRESERVATION RATES.

Objective: To describe patient characteristics at presentation, management, and fertility preservation rates among a cohort of Israeli children and adolescents with gender dysphoria (GD). Methods: We performed a retrospective chart review of 106 consecutive children and adolescents with GD (<18 years) referred to and followed at the multidisciplinary Israeli Pediatric Gender Dysphoria Clinic from March 2013 through December 2018. Results: Of the 106 patients, 10 were prepubertal (9 prepubertal transgender females), and 96 were pubertal (38 pubertal transgender females). The GD population increased 11-fold since the establishment of our clinic in 2013. The subject's median age at referral was 15.5 years (range, 4.6 to 18 years). At the time of referral, 91 (95%) of the pubertal group had completed sexual maturation in their assigned gender at birth. Thirteen (13.5%) patients had attempted suicide, and 11 (11.5%) reported having had suicidal thoughts. Fourteen (45%) pubertal transgender females and 3 (6.5%) pubertal transgender males completed fertility preservation. Gonadotropin-releasing hormone analog treatment was prescribed in 77 (80%) patients at a mean age of 15.9 ± 1.6 years. Gender-affirming hormones were prescribed in 61 (64%) patients at a mean age of 16.5 ± 1.3 years. No severe side effects were recorded. Two (2%) of the pubertal group expressed regret about medical treatment. Conclusion: Children and adolescents with GD are presenting for medical attention at increasing rates. Israeli adolescents with GD have high fertility preservation rates, perhaps attributable to cultural perspectives. Taking advantage of the option to preserve fertility can be achieved when proper counseling is both available and promoted by medical personnel. Abbreviations: GAH = gender-affirming hormone; GD = gender dysphoria; GnRHa = gonadotropin-releasing hormone analog; MHP = mental health professional.