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  1. Shankar RR, Zeitler P, Deeb A, Jalaludin MY, Garcia R, Newfield RS, et al.
    Pediatr Diabetes, 2022 Mar;23(2):173-182.
    PMID: 34779087 DOI: 10.1111/pedi.13279
    OBJECTIVE: To assess the efficacy and safety of DPP-4 inhibition with sitagliptin in youth with type 2 diabetes (T2D).

    STUDY DESIGN: This was a 54-week, double-blind, randomized, controlled clinical trial evaluating the safety and efficacy of DPP-4 inhibition with sitagliptin 100 mg once daily as initial oral therapy in youth with T2D. The 190 participants, aged 10-17 years, had HbA1c 6.5%-10% (7.0%-10% if on insulin). All were negative for pancreatic autoantibodies and overweight/obese at screening or diagnosis. The trial was placebo controlled for the first 20 weeks, after which metformin replaced placebo. The primary efficacy endpoint was change from baseline in HbA1c at Week 20.

    RESULTS: Treatment groups were well balanced at baseline (mean ± SD HbA1c = 7.5% ± 1.0, BMI percentile = 97.1% ± 6.8, age = 14.0 years ± 2.0 [57.4% <15], 60.5% female). At Week 20, least squares mean changes from baseline in HbA1c were -0.01% (sitagliptin) and 0.18% (placebo); between-group difference (95% CI) = -0.19% (-0.68, 0.30), p = 0.448. At Week 54, the changes in HbA1c were 0.45% (sitagliptin) and -0.11 (placebo/metformin). There were no notable between-group differences in the adverse event profiles through Week 54.

    CONCLUSIONS: DPP-4 inhibition with sitagliptin did not provide significant improvement in glycemic control. In this study, sitagliptin was generally well tolerated with a safety profile similar to that reported in adults. (ClinicalTrials.gov: NCT01485614; EudraCT: 2011-002528-42).

  2. Li X, Xu A, Sheng H, Ting TH, Mao X, Huang X, et al.
    Pediatr Diabetes, 2018 03;19(2):251-258.
    PMID: 28791793 DOI: 10.1111/pedi.12560
    BACKGROUND: Sulfonylurea therapy can improve glycemic control and ameliorate neurodevelopmental outcomes in patients suffering from neonatal diabetes mellitus (NDM) with KCNJ11 or ABCC8 mutations. As genetic testing results are often delayed, it remains controversial whether sulfonylurea treatment should be attempted immediately at diagnosis or doctors should await genetic confirmation.

    OBJECTIVE: This study aimed to investigate the effectiveness and safety of sulfonylurea therapy in Chinese NDM patients during infancy before genetic testing results were available.

    METHODS: The medical records of NDM patients with their follow-up details were reviewed and molecular genetic analysis was performed. Sulfonylurea transfer regimens were applied in patients diagnosed after May 2010, and glycemic status and side effects were evaluated in each patient.

    RESULTS: There were 23 NDM patients from 22 unrelated families, 10 had KCNJ11 mutations, 3 harbored ABCC8 mutations, 1 had INS mutations, 4 had chromosome 6q24 abnormalities, 1 had a deletion at chromosome 1p36.23p36.12, and 4 had no genetic abnormality identified. Sixteen NDM infants were treated with glyburide at an average age of 49 days (range 14-120 days) before genetic confirmation. A total of 11 of 16 (69%) were able to successfully switch to glyburide with a more stable glucose profile. The responsive glyburide dose was 0.51 ± 0.16 mg/kg/d (0.3-0.8 mg/kg/d), while the maintenance dose was 0.30 ± 0.07 mg/kg/d (0.2-0.4 mg/kg/d). No serious adverse events were reported.

    CONCLUSIONS: Molecular genetic diagnosis is recommended in all patients with NDM. However, if genetic testing results are delayed, sulfonylurea therapy should be considered before such results are received, even in infants with newly diagnosed NDM.

  3. Jalaludin MY, Deeb A, Zeitler P, Garcia R, Newfield RS, Samoilova Y, et al.
    Pediatr Diabetes, 2022 Mar;23(2):183-193.
    PMID: 34779103 DOI: 10.1111/pedi.13282
    OBJECTIVE: To assess the efficacy and safety of sitagliptin in youth with type 2 diabetes (T2D) inadequately controlled with metformin ± insulin.

    STUDY DESIGN: Data were pooled from two 54-week, double-blind, randomized, placebo-controlled studies of sitagliptin 100 mg daily or placebo added onto treatment of 10- to 17-year-old youth with T2D and inadequate glycemic control on metformin ± insulin. Participants (N = 220 randomized and treated) had HbA1c 6.5%-10% (7.0%-10% if on insulin), were overweight/obese at screening or diagnosis and negative for pancreatic autoantibodies. The primary endpoint was change from baseline in HbA1c at Week 20.

    RESULTS: Treatment groups were well balanced at baseline (mean HbA1c = 8.0%, BMI = 30.9 kg/m2 , age = 14.4 years [44.5% <15], 65.9% female). The dose of background metformin was >1500 mg/day for 71.8% of participants; 15.0% of participants were on insulin therapy. At Week 20, LS mean changes from baseline (95% CI) in HbA1c for sitagliptin/metformin and placebo/metformin were -0.58% (-0.94, -0.22) and -0.09% (-0.43, 0.26), respectively; difference = -0.49% (-0.90, -0.09), p = 0.018; at Week 54 the LS mean (95% CI) changes were 0.35% (-0.48, 1.19) and 0.73% (-0.08, 1.54), respectively. No meaningful differences between the adverse event profiles of the treatment groups emerged through Week 54.

    CONCLUSIONS: These results do not suggest that addition of sitagliptin to metformin provides durable improvement in glycemic control in youth with T2D. In this study, sitagliptin was generally well tolerated with a safety profile similar to that reported in adults. (ClinicalTrials.gov: NCT01472367, NCT01760447; EudraCT: 2011-002529-23/2014-003583-20, 2012-004035-23).

  4. Deeb A, Elbarbary N, Smart CE, Beshyah SA, Habeb A, Kalra S, et al.
    Pediatr Diabetes, 2020 02;21(1):5-17.
    PMID: 31659852 DOI: 10.1111/pedi.12920
  5. Xu A, Lin Y, Sheng H, Cheng J, Mei H, Ting TH, et al.
    Pediatr Diabetes, 2020 05;21(3):431-440.
    PMID: 31957151 DOI: 10.1111/pedi.12985
    OBJECTIVE: The purpose of this study was to investigate the molecular basis of maturity-onset diabetes of the young (MODY) by whole-exome sequencing (WES) and estimate the frequency and describe the clinical characteristics of MODY in southern China.

    METHODS: Genetic analysis was performed in 42 patients with MODY aged 1 month to 18 years among a cohort of 759 patients with diabetes, identified with the following four clinical criteria: age of diagnosis ≤18 years; negative pancreatic autoantibodies; family history of diabetes; or persistently detectable C-peptide; or diabetes associated with extrapancreatic features. GCK gene mutations were first screened by Sanger sequencing. GCK mutation-negative patients were further analyzed by WES.

    RESULTS: Mutations were identified in 24 patients: 20 mutations in GCK, 1 in HNF4A, 1 in INS, 1 in ABCC8, and a 17q12 microdeletion. Four previously unpublished novel GCK mutations: c.1108G>C in exon 9, and c.1339C>T, c.1288_1290delCTG, and c.1340_1343delGGGGinsCTGGTCT in exon 10 were detected. WES identified a novel missense mutation c.311A>G in exon 3 in the INS gene, and copy number variation analysis detected a 1.4 Mb microdeletion in the long arm of the chromosome 17q12 region. Compared with mutation-negative subjects, the mutation-positive subjects had lower hemoglobin A1c and initial blood glucose levels.

    CONCLUSIONS: Most MODY cases in this study were due to GCK mutations, which is in contrast to previous reports in Chinese patients. Diabetes associated with extrapancreatic features should be a clinical criterion for MODY genetic analysis. Mutational analysis by WES provided a precise diagnosis of MODY subtypes. Moreover, WES can be useful for detecting large deletions in coding regions in addition to point mutations.

  6. Chiavaroli V, Derraik JGB, Jalaludin MY, Albert BB, Ramkumar S, Cutfield WS, et al.
    Pediatr Diabetes, 2019 11;20(7):892-900.
    PMID: 31237756 DOI: 10.1111/pedi.12881
    BACKGROUND: Partial remission (PREM) by the insulin dose-adjusted HbA1c (IDAA1c) method has not been evaluated for the combined associations of ethnicity and socioeconomic status in children and adolescents with type 1 diabetes (T1D).

    OBJECTIVE: To investigate prevalence and predictors of PREM defined by IDAA1c.

    METHODS: Six hundred fourteen of 678 children (aged <15 years) with new-onset T1D (2000-2013) from a regional pediatric diabetes service (Auckland, New Zealand).

    RESULTS: Overall rate of PREM at 3 months was 42.4%, and lower in Māori/Pacific children (28.6%; P = .006) and those of other ethnicities (28.8%; P = .030) compared with New Zealand Europeans (50.4%). Comparing the most and least deprived socioeconomic quintiles, the odds of PREM were lower among the most deprived (adjusted odds ratio [aOR] 0.44; P = .019). Lower rates of PREM were seen in children aged 0 to 4.9 years (23.8%) and 10 to 14 years (40.9%) than in children aged 5 to 9.9 years (57.4%; P

  7. Hussain S, Mohd Ali J, Jalaludin MY, Harun F
    Pediatr Diabetes, 2013 Jun;14(4):299-303.
    PMID: 23350652 DOI: 10.1111/pedi.12011
    We report a rare case of permanent neonatal diabetes (PND) due to insulin (INS) gene mutation in a 51-month-old girl who presented with hyperglycemia in the neonatal period. Mutational analysis of KCNJ11 and INS was performed and this detected a novel heterozygous c.38T>G (p.Leu13Arg) INS de novo mutation. The non-conservative change substitutes the highly conserved L(13) residue within the hydrophobic core region of the preproinsulin signal peptide. Given the frequent tendency of heterozygous INS mutations to exhibit dominant negative disease pathogenesis, it is likely that the mutant preproinsulin perturbed the non-mutant counterpart progression and processing within the β-cells, and this resulted to a permanent form of congenital diabetes.
  8. Barrett T, Jalaludin MY, Turan S, Hafez M, Shehadeh N, Novo Nordisk Pediatric Type 2 Diabetes Global Expert Panel
    Pediatr Diabetes, 2020 03;21(2):158-172.
    PMID: 31804738 DOI: 10.1111/pedi.12953
    Type 2 diabetes (T2D) is suggested to progress faster in children and young people vs type 1 diabetes (T1D) in the same age group and T2D in adults. We reviewed the evidence base for this. A literature search was performed of PubMed-indexed publications between 2000 and 2018, for the terms "pediatric" and "T2D." Results were combined and filtered for those relating to "progression." Searches of abstract books from Latin American and Asian congresses were performed to include these populations. Pediatric populations were defined as <25 completed years of age. Of the articles and congress abstracts found, 30 were deemed relevant. Dividing the studies into categories based on how T2D progresses, we found the following: (a) yearly beta-cell function deterioration was shown to be 20% to 35% in children with T2D compared with 7% to 11% in adults with T2D, despite similar disease durations; (b) retinopathy progression was likely dependent on diabetes duration rather than diabetes type; however, nephropathy, neuropathy and probably hypertension progressed faster in youth-onset T2D vs T1D. Nephropathy progression was similar to adults with T2D, allowing for disease duration. Youth with T2D had a worse cardiovascular (CV) risk profile than youth with T1D, and a faster progression to CV death. (c) Progression to treatment failure was faster in youth-onset T2D vs adult-onset T2D. Substantial evidence exists for faster progression of T2D in pediatric patients vs T1D or adult-onset T2D. New treatments targeting the pathology are needed urgently to address this issue.
  9. Mohd Nor NS, Lee S, Bacha F, Tfayli H, Arslanian S
    Pediatr Diabetes, 2016 09;17(6):458-65.
    PMID: 26251318 DOI: 10.1111/pedi.12303
    BACKGROUND: There is a need for simple surrogate estimates of insulin sensitivity in epidemiological studies of obese youth because the hyperinsulinemic-euglycemic clamp is not feasible on a large scale.

    OBJECTIVE: (i) To examine the triglyceride glucose (TyG) index (Ln[fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]) and its relationship to in vivo insulin sensitivity in obese adolescents (OB) along the spectrum of glucose tolerance and (ii) to compare TyG index with triglyceride/high-density lipoprotein TG/HDL and 1/fasting insulin (1/IF ), other surrogates of insulin sensitivity.

    PATIENTS AND DESIGN: Cross-sectional data in 225 OB with normal glucose tolerance (NGT), prediabetes (preDM), and type 2 diabetes (T2DM) who had a 3-h hyperinsulinemic-euglycemic clamp and fasting lipid measurement.

    RESULTS: Insulin-stimulated glucose disposal (Rd) declined significantly across the glycemic groups from OB-NGT to OB-preDM to OB-T2DM with a corresponding increase in TyG index (8.3 ± 0.5, 8.6 ± 0.5, 8.9 ± 0.6, p 

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