Revistas

Immune cell and cytokine patterns in children with type 1 diabetes mellitus undergoing a remission phase: a longitudinal study

Aims/hypothesis Type 1 diabetes (T1D) develops in distinct stages, before and after disease onset. Whether the natural course translates into different immunologic patterns is still uncertain. This study aimed at identifying peripheral immune patterns at key time-points, in T1D children undergoing remission phase. Methods Children with new-onset T1D and healthy age and gender-matched controls were recruited at a paediatric hospital. Peripheral blood samples were evaluated by flow cytometry at three longitudinal time-points: onset (T1), remission phase (T2) and established disease (T3). Cytokine levels were quantified by multiplex assay. Fasting C-peptide, HbA1c and 25OHD were also measured. Results T1D children (n=28; 10.0�2.6 years) showed significant differences from controls in circulating neutrophils, T helper (Th)17 and natural killer (NK) cells, with relevant variations during disease progression. At onset, neutrophils, NK, Th17 and T cytotoxic (Tc)17 cells were decreased. As disease progressed, neutrophil counts recovered whereas NK counts remained low. Th17 and Tc17 cells behaviour followed the neutrophil variation pattern. B-cells were lowest in the remission phase and regulatory T-cells significantly declined after remission. Two cytokine response profiles were identified. Low cytokine-responders showed higher circulating fasting C-peptide levels at onset and longer remission periods. C-peptide inversely correlated with pro-inflammatory and cytotoxic cells. Conclusions/interpretation Our data suggest an association between immune cells, cytokine patterns and metabolic counterparts. The dynamic changes of circulating immune cells during disease progression involve key innate and acquired immune cell types. This longitudinal picture of T1D progression may enable disease staging and patient stratification, essential for individualized treatment.

Sex-related association of serum uric acid with inflammation, kidney function and blood pressure in type 1 diabetic patients

Background & Aim Recent studies suggest that uric acid (UA) is a mediator of diabetic nephropathy. We hypothesized that serum UA would associate with the prevalence of diabetic nephropathy in youth with type 1 diabetes (T1D), and that this relationship would differ by sex. Methods We examined 120 young boys and the same number of girls with T1D. C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor ? (TNF-?), uric acid, cystatin C serum concentrations, albumin excretion rate and blood pressure were also analysed. Results T1D boys had higher serum UA and creatinine concentration, as well as albumin excretion rate and estimated glomerular filtration rate than T1D girls. Moreover, newly diagnosed nephropathy was more common in male subjects in comparison to female patients. Only in T1D boys serum UA was positively correlated with concentrations of subclinical inflammatory markers (CRP, IL-6, TNF-?), the indicators of renal function (albumin excretion rate, serum cystatin C level), blood pressure and negatively correlated with anti-inflammatory IL-10. Additionally, only in T1D girls serum UA concentration was negatively correlated with HbA1c. Conclusions Serum UA is associated with nephropathy prevalence, albeit only in boys with T1D and may be an important risk factor for predicting diabetes-related cardiorenal complications in these patients.

Permanent neonatal diabetes mellitus and neurological abnormalities due to a novel homozygous missense mutation in NEUROD1

The basic helix-loop-helix(bHLH) transcription factor, NEUROD1(also known as BETA2) is involved in the development of neural elements and endocrine pancreas. Less than 10 reports of adult-onset non-insulin dependent diabetes mellitus(NIDDM) due to heterozygous NEUROD1 mutations and two cases with permanent neonatal diabetes mellitus(PNDM) and neurological abnormalities due to homozygous NEUROD1 mutations have been published.

A phase 3 multicenter, open-label, prospective study designed to evaluate the effectiveness and ease of use of nasal glucagon in the treatment of moderate and severe hypoglycemia in children and adolescents with type 1 diabetes in the home or school setting

OBJECTIVE This multicenter, open-label study was designed to evaluate real-world effectiveness and ease of use of nasal glucagon (NG) in treating moderate or severe hypoglycemic events in children and adolescents with type 1 diabetes (T1D). METHODS Caregivers were trained to administer NG (3 mg) to the child/adolescent with T1D during spontaneous, symptomatic moderate or severe hypoglycemic events, observe treatment response (defined as awakening or returning to normal status within 30 minutes), and measure blood glucose (BG) levels every 15 minutes. Data regarding adverse events and ease of use were solicited using questionnaires. RESULTS The analysis population included 14 patients who experienced 33 moderate hypoglycemic events with neuroglycopenic symptoms and BG level ?70 mg/dL. Patients returned to normal status within 30 minutes of NG administration in all 33 events. Mean BG levels increased from 55.5 mg/dL (range 42-70 mg/dL) at baseline to 113.7 mg/dL (range 79-173 mg/dL) within 15 minutes of NG administration. In most hypoglycemic events (93.9%), caregivers reported that NG administration was easy or very easy; they could administer NG within 30 seconds in 60.6% of events. There were no serious adverse events. CONCLUSIONS A single 3-mg dose of NG was effective in treating moderate, symptomatic, hypoglycemic events in children and adolescents with T1D in a real-world setting. It was easy to use and reasonably well tolerated. NG shows promise as an effective, needle-free, and user-friendly alternative to injectable glucagon.

Diabetic ketoacidosis incidence in children at first presentation of type 1 diabetes at an Australian regional hospital: the effect of health professional education

Background Diabetic Ketoacidosis (DKA) is an acute life threatening, resource intensive preventable complication of type 1 diabetes which has major biopsychosocial effects on patients and families. Incidence of paediatric DKA has been studied nationally and internationally in metropolitan centres. This study analysed the DKA incidence at first presentation of type 1 diabetes at Townsville Hospital, before and after an educational intervention. This is the first study of its kind in a regional centre in Queensland, Australia. Method The inclusion criteria consisted of children (0-18 years) diagnosed with type 1 diabetes from January 2006 to December 2016. Medical and laboratory patient data was retrospectively collected. Quantitative analysis was conducted using SPSS. Education sessions were delivered to health professionals by a paediatric endocrinologist during 2015 and 2016. DKA and its severity were defined by the International Society of Paediatric Diabetes (ISPAD) 2014 Guidelines. Results In total,106 patients met inclusion criteria. Average incidence of DKA at first presentation of type 1 diabetes was 48.10%. Pre-and post-intervention incidences were 54.90% and 25% respectively (p = 0.01). DKA severity pre-and post-intervention were severe (48.88%, 33.33%), moderate (26.67%, 16.67%), and mild (24.44%, 50%) respectively (p = 0.53). Conclusions DKA incidence at first presentation of type 1 diabetes prior to intervention, is higher than that reported by other studies in Australia: Brisbane (31.8%) and Sydney (37.7%). DKA incidence at first presentation of type 1 diabetes decreased significantly during the period of health professional education.

Neutropenia in 6 cases of childhood onset type 1 diabetes and its possible mechanisms

Objective Type 1 diabetes (T1D) is a chronic inflammatory disease caused by a selective destruction of the pancreatic ?-cells. There are few reports on peripheral neutropenia in T1D for different reasons. We reported 6 cases of childhood onset T1D combined with neutropenia and explored its possible mechanisms. Methods The clinical diagnosis and treatment course of 6 cases of childhood onset T1D combined with neutropenia, who were hospitalized in our hospital from January, 2013 to December, 2016, were studied retrospectively. Results We have diagnosed and treated 38 cases of childhood onset T1D during these period, while only 6 cases (15.79%) had neutropenia. The diagnostic ages of the 6 cases ranged from 5 to 12 years. Diabetic ketoacidosis was complicated in 5 cases. Neutropenia happened within 14-21 days of the onset of disease and 3-11 days after using insulin, respectively, and returned spontaneously to normal range within 5-9 days. The serum levels of granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF) increased slightly before the usage of insulin in all 6 cases, and decreased to normal range after the usage of insulin. Conclusion Neutropenia can be seen in childhood onset T1D, and can return spontaneously to normal range without special treatments. The possible mechanisms might be the regulation effects of insulin on G-CSF and GM-CSF.

Alpha-1 antitrypsin treatment of new-onset type 1 diabetes: an open-label, phase I clinical trial (RETAIN) to assess safety and pharmacokinetics

OBJECTIVE To determine the safety and pharmacokinetics of alpha-1 antitrypsin (AAT) in adults and children. RESEARCH DESIGN AND METHODS Short term AAT treatment restores euglycemia in the non-obese mouse model of type 1 diabetes. A phase I multicenter study in 16 subjects with new-onset type 1 diabetes studied the safety and pharmacokinetics of Aralast NPTM (AAT). This open-label, dose-escalation study enrolled eight adults ages 16-35 and eight children ages 8-15 within 100 days of diagnosis, to receive 12 infusions of AAT: a low dose of 45 mg/kg weekly for six weeks, followed by a higher dose of 90 mg/kg for six weeks. RESULTS C-peptide secretion during a mixed meal, HbA1c, and insulin usage remained relatively stable during the treatment period. At 72 hours after infusion of 90 mg/kg, mean levels of AAT fell below 2.0 g/L for 7 of 15 of the subjects. To identify a plasma level of AAT likely to be therapeutic, pharmacodynamic ex vivo assays were performed on fresh whole blood from adult subjects. PCR analyses were performed on inhibitor of IKBKE, NOD1, TLR1, and TRAD gene expression, which are important for activation of NF-?B and apoptosis pathways. AAT suppressed expression dose-dependently; 50% inhibition was achieved in the 2.5-5.0 mg/mL range. CONCLUSIONS AAT was well tolerated and safe in subjects with new-onset type 1 diabetes. Weekly doses of AAT greater than 90 mg/kg may be necessary for an optimal therapeutic effect.

Long-term Study of Tubeless Insulin Pump Therapy Compared to Multiple Daily Injections in Youth with Type 1 Diabetes: Data from the German/Austrian DPV-Registry

Objective To examine glycemic control in youth with type 1 diabetes (T1D) who switched from multiple daily injections (MDI) to a tubeless insulin pump (Omnipod� Insulin Management System, Insulet Corp., Billerica, MA) compared to patients who continued MDI therapy over a 3-year time period. Research Design and Methods This retrospective analysis of the German/Austrian Diabetes Patienten Verlaufsdokumentation (DPV) registry included data from 263 centers and 2529 patients <20 years (n=660 tubeless insulin pump; n=1869 MDI) who initiated treatment on a tubeless insulin pump as of January 1, 2013 and had 1 year of data pre-switch from MDI and 3 years of data post-switch to a tubeless pump. Outcomes included the change in HbA1c, insulin dose and BMI standard deviation score (SDS). Results Youth with T1D who switched from MDI therapy to a tubeless insulin pump showed better glycemic control at 1 year compared to patients who continued MDI treatment, adjusted mean�SE: 7.5%�0.03 (58 mmol/mol) vs. 7.7%�0.02 (61 mmol/mol); p<0.001, with no between group difference at 2- and 3-years. Total daily insulin dose was lower (p<0.001) in the tubeless insulin pump group, 0.80�0.01, 0.81�0.01 and 0.85�0.01 U/kg vs. the MDI group 0.89�0.01, 0.94�0.01 and 0.97�0.01 U/kg, at 1-, 2- and 3-years, respectively (all p<0.001). BMI (SDS) increased in both groups and was not different over time. Conclusions Treatment with a tubeless insulin pump in youth with T1D was associated with improvements in glycemic control compared to MDI after 1 year and appears to be an effective alternative to MDI.

Beta Cell Function after Intensive Subcutaneous Insulin Therapy or Intravenous Insulin Infusion at Onset of T1D in Children without ketoacidosis

Background Our aim was to see if IV insulin therapy at diagnosis preserves beta-cell function better than multiple subcutaneous injections (SC). Methods 54 children 9.9�3.5 years (range 2.8-14.9) without ketoacidosis were included in a 2 year, randomized multicenter study with insulin SC or 48-72 hours IV initially. 33 (61%) were boys, 22 (41%) were pubertal. 48 subjects completed 12 months follow-up and 43 completed 24 months. At 1, 6, 12 and 24 months, HbA1c, C-peptide and insulin/kg/24h were measured. At 24 months, a mixed-meal tolerance test (MMTT) was performed. Results HbA1c at diagnosis was 10.7%, (93 mmol/mol) for IV, 10.7%, (94 mmol/mol) for SC. During the first two full days of insulin therapy, mean plasma glucose was 8.2 mmol/l for IV, 9.5 for SC (p=0.025). Mean insulin dose was 1.5 U/kg/day for IV vs. 1.0 for SC (p=0.001). 16 (7 in IV, 9 in SC group) started with insulin pumps during the follow-up. At 24 months we saw no significant differences: HbA1c (7.5%, 58 mmol/mol, for IV, 7.2%, 55 mmol/mol, for SC; ns), insulin doses (0.79 vs. 0.88 U/kg/day; ns), fasting C-peptide (0.08 vs. 0.12 nmol/l; ns), maximal MMTT response (0.19 vs. 0.25 nmol/l; ns) and AUC (18.26 vs. 23.9 nmol/l*min; ns). Peak C-peptide > 0.2 nmol/l in the combined IV and SC groups correlated significantly with HbA1c and C-peptide at onset in a multiple regression. Conclusion Residual beta cell function at 2 years seems to be independent from initial insulin regimens but related to HbA1c and c-peptide at onset.

Brain injury markers: S100 calcium-binding protein B, neuron-specific enolase and glial fibrillary acidic protein in children with diabetic ketoacidosis

Background To investigate serum levels of brain injury markers in diabetic ketoacidosis (DKA) and the relation of these markers with clinical and radiological findings of brain injury and laboratory results. Methods Twenty-nine patients with DKA, 30 with type 1 diabetes mellitus (T1DM), and 35 healthy children were included. Clinical and laboratory findings, and the Glasgow Coma Scale (GCS) were recorded. In the DKA group, neuron-specific enolase (NSE), S100 calcium-binding protein B (S100B) and glial fibrillary acidic protein (GFAP) levels were measured at baseline and 6 and 12?hours after treatment. Magnetic resonance imaging was performed in the DKA group to demonstrate any brain injury. Results No clinical or radiological findings of brain injury were found in any of the patients with DKA. In the DKA group, S100B was significantly higher than the healthy control and T1DM groups, while GFAP and NSE levels were not different from controls and T1DM patients. No significant differences were found in GFAP, NSE and S100B levels according to severity of DKA, diabetes duration and GCS. Conclusion NSE and GFAP levels do not increase in DKA patients without overt brain injury. Elevated levels of S100B, which is also synthesized from non-neuronal tissues, might arise from peripheral sources. A lack of concurrent increase in serum levels of these brain injury markers might result from the yet intact blood brain barrier or a true absence of neuronal damage. In order to reveal subclinical brain injury related to DKA, there is a need for studies concurrently assessing neurocognitive functions.

Interleukin-7 receptor ?-chain haplotypes differentially affect soluble IL-7 receptor and IL-7 serum concentrations in children with type 1 diabetes

Background Interleukin-7 receptor ?-chain (IL7RA) haplotypes are associated with susceptibility for development of autoimmune diseases, including type 1 diabetes (T1D). A protective IL7RA haplotype which causes lower soluble IL-7R (sIL-7R) serum levels is hypothesized to restrict IL-7-availability for self-reactive T cells. Functional mechanisms affected by a risk-associated IL7RA haplotype are unknown. Methods We investigated the influence of IL7RA haplotypes (tagged by rs6897932T for the protective or by rs1494555G for the risk haplotype) on sIL-7R and IL-7 serum concentrations as well as disease manifestation of children with T1D (n =?259). Possible effects of differential IL-7 serum concentrations on IL-7-mediated in vitro T cell functions (i.e. IL-7R regulation and cytokine expression) were measured in a second study group of children with T1D (n =?42). Results We detected lower sIL-7R serum concentrations in children with T1D carrying protective or risk haplotypes as compared to reference haplotypes. sIL-7R levels were lowest in T1D children with the protective haplotype and lower IL-7 serum levels were exclusively detected in this study group. We found no evidence for dependency between IL-7 and sIL-7R serum concentrations and no association with T1D manifestation. Neither IL-7 nor sIL-7R serum levels were associated with mIL-7R regulation or IL-7-promoted T cell cytokine expression. Conclusions Children with T1D carrying autoimmunity risk- or protection-associated IL7RA haplotypes had both lower sIL-7R serum concentrations as compared to the reference haplotype, but only T1D children with the protective haplotype had lower IL-7 serum levels. Our results suggest additional functional mechanisms of autoimmunity-associated IL7RA variants independent from sIL-7R mediated regulation of IL-7 availability for T cells.

The influence of food order on postprandial glucose levels in children with type 1 diabetes

Objective To evaluate the effect of the order of intake of carbohydrates, protein, and fat on postprandial glucose levels in children with type 1 diabetes (T1D). Our hypothesis was that postprandial glucose levels would be lower when fat and protein are consumed prior to carbohydrates, compared to a meal where all macronutrients are combined. Methods A randomized, open-label, within-subject crossover study was conducted. Twenty patients aged 7 to 17 years diagnosed with T1D for >1?year consumed 2 isocaloric meals (with similar composition) in random order. In 1 meal, the protein and fat part was consumed 15 minutes prior to the carbohydrates (test meal). In the other meal, all macronutrients were consumed together (standard meal). Capillary blood glucose measurements and continuous glucose monitoring system were used to assess multiple glucose levels during a 3-hour postprandial period. Results Overall, mean glucose levels were 1 mmol/L lower following the test meal compared to the standard meal (9.30?� 3.20 vs 10.24?� 3.35?mmol/L; P

A plateau in new onset type 1 diabetes: Incidence of pediatric diabetes in the United States Military Health System

Objectives To describe the incidence and prevalence of type 1 diabetes among pediatric dependents of the US Department of Defense. Methods The Military Health System (MHS) data repository was used to identify pediatric patients (?17 years of age) with type 1 diabetes from January 1, 2007 to December 31, 2012. Annual incidence, annual prevalence and adjusted incidence were calculated and stratified by sex, age group, and region of residence. Results Within a 6-year study period from 2007 to 2012, 5616 pediatric patients with type 1 diabetes were identified; 57% male, mean (SD) age of 10.9 (4.2) years. Annual type 1 diabetes incidence (per 100?000 persons) over the 5-year time period ranged from 20.7/100?000 to 21.3/100?000. Incidence for each year was highest in the 10 to 14 years age group and ranged from 30.9/100?000 in 2008 to 35.2/100?000 in 2011. Annual type 1 diabetes prevalence (per 1000 persons) remained stable throughout the study period at 1.5/1000. Adjusted incidence for males was significantly higher compared to females (21.0/100?000 vs 18.1/100?000; P?=?.001). During the study period, annual incidence remained steady (test for trend, P?=?.984). Conclusions The incidence of type 1 diabetes among children appears to plateau during the study period, suggesting a steady state of type 1 diabetes within this pediatric population. The MHS provides an accurate and up to date look at incidence of type 1 diabetes and may reflect broader trends of incidence of pediatric disease for the United States as a whole.

Successful off-label sulfonylurea treatment of neonatal diabetes mellitus due to chromosome 6 abnormalities

Chromosome 6 abnormalities such as paternal uniparental isodisomy, paternal 6q24 duplication, and maternal DMR (differentially methylated region) hypomethylation are a common cause of transient neonatal diabetes mellitus (TNDM). Oral sulfonylurea (SU) is used off-label to treat permanent neonatal diabetes mellitus owing to potassium channel mutation but has not been evaluated in TNDM. Our objective was to evaluate the efficacy and safety of SU therapy in chromosome 6-related TNDM. Description of 3 case reports and literature review was the subject of the study. SU therapy was successful in 2 patients (initiated during neonatal life in 1 patient and during relapse in the other) but failed in the other despite the use of high dosage. The literature review identified 11 cases of patients with chromosome 6-related TNDM treated with SU, including 4 treated before remission and 7 after the relapse. SU therapy was consistently effective, although 4 patients treated after the relapse required multiple oral medications. None of the patients needed associated insulin therapy. No side effects of SU or complications of diabetes were reported. SU seems effective and safe in chromosome 6-related TNDM treatment when used to treat the initial episode of diabetes or the relapse. It improves patients? and families? quality of life. SU is available only as oral tablets. A pediatric dosage form would facilitate the treatment of neonates and infants.

Advancing diabetes management in adolescents: Comparative effectiveness of mobile self-monitoring blood glucose technology and family-centered goal setting

Background As adolescents gain autonomy, it remains important for parents to be involved with diabetes management to avoid deterioration in glycemic control. Technologies for self-monitoring of blood glucose (SMBG) allow for remote monitoring in real-time by parents. This research compared 3 strategies for improving SMBG and diabetes self-care in the short-term. These strategies were: (1) health information technology (HIT)-enhanced blood glucose meter that shared blood glucose data among patients, their parent, and care providers, and allowed for text messaging; (2) family-centered goal setting; and (3) a combination of (1) and (2). Methods One hundred twenty-eight participants enrolled; 97 adolescent-parent pairs attended clinic at 3-month intervals during the 6-month intervention. Differences between treatment groups were evaluated using analysis of variance (ANOVAs) for continuous variables and ?2 tests for frequencies. Within patient changes were evaluated using paired t tests. Results Participants in the HIT-enhanced SMBG group had no change in mean glycosylated hemoglobin (HbA1c). Participants assigned to family-centered goal setting had a non-significant decrease in HbA1c of ?0.3% (P?=?.26) from baseline to 6 months. Participants in the combined approach had a significant decrease in HbA1c of ?0.6% (P?=?.02) from baseline to 3 months, but the decrease of ?0.4% at 6 months was non-significant (P?=?.51). The change in HbA1c from baseline to 3 months was greater for the combined approach than for the HIT-enhanced SMBG (P?=?.05) or family-centered goal setting (P?=?.01). Conclusions Our data suggest that utilizing the family-centered goal setting strategy when implementing HIT-enhanced diabetes technology deserves further study.

?KiDS and Diabetes in Schools? project: Experience with an international educational intervention among parents and school professionals

Background Although it is known that school care is a major challenge in diabetes treatment, there is still no published international initiative. Objectives The aims of this study were to introduce an international educational intervention tool, the International Diabetes Federation (IDF) KiDS and Diabetes in Schools project (KiDS project), and to describe its impact on diabetes knowledge and behavior of caregivers and school professionals. Methods The KiDS project was developed with the support of IDF and the International Society for Pediatric and Adolescent Diabetes and provides online free material in 10 languages, directed to caregivers and school personnel. A pilot evaluation of the KiDS intervention was performed in Brazil. An educational intervention was conducted in 5 primary schools, with 42 parents and school staff, followed by 2 individual interviews after 1 and 3?months. The results were evaluated in a qualitative study with a descriptive design based on content analysis. Results School staff acquired new knowledge on diabetes and its treatment. They felt more confident when helping students with diabetes and said the educational intervention promoted a positive impact on the teacher-student relationship, on the caring for health, and on school infrastructure. Family members of children with diabetes stated that the educational intervention gave them an opportunity to strengthen and update information on treatment and improve their knowledge. Conclusions The KiDS project is the first international tool directed to foster a safe and supportive environment and a better understanding of diabetes in schools. In this pilot evaluation, it achieved the goal of informing and changing the behavior of parents and school staff, thus improving the care provided to children with diabetes in schools.

Young children with type 1 diabetes can achieve glycemic targets without hypoglycemia: Results of a novel intensive diabetes management program

Background Young children with type 1 diabetes (T1D) present unique challenges for intensive diabetes management. We describe an intensive diabetes program adapted for young children and compare glycemic control, anthropometry, dietary practices and insulin regimens before and after implementation. Methods Cross sectional data from children with T1D aged ?0.5 to <7.0?years attending the John Hunter Children's Hospital (JHCH), Australia in 2004, 2010 and 2016 were compared. Outcome measures were glycemic control assessed by hemoglobin A1c (HbA1c); severe hypoglycemia episodes; body mass index standard deviation scores (BMI-SDS); diabetes ketoacidosis (DKA) episodes; and insulin regimen?twice daily injections, multiple daily injections, or continuous subcutaneous insulin infusion. Results Mean HbA1c declined by 12?mmol/mol over the study period (P?

A phase I study of anti-inflammatory therapy with rilonacept in adolescents and adults with type 1 diabetes mellitus

Background The innate immune system may be activated around the time of diagnosis of type 1 diabetes (T1D). Components of this system, including cytokines such as interleukin-1? (IL-1?) represent potential therapeutic targets for disease modifying therapy. Objective We conducted a phase 1 trial of rilonacept, an IL-1 cytokine trap, in patients with T1D. Subjects and methods Thirteen T1D patients (10 males) with median age (interquartile range, IQR) of 17 years (16-18), a median (IQR) of 5 months (5-7) since diagnosis. Rilonacept was administered subcutaneously for 26 weeks. Incidence of infections was the primary end-point. Results There were 85 adverse events; 13 were Grade 2, of which 9 (8 infectious) were judged ?possibly related? to the drug. The mean (SD) C-peptide on 2-hour mixed meal tolerance tests decreased from 0.87 (0.42) to 0.59 (0.29) ng/mL (P?=?.01 by paired t test) during 6?months on treatment. Hemoglobin A1c (HbA1c) increased from 6.8 (1.1) to 7.3 (1.1) (P?=?.05), but there was not a significant change in daily insulin dose (0.41?�?0.23 to 0.47?�?0.18), or in insulin dose-adjusted HbA1c (IDAA1c, 8.4?�?1.8 to 9.0?�?1.5). Subjects in ?remission,? defined as HbA1c <6.5 and a total daily insulin dose <0.5 units/kg/24 h, decreased from 5 to 4. There were no significantly differentially expressed genes in peripheral blood leukocytes before and after rilonacept. Conclusions Rilonacept treatment for 6?months is well-tolerated in individuals with T1D of recent onset, but is unlikely to be efficacious as a single agent in preserving beta cell function.

Severe hypoglycemia and diabetic ketoacidosis in young persons with preschool onset of type 1 diabetes mellitus: An analysis of three nationwide population-based surveys

Objectives To describe incidence rates and temporal trends of severe hypoglycemia (SH) and of hospitalizations for SH or diabetic ketoacidosis (DKA) in persons with early-onset, long-term type 1 diabetes (T1D) and associations of these short-term complications with potential risk factors. Methods This study includes data of 1,875 persons 11.2 to 21.9?years of age with early-onset (<5?years) and long-term (>10?years) T1D from 3 cross-sectional nationwide, population-based surveys conducted in 2009/2010, 2012/2013 and 2015/2016 using standardized questionnaires. Negative binomial regression was used to estimate incidence rates per 100 person-years (py), temporal trends and associations between potential risk factors and outcomes. Results The crude incidence rate of SH showed a decreasing trend over time (P for trend?=?.004), disappearing after adjustment for confounders (P for trend?=?.341). In contrast, adjusted rates of SH- and DKA-associated hospitalizations did not change significantly between 2009 and 2016 (P for trend?=?.306 and .774, respectively). Associations between sex, diabetes duration, insulin treatment regimen, hypoglycemia awareness as well as physical activity and SH were found, while family structure was associated with hospitalizations for SH. Family structure, socioeconomic status (SES), diabetes duration, and hemoglobin A1c values showed associations with DKA-related hospitalizations. Conclusions After adjustment, rates of SH and SH- or DKA-associated hospitalization showed no significant changes in recent years. Structured education programs focusing on high-risk groups as, for example, persons with T1D living with 1 biological parent and the parents? partner or those with a low SES, should be implemented to reduce incidence rates of hospitalizations.

Type 1 diabetes, sport practiced, and ankle joint mobility in young patients: What is the relationship?

Background/Objective It is known that patients with diabetes can develop limited joint mobility (LJM) and that this can depend on the metabolic control maintained and the duration of the disease. The aims of this study were to verify the presence of ankle joint mobility (AJM) deficits in both plantar and dorsiflexion in young type 1 diabetic patients (T1D) considering also the possible role of sport practiced as a further factor, able to modify AJM. Methods AJM was evaluated by an inclinometer in 82 T1D patients (M/F: 48/34), mean age 12.9 �?2.6 years, body mass index (BMI) 19.7 �?3.6 kg/m2, duration of diabetes 5.6 �?3.3 years, mean HbA1c 7.5 �?1.0% and in 226 healthy controls (M/F: 146/80), age-, gender-, and BMI-matched practicing different sports (soccer, volleyball, basketball, and dance). Results The patients? ankle range of motion was significantly lower than that in controls (132.7 �?22.3� vs 126.1 �?17.9�; P?

Clinical heterogeneity of hyperinsulinism due to HNF1A and HNF4A mutations

Background Dominant inactivating mutations in HNF1A and HNF4A have been described to cause hyperinsulinism (HI) before evolving to diabetes. However, information available in the literature regarding the clinical phenotype is limited. Objective To report the prevalence of HNF1A and HNF4A mutations in a large cohort of children with HI, and to describe their genotypes and phenotypes. Design Retrospective descriptive study. Methods Medical records were reviewed to extract clinical information. Mutation analysis was carried out for 8 genes associated with HI (ABCC8, KCNJ11, GLUD1, GCK, HADH, HNF4A, HNF1A, and UCP2). Results HNF1A and HNF4A mutations were identified in 5.9% (12 out of 204; HNF1A?=?7, HNF4A?=?5) of diazoxide-responsive HI probands. The clinical phenotypes were extremely variable. Two children showed evidence of ketone production during hypoglycemia, a biochemical profile atypical for hyperinsulinism. At the time of analysis, diazoxide was discontinued in 5 children at a median age of 6.8?years. None had developed diabetes mellitus at a median age of 7.0?years. Conclusions Given the heterogeneous clinical phenotypes of HNF1A- and HNF4A-HI, all children with transient, diazoxide-responsive HI without clear history of perinatal stress, should be screened for HNF1A and HNF4A mutations as it predicts the clinical course and affects the subsequent management plan.

Increased prevalence of disordered eating in the dual diagnosis of type 1 diabetes mellitus and celiac disease

Background Disordered eating behaviors (DEBs) may lead to full blown eating disorders. Both type 1 diabetes mellitus (T1DM) and celiac disease (CD) have been linked to DEBs. Objective To compare the presence of DEBs between adolescents and young adults with a dual diagnosis of T1DM and CD, and individuals with only one of the diagnoses. Methods Individuals with a dual diagnosis of T1DM and CD (?T1DM?+?CD group? n?=?39), with a diagnosis of T1DM only (?T1DM group? n?=?97) and with a diagnosis of CD only (?CD group? n?=?267) filled the Eating Attitude Test-26 (EAT-26) questionnaire. Those with T1DM completed in addition to the Diabetes Eating Problem Survey-Revised (DEPS-R). Results The study population comprised of 403 individuals, of whom 65% were females. There were no statistically significant differences among the groups in distribution of sex, age, hemoglobin A1c (HbA1c) levels, age of disease diagnosis and duration. The prevalence of DEBs in the T1DM?+?CD group was 3-fold higher (26.0%) than in the T1DM (8.2%) and CD (8.2%) groups (P?=?.003). This trend was observed for both females and males. Multivariate analysis demonstrated that the T1DM?+?CD group had an increased risk for DEBs (odds ratio, OR: 4.7, 95% confidence interval, CI: 1.9-11.2, P?=?.001) after adjustment for age, sex, and body mass index. Additionally, being female, older and overweight increased the risk for DEBs. HbA1c values were not associated with an increased DEBs rate. Conclusions Individuals with the dual diagnoses of T1DM and CD have an increased likelihood to develop DEBs compared to those with only one of these diagnoses.

Oral contraception in adolescents with type 1 diabetes and its association with cardiovascular risk factors. A multicenter DPV study on 24 011 patients from Germany, Austria or Luxembourg

Objective To investigate differences in cardiovascular risk factors and metabolic control in girls with type 1 diabetes with or without use of oral contraceptives (OC) from the multicenter ?diabetes prospective follow-up? (DPV) registry. Methods Twenty-four thousand eleven adolescent girls (13 to

High frequencies of dermatological complications in children using insulin pumps or sensors

Background Dermatological complications in children and adolescents that are related to continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM) have not been well-characterized. This study examined the prevalence and characteristics of different types of dermatological complications. Methods Online questionnaires regarding dermatological complications related to CSII and/or CGM were returned from a total of 144 children and adolescents, aged 2 to 20 years. Both previous and current skin problems were reported along with their clinical characteristics. Descriptive statistics, ?2 tests, and multivariate analyses were used to evaluate the data. Results Of 143 patients using CSII, 90% had previous and 63% reported current dermatological complications. Non-specific eczema was most frequently reported and was currently present in 25.7% of the patients. These results were independent of age and current CGM use. Among the 76 patients using CGM, 46% reported current dermatological complications. A history of atopy was associated with dermatological complications in individuals using CSII, but not CGM. The patients rated CGM-related dermal issues as significantly worse than those associated with CSII (P?

Factitious hypoglycemia in children and adolescents with diabetes

Background Factitious hypoglycemia is a condition of self-induced hypoglycemia due to surreptitious administration of insulin or oral hypoglycemic agents. In adults, it is an uncommon, but well known clinical entity observed in individuals with and without diabetes. Objectives To report a case of factitious hypoglycemia highlighting diagnostic pitfalls, to identify common characteristics of children and adolescents with factitious hypoglycemia, and to examine whether the information on long-term outcome exists. Methods We present a case of an adolescent with type 1 diabetes who had self-induced hypoglycemia of several years? duration; and we conducted a systematic literature review on factitious hypoglycemia in pediatric patients with diabetes. Results We identified a total of 83 articles of which 14 met the inclusion criteria (describing 39 cases). All but 1 individual had type 1 diabetes and the majority was female (63%). Average age was 13.5?�?2.0?years with the youngest patient presenting at the age 9.5?years. Blood glucose control was poor (hemoglobin A1c: 12.1?�?4.0%). In 35%, psychiatric disorders were mentioned as contributing factors. Only 3 reports provided follow-up beyond 6 months. Conclusions Factitious hypoglycemia typically occurs in adolescents with type 1 diabetes who use insulin to induce hypoglycemia. Awareness of this differential diagnosis and knowledge of potentially misleading laboratory results may facilitate earlier recognition and intervention. Little information exists on effective treatments and long-term outcome.

Intensive remote monitoring versus conventional care in type 1 diabetes: A randomized controlled trial

Objective While frequent contact with diabetes care providers may improve glycemic control among patients with type 1 diabetes (T1D), in-person visits are labor-intensive and costly. This study was conducted to assess the impact of an intensive remote therapy (IRT) intervention for pediatric patients with T1D. Methods Pediatric patients with T1D were randomized to IRT or conventional care (CC) for 6?months. Both cohorts continued routine quarterly clinic visits and uploaded device data; for the IRT cohort, data were reviewed and patients were contacted if regimen adjustments were indicated. Glycated hemoglobin (HbA1c) change from baseline was assessed at 6 and 9?months. Diabetes-related quality of life (QoL), healthcare services utilization, and hypoglycemic events were also tracked. Results Among 117 enrollees (60 IRT, 57 CC), mean (SD) 6-month %HbA1c change for IRT vs CC was ?0.34 (0.85) (?3.7 mmol/mol) vs ?0.05 (0.74) (?0.5 mmol/mol) overall (P?=?.071); ?0.15 (0.67) (1.6 mmol/mol) vs ?0.02 (0.66) (0.2 mmol/mol) for ages 8 to 12 (P?=?.541); and ?0.50 (0.95) (?5.5 mmol/mol) vs ?0.06 (0.80) (?0.7 mmol/mol) for ages 13 to 17 (P?=?.056). Diabetes-related QoL increased by 6.5 and 1.3 points for IRT and CC, respectively (P?=?.062). Three months after intervention cessation, %HbA1c changed minimally among treated children aged 8 to 12 but increased by 0.22 (0.89) (2.4 mmol/mol) among those aged 13 to 17. Conclusions IRT substantially affected diabetes metrics and improved QoL among pediatric patients with T1D. Adolescents experienced a stronger treatment effect, but had difficulty in sustaining improved control after intervention cessation.

Effects of residential summer camp on body mass index and body composition in type 1 diabetes

Background Body mass index (BMI) and fat mass may be higher in children with diabetes compared to healthy peers. It is not certain how diabetic children respond to exercise and diet interventions. Objective To investigate the effect of summer camp on BMI and body composition in children with type 1 diabetes. Methods Five hundred eighty-six children (5-19 years, 518 with type 1 diabetes, 68 without diabetes) were followed while attending camp. BMI z-scores (BMIz) and body composition (bioelectrical impedance analysis) were measured at the beginning and end of each 19-day session. Diet and activity were directly supervised, blood glucose closely monitored. A nested diabetic/non-diabetic sib pair analysis was also conducted. Changes in BMIz and percent fat mass (%FM) were the primary outcomes. Findings were confirmed by analysis of data from 612 campers (549 with diabetes) the following summer. Results At entry, campers with diabetes had higher BMIz and %FM. They tended to gain BMIz (0.04 � 0.01) whereas non-diabetic campers lost (?0.16 � 0.11, P < .0001). BMIz increases were positively correlated with precamp hemoglobin A1c values. The differences in initial values and changes in BMIz remained when campers with diabetes were compared to their siblings. All experienced a similar reduction in %FM. Similar results were obtained the following summer. Conclusions Children with diabetes may, therefore, accrue more lean body tissue with increased exercise and a healthy diet than those without diabetes. This effect is greatest in those with initially poor metabolic control.

Whole-exome sequencing for mutation detection in pediatric disorders of insulin secretion: Maturity onset diabetes of the young and congenital hyperinsulinism

Background To assess the utility of whole-exome sequencing (WES) for mutation detection in maturity-onset diabetes of the young (MODY) and congenital hyperinsulinism (CHI). MODY and CHI are the two commonest monogenic disorders of glucose-regulated insulin secretion in childhood, with 13 causative genes known for MODY and 10 causative genes identified for CHI. The large number of potential genes makes comprehensive screening using traditional methods expensive and time-consuming. Methods Ten subjects with MODY and five with CHI with known mutations underwent WES using two different exome capture kits (Nimblegen SeqCap EZ Human v3.0 Exome Enrichment Kit, Nextera Rapid Capture Exome Kit). Analysis was blinded to previously identified mutations, and included assessment for large deletions. The target capture of five exome capture technologies was also analyzed using sequencing data from >2800 unrelated samples. Results Four of five MODY mutations were identified using Nimblegen (including a large deletion in HNF1B). Although targeted, one mutation (in INS) had insufficient coverage for detection. Eleven of eleven mutations (six MODY, five CHI) were identified using Nextera Rapid (including the previously missed mutation). On reconciliation, all mutations concorded with previous data and no additional variants in MODY genes were detected. There were marked differences in the performance of the capture technologies. Conclusions WES can be useful for screening for MODY/CHI mutations, detecting both point mutations and large deletions. However, capture technologies require careful selection.

The contribution of physical fitness to individual and ethnic differences in risk markers for type 2 diabetes in children: The Child Heart and Health Study in England (CHASE)

Background The relationship between physical fitness and risk markers for type 2 diabetes (T2D) in children and the contribution to ethnic differences in these risk markers have been little studied. We examined associations between physical fitness and early risk markers for T2D and cardiovascular disease in 9- to 10-year-old UK children. Methods Cross-sectional study of 1445 9- to 10-year-old UK children of South Asian, black African-Caribbean and white European origin. A fasting blood sample was used for measurement of insulin, glucose (from which homeostasis model assessment [HOMA]-insulin resistance [IR] was derived), glycated hemoglobin (HbA1c), urate, C-reactive protein (CRP), and lipids. Measurements of blood pressure (BP) and fat mass index (FMI) were made; physical activity was measured by accelerometry. Estimated VO2 max was derived from a submaximal fitness step test. Associations were estimated using multilevel linear regression. Results Higher VO2 max was associated with lower FMI, insulin, HOMA-IR, HbA1c, glucose, urate, CRP, triglycerides, LDL-cholesterol, BP and higher HDL-cholesterol. Associations were reduced by adjustment for FMI, but those for insulin, HOMA-IR, glucose, urate, CRP, triglycerides and BP remained statistically significant. Higher levels of insulin and HOMA-IR in South Asian children were partially explained by lower levels of VO2max compared to white Europeans, accounting for 11% of the difference. Conclusions Physical fitness is associated with risk markers for T2D and CVD in children, which persist after adjustment for adiposity. Higher levels of IR in South Asians are partially explained by lower physical fitness levels compared to white Europeans. Improving physical fitness may provide scope for reducing risks of T2D.

Severe insulin resistance in disguise: A familial case of reactive hypoglycemia associated with a novel heterozygous INSR mutation

Aim Hypoglycemia in childhood is very rare and can be caused by genetic mutations or insulin-secreting neoplasms. Postprandial hypoglycemia has previously been associated with insulin receptor (INSR) gene mutations. We aimed to identify the cause of postprandial hypoglycemia in a 10-year-old boy. Subjects We studied the symptomatic proband and his apparently asymptomatic mother and elder brother. All of them were lean. Methods Metabolic screening of the proband included a 5-hour oral glucose tolerance test (OGTT), angio-magnetic resonance imaging, and 18F-dihydroxyphenylalanine positron emission tomography/computed tomography imaging of the pancreas. INSR gene sequencing and in vitro functional studies of a novel INSR mutation were also undertaken. Results Fasting hyperinsulinemia was detected during metabolic screening, and 5-hour OGTT showed hypoglycemia at 240? in the proband, his mother, and brother. Pancreatic imaging showed no evidence of neoplasia. Acanthosis nigricans with high fasting insulin levels in the proband suggested severe insulin resistance and prompted INSR gene sequencing, which revealed the novel, heterozygous p.Phe1213Leu mutation in the patient and his family members. In vitro studies showed that this mutation severely impairs insulin receptor function by abolishing tyrosine kinase activity and downstream insulin signaling. Conclusions The identification of etiological cause of hypoglycemia in childhood may be challenging. The combination of fasting hyperinsulinemia with acanthosis nigricans in a lean subject with hypoglycemia suggests severe insulin resistance and warrants INSR gene screening.

Higher body mass index predicts cardiac autonomic dysfunction: A longitudinal study in adolescent type 1 diabetes

Background Obesity is associated with an increased risk of cardiovascular morbidity in adults with diabetes. Objective To examine the predictive role of body mass index (BMI) and adiposity on cardiac autonomic function in childhood onset type 1 diabetes. Subjects Two hundred and fifty-three participants with type 1 diabetes (aged 8-30 years) were assessed for diabetes complications at a tertiary hospital, and followed over 7?years (total 922 visits). Methods Heart rate variability (HRV) measures assessed by 10-minute electrocardiography recording using LabChart Pro were standard deviation of RR intervals, time between consecutive QRS complexes, [SDNN], root mean squared difference of successive RR intervals (RMSSD), triangular index (TI), and low to high frequency ratio [LF:HF]. Multivariable generalized estimating equations were used to model the longitudinal associations between HRV measures and clinical variables (BMI standard deviation scores [SDS], waist:height ratio, total daily insulin dose/kg (TDD) and hemoglobin A1c [HbA1c]). Results At baseline, mean age was 14.4?�?2.7?years, diabetes duration 7.1?�?3.7?years, HbA1c 8.3%?�?1.5% (67?�?16?mmol/mol), and 33% were overweight/obese (BMI ?85th percentile). At final visit, mean age was 18.5?�?2.7?years, duration 11.3?�?3.9?years, HbA1c 9.0%?�?1.8% (75?�?20?mmol/mol), and 40% were overweight/obese. Adiposity (higher BMI SDS or waist: height ratio) was a significant predictor of worse HRV (lower SDNN, RMSSD; P?

Comprehensive human leukocyte antigen genotyping of patients with type 1 diabetes mellitus in Taiwan

Background Type 1 diabetes (T1D) mellitus is an autoimmune disorder involving both complex genetic and environmental factors. The incidence rates are low in Asian countries, and the specific, explanatory genetic factors underlying this have been investigated. The aim of this study was to elucidate the association of human leukocyte antigen (HLA) alleles/haplotypes with T1D in Taiwan. Methods We performed direct comprehensive genotyping of 6 classical HLA loci (HLA-A, -B, -C, -DPB1, -DQB1, and -DRB1) to 4-digit resolution in 104 unrelated T1D patients and 504 controls. Twenty-four of the 104 patients also exhibited thyroid autoimmunity. Results Three major susceptibility haplotypes were identified: DRB1*03:01-DQB1*02:01 (odds ratio [OR]?=?5.39 under the dominant model, P?=?2.3?�?10?13), DRB1*04:05-DQB1*04:01 (OR?=?2.44, P?=?5.0?�?10?4), and DRB1*09:01-DQB1*03:03 (OR?=?2.02, P?=?1.4?�?10?3); one protective haplotype was identified: DRB1*08:03-DQB1*06:01 (OR?=?0.10, P?=?1.6?�?10?3). DRB1*03:01-DQB1*02:01, the major T1D susceptibility haplotype, was found at a lower frequency in T1D patients with thyroid autoimmunity. The T1D protective allele DRB1*12:02 was shown to be protective against Graves? disease in our previous report. Conclusion In addition to clarifying the roles of several known T1D HLA alleles and haplotypes, we discovered that the DRB1*08:03-DQB1*06:01 haplotype is protective against T1D. The DRB1*12:02 allele protected against both T1D and Graves? disease.

Effects of insulin resistance on the association between the circulating retinol-binding protein 4 level and clustering of pediatric cardiometabolic risk factors

Objectives Retinol-binding protein 4 (RBP4) and insulin resistance (IR) are clinical parameters associated with cardiometabolic diseases. The mediating and modifying roles of IR on children?s susceptibility to cardiometabolic disorders are undetermined. This study investigated the mediating and modifying effects of the homeostatic model assessment of IR (HOMA-IR) on the relationship between the serum RBP4 level and clustering of pediatric cardiometabolic risk factors. Methods We assessed the diet, physical activity, cardiometabolic risk factors, and clinical parameters of 272 randomly selected adolescents from a large-scale cross-sectional study (n?=?2727). Two HOMA-IRs (HOMA1-IR and HOMA2-IR) were used to evaluate the designated effects. Results Levels of serum RBP4 positively correlated with the levels of the 2 HOMA-based-IRs, and HOMA-IR correlated to all components of pediatric metabolic syndrome (MetS), the number of abnormal components, and a body-weight-weighted principal component score extracted from 12 cardiometabolic risk factors. Increased RBP4 levels had positive effects on waist circumference (WC), triglyceride, and the number of abnormal MetS components (0.310?cm, 1.384??g/dL, and 0.021 item elevations, respectively), and the HOMA-IRs explained 17.7% to 21.9%, 11.8% to 27.6%, and 23.8% to 25.0% of these effects. The association of WC and the number of abnormal MetS components with the serum RBP4 level was enhanced by higher HOMA-IR (? for interaction, 0.13 and 0.01 for HOMA1-IR, and 0.32 and 0.02 for HOMA2-IR, respectively). Conclusions HOMA-IR is associated with the circulating RBP4 level and cardiometabolic risk factors in adolescents. Pediatric HOMA-IR may have mediating and modifying effects on the positive correlations between RBP4 and the clustering of MetS components.

Diabetes distress is more strongly associated with HbA1c than depressive symptoms in adolescents with type 1 diabetes: Results from Diabetes MILES Youth?Australia

Background Glycated hemoglobin (HbA1c) is higher during adolescence than at any other life stage. Some research among adolescents indicates that depressive symptoms are associated with suboptimal HbA1c. However, research among adults suggests diabetes distress is a stronger predictor of HbA1c than depressive symptoms. Objective To determine the relative contributions of depressive symptoms and diabetes distress to explain the variance in HbA1c among adolescents with type 1 diabetes. Participants and methods Diabetes MILES Youth Study respondents aged 13 to 19 years completed questionnaires assessing depressive symptoms (Patient Health Questionnaire for Adolescents: PHQA-8), diabetes distress (Problem Areas in Diabetes-Teen version: PAID-T), and self-reported socio-demographic and clinical variables, including their most recent HbA1c. Stepwise hierarchical multiple regression was conducted to examine the contributions of depressive symptoms and diabetes distress to HbA1c. Results Participants (N?=?450) had a (mean?�?SD) age of 15.7?�?1.9?years; diabetes duration of 6.9?�?4.3?years; and 38% (n?=?169) were male. Twenty-one percent (n?=?96) experienced moderate-to-severe depressive symptoms (PHQA-8???11) and 36% (n?=?162) experienced high diabetes distress (PAID-T?>?90). In the final regression model, HbA1c was explained by: diabetes duration (??=?.14, P?=?.001), self-monitoring of blood glucose (??=??.20, P?

Incidence of childhood onset type 1 diabetes in Western Australia from 1985 to 2016: Evidence for a plateau

Objective To determine the incidence of childhood type 1 diabetes mellitus (T1D) in Western Australia from 2011 to 2016, and to examine the temporal trends between 1985 and 2016. Methods An observational cohort study was undertaken of all children newly diagnosed with T1D aged 0 to 14 years in Western Australia from 1985 to 2016. Cases were identified from the Western Australian Children's Diabetes Database, a population-based diabetes register previously estimated to be >99% complete. Annual age-standardized and age- and sex-specific incidence rates were calculated and the Joinpoint Regression Program used to identify any significant changes in trends over the study period. Results A total of 2499 cases were included (1272 boys, 1227 girls). The overall mean annual incidence was 19.1/100?000 person years (95% confidence interval, CI: 18.3-19.8), with no significant difference found between boys and girls. The mean annual incidence of 12.1/100?000 person years (95% CI: 11.1-13.1) in 0 to 4-years was significantly lower than that observed in 5 to 9 (21.6/100?000 [95% CI: 20.2-23.0]) and 10 to 14 (23.5/100?000 [95% CI: 22.1-25.0]) years. Joinpoint regression analysis identified a significant change in the temporal trend occurring in 2003. From 1985 to 2003, the incidence increased on an average of 3.3% per year (95% CI: 1.9-4.7). However, from 2003 to 2016, no significant change in the temporal trend occurred (?0.6% per year [95% CI: ?2.4-1.2]). Conclusions This study provides evidence for a possible plateauing in the incidence of childhood T1D in Western Australia, following a peak in 2003. Ongoing monitoring of the incidence will be essential to determine how temporal trends continue to evolve.

Cardiovascular autonomic neuropathy in adolescents and young adults with type 1 and type 2 diabetes: The SEARCH for Diabetes in Youth Cohort Study

Objective To estimate the prevalence of and risk factors for cardiovascular autonomic neuropathy (CAN) in adolescents and young adults with type 1 and type 2 diabetes enrolled in the SEARCH for Diabetes in Youth Study. Methods The study included 1646 subjects with type 1 diabetes (age 18?�?4?years, diabetes duration 8?�?2?years, HbA1c 9.1?�?1.9%, 76% non-Hispanic Whites) and 252 with type 2 diabetes (age 22?�?4?years, diabetes duration 8?�?2?years, HbA1c 9.2?�?3.0%, 45% non-Hispanic Blacks). Cross-sectional and longitudinal risk factors were assessed at baseline and follow-up visits. Area under the curve (AUC) was used to assess the longitudinal glycemic exposure and cardiovascular risk factors. CAN was assessed by time and frequency domain indices of heart rate variability (HRV). CAN was defined as the presence of ?3 of 5 abnormal HRV indices. Results The prevalence of CAN was 12% in adolescents and young adults with type 1 diabetes and 17% in those with type 2 diabetes. Poor long-term glycemic control (AUC HbA1c), high blood pressure, and elevated triglyceride levels were correlates of CAN in subjects with type 1 diabetes. In those with type 2 diabetes, CAN was associated with elevated triglycerides and increased urinary albumin excretion. Conclusions The prevalence of CAN in this multiethnic cohort of adolescents and young adults with type 1 and type 2 diabetes are comparable to those reported in adults with diabetes. Suboptimal glycemic control and elevated triglycerides were the modifiable risk factors associated with CAN.

Effect of severe obesity in childhood and adolescence on risk of type 2 diabetes in youth and early adulthood in an American Indian population

Objectives The risk of early-onset type 2 diabetes associated with the severity of obesity in youth is not well understood. This study aims to determine metabolic alterations and type 2 diabetes risk among American Indian children who are obese or severely obese. Methods Incidence rates of diabetes before 20?years (youth-onset) and 45 years were computed in 2728 children who were from 5 to <10?years and 4317 adolescents who were from 10 to <18 years without diabetes examined between 1965 and 2007. Obesity was defined as age-sex-adjusted body mass index (BMI) ?95th percentile, and its severity was quantified as the percentage of the 95th percentile (%BMIp95). Results In the younger cohort, 0.9% of those non-obese and 2.9% of those with 100% to <120%BMIp95 had impaired glucose tolerance (IGT) compared to 8.6% of those with ?140%BMIp95. In the older cohort, 2.9% of those non-obese and 9.8% of those with 100% to <120%BMIp95 had IGT compared to 13.3% of those with ?160%BMIp95. The incidence of youth-onset diabetes was 3.8 and 4.9/1000 person-years in the child and adolescent cohorts, respectively, and before the age of 45 was 12.3 and 16.8/1000 person-years, respectively. Incidence rates of youth-onset diabetes in those with the most severe obesity (?140%BMIp95) were 2.3 to 5.1 times as high as in those with the least severe obesity (100 to <120%BMIp95), and for onset of diabetes before the age of 45 were 1.6 to 2.2 times as high. Conclusions Severe obesity in an American Indian population is a major driver of type 2 diabetes developing in adolescents and young adults.

Clinical and biochemical features at diagnosis of type 1 diabetes in patients between 0 and 18 years of age from Jordan

Objective Data regarding type 1 diabetes mellitus (T1D) in Jordan are extremely scarce. We aim to evaluate the clinical and laboratory characteristics at diagnosis of T1D in a group of children from Jordan. Methods The records of 437 (boys/girls: 224/213) children with type 1 diabetes followed in the years 2012 to 2016 were evaluated retrospectively. The data were assessed by sex and age subgroups (<5, 6-10, and 11-18 years). Results Mean age of children at diagnosis was 7.3?�?3.6 years. The first peak in the number of T1D cases in terms of age at diagnosis was observed in the age group between 6 and 8 years (n?=?116 [26.5%], 95% confidence interval [CI]: 22.3%-30.6%). This was followed by the age group of 3 to 5 years (n?=?108 [24.7%], 95% CI: 20.6%-28.7%). Although the patients mostly presented in winter (30.0%, 95% CI: 25.6%-34.3%), no season-related significant differences were found. The frequency of ketoacidosis at diagnosis was 40.7% (95% CI: 36%-45.3%). At presentation, 22.8% (95% CI: 18.9%-26.7) of our patients had a positive history of T1D in their extended families. In addition, 61.1% (95% CI: 56.5%-65.7%) of the patients were started on premixed insulin at diagnosis. Conclusion The findings possibly indicate a decreasing age of T1D onset in Jordanian patients. The high frequency of ketoacidosis at presentation is noteworthy. In addition, the initial insulin protocols are not in accordance with the recommended insulin therapy for children and adolescents with T1D.

Incidence and prevalence trends of youth-onset type 2 diabetes in a cohort of Canadian youth: 2002-2013

Objective Youth-onset type 2 diabetes is an emerging disease. We estimated incidence and prevalence trends of youth-onset type 2 diabetes between 2002 and 2013 in the Canadian province of British Columbia. Methods This population-based cohort study used a validated diabetes case-finding definition and algorithm to differentiate type 2 from type 1 diabetes to identify youth <20 years with type 2 diabetes within linked population-based administrative data. Age-standardized incidence and prevalence were calculated. JoinPoint regression and double exponential smooth modeling were used. Results From 2002/2003 to 2012/2013, the incidence of youth-onset type 2 diabetes increased from 3.45 (95% confidence interval, CI: 2.43, 4.80) to 5.16 (95% CI: 3.86, 6.78)/100?000. The annual percent change (APC) in incidence was 3.74 (95% CI: 1.61, 5.92; P?=?0.003) overall, while it was 5.94 (95% CI: 1.84, 10.20; P?=?0.009) and 0.53 (95% CI: ?5.04, 6.43; P?=?0.837) in females and males, respectively. The prevalence increased from 0.009% (95% CI: 0.007, 0.011) in 2002/2003 to 0.021% (95% CI: 0.018, 0.024) in 2012/2013 with an APC of 7.89 (95% CI: 6.41, 9.40; P?

Sex- and age-dependent effects of celiac disease on growth and weight gain in children with type 1 diabetes: Analysis of the type 1 diabetes Exchange Clinic Registry

Background Celiac disease (CD) is common in patients with type 1 diabetes (T1D) and effects of CD on growth in children with T1D remain unclear. Methods We analyzed heights, weights, and body mass index (BMI) in 215 matched pediatric CD/control pairs in the T1D Exchange Clinic Registry. CD was defined by a clinic-reported diagnosis and positive celiac serology (n?=?80) and/or positive small bowel biopsy (n?=?135). Cases and controls were matched by age (mean: 14?years), diabetes duration (median: 7 years), sex (57% female), and clinic site. There were 5569 height/weight measurements. Results Gluten was restricted for varying periods of time in 61% of females and 51% of males with CD. Females with CD were shorter than female controls at all ages (P?=?0.01). Weight z-scores were initially lower in preschool females with CD but similar to controls by middle childhood. Males with CD were initially shorter but adult heights were similar. Height in both sexes and weight in males were lower in CD participants diagnosed at younger age. Growth in T1D children with biopsy-proven CD, 76% of them were gluten-restricted, was comparable to that of T1D controls. Conclusion Concurrent CD impairs linear growth in T1D females at all stages of development and in young T1D males. Young females with CD have lower weights, but both sexes have similar weights by middle childhood. Children younger at CD onset remain shorter throughout childhood; males younger at CD onset have persistently lower weights. Long-term gluten restriction may restore weight gain and linear growth in children with CD and T1D.

Pharmacokinetics and pharmacodynamics of canagliflozin in pediatric patients with type 2 diabetes

Objective Canagliflozin, a sodium glucose cotransporter 2 inhibitor approved for the treatment of adults with type 2 diabetes (T2D), increases urinary glucose excretion (UGE) and lowers plasma glucose (PG) levels by reducing the renal threshold for glucose (RTG). This study assessed the pharmacokinetics (PK) and pharmacodynamics (PD) of canagliflozin in pediatric T2D patients. Methods Patients, aged 10 to 17 years with mean weight 107.2 kg and body mass index 38.2 kg/m2, underwent PK and PD assessments after receiving a single daily dose of canagliflozin 100?mg (n?=?8) or 300?mg (n?=?9) for 14 days. Data are presented as mean (SD). Results There were dose-dependent increases in the PK of canagliflozin 100 and 300?mg, with maximum plasma concentrations and areas under plasma concentration curves that were similar to the corresponding values in adults. Mean 24-hour RTG fell to 84.6 (13.8) mg/dL with canagliflozin 100?mg and to 69.1 (9.6) mg/dL with canagliflozin 300?mg; also consistent with reductions in RTG in adults. Mean 24-hour UGE increased from 5.3 (10.5) g at baseline to 74.1 (37.4) g with canagliflozin 100?mg and from 0.1 (0.04) g to 68.6 (26.5) g with canagliflozin 300?mg. Both doses were well tolerated and the tablets had acceptable taste, smell, and swallowability. Conclusions In pediatric T2D patients, canagliflozin 100 and 300?mg had PK and PD characteristics similar to those in adults with T2D, which is likely due to the relative maturity and increased body weight of youth affected with this disorder.

Relationships among cardiorespiratory fitness, muscular fitness, and cardiometabolic risk factors in Japanese adolescents: Niigata screening for and preventing the development of non-communicable disease study-Agano (NICE EVIDENCE Study-Agano) 2

Objective To examine the independent and combined associations of cardiorespiratory fitness (CRF) and muscular fitness (MF) with cardiometabolic risk factors in Japanese adolescents. Methods A cross-sectional study including 993 Japanese adolescents (aged 13-14 years) was undertaken. Height, body mass, blood pressure, lipid profile (non-fasting), and HbA1c were measured. The physical fitness (PF) test included measurements of CRF (20?m multistage shuttle run test), upper limb strength (hand grip strength), lower limb strength (standing long jump), and muscular endurance (sit-ups). The clustered cardiometabolic risk (CCMR) was estimated by summing standardized Z-scores of body mass index (BMI), mean arterial pressure (MAP), non-high-density lipoprotein cholesterol (non-HDL-C), and HbA1c. Results Linear regression analysis showed that all PF factors except for muscular endurance were inversely correlated with CCMR (P?

Camp-based multi-component intervention for families of young children with type 1 diabetes: A pilot and feasibility study

Background Managing type 1 diabetes mellitus (T1DM) in preschool-aged children has unique challenges that can negatively impact glycemic control and parental coping. Objective To evaluate the impact of a camp-based multi-component intervention on glycated hemoglobin A1c (HbA1c) in young children with T1DM and psychosocial measures for their parents. Subjects and methods Two separate cohorts of 18 children (ages 3-5?years) and their families participated in a camp-based intervention that included didactic and interactive parent education, child-centered education and family-based recreational activities. In Camp 1.0, measures of HbA1c, parental fear of hypoglycemia, mealtime behaviors and quality of life (QOL) were compared before and after an initial session (I) and follow-up booster session (II) 6?months later. Based on these results, the intervention was consolidated into 1 session (Camp 2.0) and repeated with additional measures of parental stress and parental self-efficacy with diabetes management tasks. Results Participants in Camp 2.0 exhibited a significant decrease in mean HbA1c level (?0.5%, P?=?.002) before and after camp. Mothers exhibited a significant improvement in diabetes-specific QOL (Camp 1.0/Session I and Camp 2.0) and reduction in stress as measured on the Pediatric Inventory for Parent (PIP) assessment (Camp 2.0). The booster session in Camp 1.0 showed no added benefit. Conclusions A family centered, camp-based multi-component intervention in young children with T1DM improved HbA1c and perceived QOL and stress in their mothers.

No change in type 2 diabetes prevalence in children and adolescents over 10 years: Update of a population-based survey in South Germany

Objective of this study was to analyze prevalence changes in type 2 diabetes (T2D) among children and adolescents over the last 10?years. We performed a cross-sectional survey in Baden-W�rttemberg (BW), Germany, by using a written questionnaire and comparing these results with T2D prevalence data from the same area retrieved in 2004/2005. In 2016, 50 patients with T2D under 20 years of age were registered in BW, Germany, which corresponds to a prevalence rate of 2.42 per 100?000 (95% confidence interval [CI]: 1.75-3.09). The prevalence rate found in the same geographic area 10?years prior was 2.30 per 100?000 (95% CI: 1.70-2.90). Overall, 70% of T2D patients of this age group were treated by adult diabetologists. Concisely the prevalence of T2D in children and adolescents is still low in South Germany, remaining practically unchanged over the past decade.

Enteroinsular hormones in two siblings with Donohue syndrome and complete leptin deficiency

The main biochemical hallmark of the rare and lethal condition of Donohue syndrome (DS) is hyperinsulinemia. The roles of the gut and other pancreatic hormones involved in glucose metabolism, satiety and energy expenditure have not been previously reported in DS. Two siblings with genetically confirmed DS and extremely low weight underwent a mixed meal (MM) test where pancreatic hormones insulin, C-peptide, glucagon, active amylin, pancreatic polypeptide (PP) as well as gut hormones active glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), ghrelin, peptide YY (PYY) and leptin were analyzed using a Multiplex assay. Results were compared to those of 2 pediatric controls. As expected, concentrations of insulin, C-peptide and amylin were very high in DS cases. The serum glucagon concentration was undetectable at the time of hypoglycemia. GIPs concentrations were lower in the DS, however, this was not mimicked by the other incretin, GLP-1. Ghrelin concentrations were mainly undetectable (<13.7 pg/mL) in all participants. DS cases had higher PYY and dampened PP concentrations. Leptin levels remained completely undetectable (<137.0 pg/mL). Patients with DS have extremely high amylin levels, completely undetectable serum glucagon and leptin levels with abnormal satiety regulating hormone PP with a relatively normal ghrelin response during a MM test. The low serum GIP might be acting as physiological brake on insulin secretion. The undetectable serum leptin levels suggest the potential of using leptin analogues as therapy for DS patients.

Hospital admission in children and adolescents with or without type 1 diabetes from Germany: An analysis of statutory health insurance data on 12 million subjects

Objective To compare the chance of hospital admissions in children and adolescents with type 1 diabetes (T1D) to that without T1D from Germany. Methods Data were provided by the German information system for health care data which contains information on all patients with a statutory health insurance. The years 2009 and 2011 were considered. Children and adolescents (0 to ?19 years of age; n =?12?030?242) were included. Unadjusted odds ratios (ORs) with 95% confidence interval (95% CI) were used to compare the hospitalization rate for patients with (n =?26?444) or without T1D (12?003?798). T1D was identified by documented insulin treatment and by ICD-code E10/14. Results were stratified by age-group (0-5; >5-10; >10-15, >15-19 years) and gender. Results In all age-groups, the hospitalization chance in patients with T1D was higher compared to that of their peers (database 2011). The highest OR was observed in >5 to 10-year-old patients (OR 8.1; 95% CI: 7.7-8.5), followed by patients >10 to 15 years (OR 7.4; 95% CI: 7.1-7.7) and patients ?5?years (OR 5.3; 95% CI: 4.8-5.7). The lowest OR was present in patients >15 to 19 years (OR 4.0; 95% CI: 3.9-4.2). Overall, OR for hospital admission were higher in girls with T1D compared to boys. The most frequent reasons for hospitalization in T1D were ?T1D without complications? (68.4%) and ?T1D with ketoacidosis? (18.6%). Conclusions Children and adolescents with T1D in Germany had a 4 to 8 times higher hospitalization chance compared to children without T1D. The OR in T1D patients compared to peers were higher in girls than in boys. High rates of elective hospital admission in Germany may contribute to these results.

Risk of recurrent severe hypoglycemia remains associated with a past history of severe hypoglycemia up to 4?years: Results from a large prospective contemporary pediatric cohort of the DPV initiative

Objectives In a contemporary cohort of youth with type 1 diabetes, we examined the interval between episodes of severe hypoglycemia (SH) as a risk factor for recurrent SH or hypoglycemic coma (HC). Methods This was a large longitudinal observational study. Using the DPV Diabetes Prospective follow-up data, we analyzed frequency and timing of recurrent SH (defined as requiring assistance from another person) and HC (loss of consciousness or seizures) in 14?177 youths with type 1 diabetes aged <20 years and at least 5?years of follow-up. Results Among 14?177 patients with type 1 diabetes, 72% (90%) had no, 14% (6.8%) had 1 and 14% (3.2%) >1 SH (HC). SH or HC in the last year of observation was highest with SH in the previous year (odds ratio [OR] 4.7 [CI 4.0-5.5]/4.6 [CI 3.6-6.0]), but remained elevated even 4?years after an episode (OR 2.0 [CI 1.6-2.7]/2.2 [CI 1.5-3.1]). The proportion of patients who experienced SH or HC during the last year of observation was highest with SH/HC recorded during the previous year (23% for SH and 13% for HC) and lowest in those with no event (4.6% for SH and 2% for HC) in the initial 4?years of observation. Conclusions Even 4?years after an episode of SH/HC, risk for SH/HC remains higher compared to children who never experienced SH/HC. Clinicians should continue to regularly track hypoglycemia history at every visit, adjust diabetes education and therapy in order to avoid recurrences.

Asthma in children and adolescents with type 1 diabetes in Germany and Austria: Frequency and metabolic control

Objective To investigate the prevalence of asthma in young patients with type 1 diabetes mellitus (T1D) from Austria and Germany and its influence on their metabolic control. Methods This prospective, multicenter observational cohort study was based on the DPV-registry (German/Austrian DPV initiative) including 51?926 patients with T1D (<20 years). All clinical data were documented prospectively. To identify patients with additional asthma, the entry of the diagnosis asthma as well as asthma medication was used for classification. Results 1755 patients (3.4%) of the cohort had the diagnosis asthma or received asthma-specific drugs. Patients with asthma needed higher insulin doses (0.88?�?0.3 vs 0.84?�?0.3 U/kg, P?

Hypoglycemia in sulfonylurea-treated KCNJ11-neonatal diabetes: Mild-moderate symptomatic episodes occur infrequently but none involving unconsciousness or seizures

Background Neonatal diabetes mellitus (NDM) caused by mutations in KCNJ11 can be successfully treated with high dose oral sulfonylureas; however, little data is available on the risk of hypoglycemia. Objective To determine the frequency, severity, and clinical significance of hypoglycemia in KCNJ11-related NDM. Methods Utilizing the University of Chicago Monogenic Diabetes Registry, parents completed an online questionnaire addressing hypoglycemia. Continuous glucose monitoring (CGM) data was available for 7 subjects. Results Thirty subjects with KCNJ11-related permanent NDM (166 patient-years on sulfonylurea) had median sulfonylurea dose of 0.39 mg/kg/day (0.24-0.88 IQR, interquartile range) with median HbA1c 5.7% (39 mmol/mol) (5.5-6.1 IQR, 37-43 mmol/mol). Hypoglycemia (<70 mg/dL) was reported monthly once or less frequently in 89.3% of individuals, but 3 (10.7%) reported once weekly or more. Of all hypoglycemic episodes reported, none involved seizures or unconsciousness and thus did not meet the current ISPAD definition of severe hypoglycemia. Seven individuals wore a CGM for a total of 912 hours with blood sugars falling below 70 mg/dL for 5.8% of the time recorded, similar to ranges reported for people without diabetes. Conclusions In our cohort of KCNJ11-related permanent NDM, hypoglycemia is infrequent and mild despite the high doses of sulfonylurea used and near-normal level of glycemic control. Long-term follow-up on larger numbers will be required to clarify the incidence and determinants of hypoglycemia in this unique population.

The proportion of familial cases of type 1 diabetes is increasing simultaneously with the disease incidence: Eighteen years of the Israeli Pediatric Diabetes Registry

Background The global rise in incidence of type 1 diabetes (T1D) is too rapid to be attributed to susceptible genetic background, pinpointing a significant role for environmental factors. Unlike the theory that the need for genetic susceptibility has lessened over time, we hypothesized that the rise in T1D incidence is faster in a genetically susceptible population. Subjects and methods The study population comprised of 5080 patients aged 0 to 17 years who were reported to the National Israel Diabetes Registry between 1997 and 2014. The patients were divided into familial cases (first-degree relative has T1D), and sporadic cases. Demographic and clinical data were retrieved from the registry. The change in annual percent (from the entire cohort) was computed separately for the sporadic and familial cohorts. Results The familial (n?=?546; 10.7%) and sporadic (n?=?4534; 89.3%) cases were comparable for gender, ethnicity, and age at diagnosis. Consanguinity was more common in the familial vs sporadic group (10% vs 6.1%; P?=?.001). The average annual percent change increased by 1.9% in the familial cases and decreased by 0.2% in the sporadic cases (P?=?.04). Conclusions The rapid rise in the proportion of familial cases of T1D suggests that environmental factors impose higher diabetogenic pressure in patients with a susceptible genetic background.

FOXP3 mutations causing early-onset insulin-requiring diabetes but without other features of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome

Diabetes occurs in 1/90?000 to 1/160?000 births and when diagnosed under 6?months of age is very likely to have a primary genetic cause. FOXP3 encodes a transcription factor critical for T regulatory cell function and mutations are known to cause ?immune dysregulation, polyendocrinopathy (including insulin-requiring diabetes), enteropathy, X-linked? (IPEX) syndrome. This condition is often fatal unless patients receive a bone-marrow transplant. Here we describe the phenotype of male neonates and infants who had insulin-requiring diabetes without other features of IPEX syndrome and were found to have mutations in FOXP3. Whole-exome or next generation sequencing of genes of interest was carried out in subjects with isolated neonatal diabetes without a known genetic cause. RT-PCR was carried out to investigate the effects on RNA splicing of a novel intronic splice-site variant. Four male subjects were found to have FOXP3 variants in the hemizygous state: p.Arg114Trp, p.Arg347His, p.Lys393Met, and c.1044+5G>A which was detected in 2 unrelated probands and in a brother diagnosed with diabetes at 2.1?years of age. Of these, p.Arg114Trp is likely a benign rare variant found in individuals of Ashkenazi Jewish ancestry and p.Arg347His has been previously described in patients with classic IPEX syndrome. The p.Lys393Met and c.1044+5G>A variants are novel to this study. RT-PCR studies of the c.1044+5G>A splice variant confirmed it affected RNA splicing by generating both a wild type and truncated transcript. We conclude that FOXP3 mutations can cause early-onset insulin-requiring diabetes with or without other features of IPEX syndrome.

Impaired fasting glucose and the metabolic profile in Danish children and adolescents with normal weight, overweight, or obesity

Objective Whether the definitions of impaired fasting glucose (IFG) from the American Diabetes Association (ADA) and the World Health Organization (WHO) differentially impact estimates of the metabolic profile and IFG-related comorbidities in Danish children and adolescents is unknown. Methods Two thousand one hundred and fifty four (979 boys) children and adolescents with overweight or obesity (median age 12 years) and 1824 (728 boys) children with normal weight (median age 12 years) from The Danish Childhood Obesity Biobank were studied. Anthropometrics, blood pressure, puberty, and fasting concentrations of glucose, insulin, glycosylated hemoglobin (HbA1c), and lipids were measured. Results About 14.1% of participants with overweight or obesity exhibited IFG according to the ADA and 3.5% according to the WHO definition. Among individuals with normal weight, the corresponding prevalences were 4.3% and 0.3%. IFG was associated with a higher systolic blood pressure, higher concentrations of HbA1c, insulin, C-peptide (P?

Safety and efficacy of autoantigen-specific therapy with 2 doses of alum-formulated glutamate decarboxylase in children with multiple islet autoantibodies and risk for type 1 diabetes: A randomized clinical trial

Objective Treatments have failed to delay or stop the autoimmune process, preceding onset of type 1 diabetes. We investigated if autoantigen-specific treatment with alum-formulated glutamate decarboxylase (GAD-Alum) was safe and affected progression to type 1 diabetes in children with islet autoimmunity. Methods In an investigator-initiated, double-blind, placebo-controlled clinical trial, non-diabetic children aged 4 to 17.9?years with autoantibodies to glutamate decarboxylase (GADA) and at least one of insulinoma-associated protein 2, insulin or zinc-transporter 8, were randomized, stratified by 2 or ?3 islet autoantibodies, to 2 injections of 20 ?g GAD-Alum or placebo, 30?days apart. Main outcome was safety, investigated by adverse events, hematology, chemistry, thyroid and celiac autoimmunity and titers of islet autoantibodies, and efficacy, investigated by cumulative incidence of diabetes onset over 5-year follow-up. Secondary variables: change in first-phase insulin release (FPIR) after intravenous glucose tolerance tests, fasting, 120 minutes and Area under the curve (AUC) C-peptide and p-glucose after oral glucose tolerance tests and HbA1c. Results Fifty children (median age: 5.2) were assigned 1:1 to GAD-Alum or placebo, all receiving full treatment and included in the analyses. GAD-Alum did not affect any safety parameter, while GADA titers increased (P?=?.001). Time to clinical diagnosis was not affected by treatment (hazard ratio, HR?=?0.77, P?=?.574) in the full population or in the separate stratum groups. Treatment did not affect any of the secondary variables. Conclusions GAD-Alum as a subcutaneous prime and boost injection was safe in prediabetic young children but did not affect progression to type 1 diabetes. The safety of GAD-Alum should prove useful in future prevention studies.

Cardiovascular autonomic dysfunction predicts increasing albumin excretion in type 1 diabetes

Objective To determine the potential role of cardiovascular autonomic dysfunction in the development of renal complications in young people with type 1 diabetes (T1D). Methods In this prospective study, 199 children and adolescents recruited to the Oxford Regional Prospective Study underwent assessment of autonomic function ~5?years after diagnosis, and were subsequently followed with longitudinal assessments of HbA1c and urine albumin-creatinine ratio (ACR) over 8.6?�?3.4?years. Autonomic function was assessed with 4 standardized tests of cardiovascular reflexes: heart rate (HR) response to (1) Valsalva Maneuver, (2) deep breathing, (3) standing, and (4) blood pressure (BP) response to standing. Linear mixed models were used to assess the association between autonomic parameters and future changes in ACR. Results Independent of HbA1c, each SD increase in HR response to Valsalva Maneuver predicted an ACR increase of 2.16% [95% CI: 0.08; 4.28] per year (P?=?.04), while each SD increase in diastolic BP response to standing predicted an ACR increase of 2.55% [95% CI: 0.37; 4.77] per year (P?=?.02). The effect of HR response to standing on ACR reached borderline significance (?2.07% [95% CI: ?4.11; 0.01] per year per SD increase, P?=?.051). Conclusions In this cohort of young people with T1D, enhanced cardiovascular reflexes at baseline predicted future increases in ACR. These results support a potential role for autonomic dysfunction in the pathogenesis of diabetic nephropathy.

Feasibility and pilot study of an intervention to support active lifestyles in youth with type 1 diabetes: The ActivPals study

Background Evidence suggests youth with type 1 diabetes (T1D) have lower levels of physical activity (PA) than the general population. The ActivPals intervention aimed to support youth with T1D to lead an active lifestyle. Methods Twenty youth aged 7 to 16?years with T1D were recruited to a pilot randomized controlled trial. PA and quality of life (QoL) were measured using Actigraph GT3X+ monitor and Pediatric QoL scales at baseline and 1-month follow-up. A two-way, mixed ANOVA showed indicative effects of the intervention. Qualitative interviews were carried out with 16 participants to explore perceptions of the intervention. Results An increase in moderate to vigorous PA was reported in intervention and control groups from baseline to follow-up (F(1, 14)?=?5.83; P?=?.03), with no significance between group differences. Participants in both groups reported significantly less overall diabetes ?problems? (F(1, 16)?=?7.93; P?=?.012) and significantly less lifestyle ?problems? (F(1, 16)?=?7.39; P?=?.015) at follow-up. However, both groups also reported significant increases in ?problems? with the day-to-day diabetes routine (F(1,16)?=?6.48; P?=?.022) at follow-up. Parents reported significant increased worry about their child's diabetes at follow-up, in both groups (F(1, 14)?=?5.83; P?=?.046). There was no significant increase in reported hypoglycemic occurrences despite increased PA. The qualitative data highlight that goal setting, self-monitoring, and social support were effective motivators for increasing PA. Conclusions A larger trial with longer follow-up should be conducted to explore the effect of the intervention on PA in youth with T1D.

Randomized, double-blind, placebo-controlled dose-finding study of the dipeptidyl peptidase-4 inhibitor linagliptin in pediatric patients with type 2 diabetes

Objective To identify the dose of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin in pediatric patients with type 2 diabetes (T2D). Methods Double-blind, randomized, controlled parallel group study comparing linagliptin 1 and 5?mg once daily, with placebo in 39 patients with T2D aged 10 to below 18 years. The primary efficacy endpoint was the change from baseline in glycated hemoglobin (HbA1c) after 12 weeks of treatment. The key pharmacodynamic endpoint was DPP-4 inhibition during steady-state. Results Compared to placebo, there was a dose-dependent reduction in mean HbA1c of 0.48% and 0.63% with linagliptin 1 and 5?mg, respectively, associated with corresponding declines in mean fasting plasma glucose (FPG) of 5.6 and 34.2?mg/dL. Median DPP-4 inhibition was 38% with linagliptin 1?mg and 79% with linagliptin 5?mg. Geometric mean trough levels of linagliptin were 3.80 and 7.42?nmol/L in the 1 and 5?mg groups, respectively; levels that were slightly higher than in adult patients with T2D that were most likely caused by higher plasma DPP-4 concentrations in the study population. There were no drug-related adverse events during treatment with either dose of linagliptin. Conclusions Linagliptin was well tolerated and induced dose-dependent DPP-4 inhibition that was accompanied by corresponding reductions in HbA1c and FPG levels in young people with T2D. The results are consistent with the clinical efficacy and safety profile that have been reported for linagliptin in adult patients with T2D, favoring linagliptin 5?mg over 1?mg.

Low-grade inflammation and muscular fitness on insulin resistance in adolescents: Results from LabMed Physical Activity Study

Background Low muscular fitness (MF) and low-grade inflammation has been linked to insulin resistance (IR). Objective To evaluate the associations between MF and a clustered score of inflammatory biomarkers on IR and to investigate the combined impact of MF and inflammation on IR in adolescents. Methods This is a cross-sectional analysis with 529 adolescents (267 girls) aged 12 to 18 years. Pubertal stage, socioeconomic status, adherence to the Mediterranean diet, cardiorespiratory fitness, and waist circumference were assessed. Standing long-jump and isometric handgrip dynamometry were used as indicators of MF. Continuous score of clustered inflammatory biomarkers (InflaScore) (sum of Z-scores of C-reactive protein, C3, C4, fibrinogen, and leptin) and IR (homeostasis model assessment of insulin resistance [HOMA-IR] estimated from fasting serum insulin and glucose) were assessed. Results HOMA-IR and fasting insulin were positively associated with InflaScore and negatively associated with MF, independently of age, sex, pubertal stage, socioeconomic status, adherence to the Mediterranean diet, cardiorespiratory fitness, and waist circumference. Adolescents classified as High InflaScore/Unfit showed significantly higher HOMA-IR when compared than those with High InflaScore/Fit and those with Low InflaScore/Fit (F(3,519)?=?4.761, P?

The influence of body mass index and age on C-peptide at the diagnosis of type 1 diabetes in children who participated in the diabetes prevention trial-type 1

Background/Objective The extent of influence of BMI and age on C-peptide at the diagnosis of type 1 diabetes (T1D) is unknown. We thus studied the impact of body mass index Z-scores (BMIZ) and age on C-peptide measures at and soon after the diagnosis of T1D. Methods Data from Diabetes Prevention Trial-Type 1 (DPT-1) participants <18.0?years at diagnosis was analyzed. Analyses examined associations of C-peptide measures with BMIZ and age in 2 cohorts: oral glucose tolerance tests (OGTTs) at diagnosis (n?=?99) and mixed meal tolerance tests (MMTTs) <6?months after diagnosis (n?=?80). Multivariable linear regression was utilized. Results Fasting and area under the curve (AUC) C-peptide from OGTTs (n?=?99) at diagnosis and MMTTs (n?=?80) after diagnosis were positively associated with BMIZ and age (P?

Hvidoere Smiley Faces: International diabetes quality of life assessment tool for young children

Background Few diabetes-specific quality of life (QOL) tools are available for young children. Objectives To design and evaluate, a new age-specific QOL questionnaire and its associations with treatment regimens and metabolic control. Methods Clinical, demographic data and centrally analyzed HbA1c were collected on 1133 children <11?years (girls 48%; mean?�?SD age 8.0?�?2.1?years; diabetes duration ?1?year) from 18 centers (Europe, Japan, North America and Australia). Children completed the 10-item Smiley Faces QOL questionnaire constructed for the study, and children ?7?years also completed the KIDSCREEN-10 Index. Results In total, 1035 children completed the new Smiley Faces questionnaire which was well understood by 993 (70% ?4?years and 96% ?5?years, respectively). Internal consistency and reliability were good (Cronbach's ??=?.73). Inter-item correlation ranged r?=?0.047 to 0.451 indicating each item measures separate aspects of children's satisfaction construct. Convergent validity assessed by comparison to the HrQOL KIDSCREEN-10 Index showed moderate correlation coefficient 0.501. Factor analysis revealed 3 factors explaining 51% of the variance. Children reported good QOL with most items positive, mean values between 1 and 2 on a 5-point scale (lower scores indicating greater QOL). Diabetes satisfaction was unrelated to age, diabetes duration, HbA1c, or severe hypoglycemia. Girls were more satisfied than boys. Children on intensive regimens reported better QOL (P?

Thrombocytopenia-associated multi-organ failure secondary to hyperglycemic, hyperosmolar non-ketotic syndrome: A case report

Thrombocytopenia associated multi-organ failure (TAMOF) is a clinical syndrome with features of new onset thrombocytopenia, increased lactate dehydrogenase, and multi-organ failure in critically ill patients. TAMOF can be the initial presentation of an underlying disease process or can develop during the course of illness either during the hospital stay. TAMOF has a high mortality rate if not treated; therefore, early detection is critical. TAMOF has been rarely reported in diabetic ketoacidosis. We are describing the first case of a patient diagnosed with hyperglycemic, hyperosmolar non-ketotic syndrome who developed TAMOF on the third day of his hospital course. In addition to supportive care in the intensive care unit the patient received serial therapeutic plasma exchanges and improved quickly after treatment. Early diagnosis and treatment of TAMOF decreases morbidity and mortality.

Predictive hyperglycemia and hypoglycemia minimization: In-home double-blind randomized controlled evaluation in children and young adolescents

Objective The primary objective of this trial was to evaluate the feasibility, safety, and efficacy of a predictive hyperglycemia and hypoglycemia minimization (PHHM) system vs predictive low glucose suspension (PLGS) alone in optimizing overnight glucose control in children 6 to 14 years old. Research Design and Methods Twenty-eight participants 6 to 14 years old with T1D duration ?1?year with daily insulin therapy ?12 months and on insulin pump therapy for ?6?months were randomized per night into PHHM mode or PLGS-only mode for 42 nights. The primary outcome was percentage of time in sensor-measured range 70 to 180?mg/dL in the overnight period. Results The addition of automated insulin delivery with PHHM increased time in target range (70-180?mg/dL) from 66?�?11% during PLGS nights to 76?�?9% during PHHM nights (P<.001), without increasing hypoglycemia as measured by time below various thresholds. Average morning blood glucose improved from 176?�?28?mg/dL following PLGS nights to 154?�?19?mg/dL following PHHM nights (P<.001). Conclusions The PHHM system was effective in optimizing overnight glycemic control, significantly increasing time in range, lowering mean glucose, and decreasing glycemic variability compared to PLGS alone in children 6 to 14 years old.

Targets and teamwork: Understanding differences in pediatric diabetes centers treatment outcomes

Objective The reason for center differences in metabolic control of childhood diabetes is still unknown. We sought to determine to what extent the targets, expectations, and goals that diabetes care professionals have for their patients is a determinant of center differences in metabolic outcomes. Research Design and Methods Children, under the age of 11 with type 1 diabetes and their parents treated at the study centers participated. Clinical, medical, and demographic data were obtained, along with blood sample for centralized assay. Parents and all members of the diabetes care team completed questionnaires on treatment targets for hemoglobin A1c (HbA1c) and recommended frequency of blood glucose monitoring. Results Totally 1113 (53% male) children (mean age 8.0?�?2.1?years) from 18 centers in 17 countries, along with parents and 113 health-care professionals, participated. There were substantial differences in mean HbA1c between centers ranging from 7.3?�?0.8% (53?mmol/mol?�?8.7) to 8.9?�?1.1% (74?mmol/mol?�?12.0). Centers with lower mean HbA1c had (1) parents who reported lower targets for their children, (2) health-care professionals that reported lower targets and more frequent testing, and (3) teams with less disagreement about recommended targets. Multiple regression analysis indicated that teams reporting higher HbA1c targets and more target disagreement had parents reporting higher treatment targets. This seemed to partially account for center differences in Hb1Ac. Conclusions The diabetes care teams? cohesiveness and perspectives on treatment targets, expectations, and recommendations have an influence on parental targets, contributing to the differences in pediatric diabetes center outcomes.

The effect of impaired glucose metabolism on weight loss in multidisciplinary childhood obesity treatment

Objective To investigate whether children and adolescents exhibiting an impaired glucose metabolism are more obese at treatment entry and less likely to reduce their degree of obesity during treatment. Methods The present study is a longitudinal observational study, including children and adolescents from the Children's Obesity Clinic, Holb�k, Denmark. Anthropometrics, pubertal development, socioeconomic status (SES), and fasting concentrations of plasma glucose, serum insulin, serum C-peptide, and whole blood glycosylated hemoglobin (HbA1c) were collected at treatment entry and at follow-up. Proxies of Homeostasis Model Assessment 2-insulin sensitivity (HOMA2-IS) and Homeostasis Model Assessment 2-?-cell function (HOMA2-B) were calculated with the Homeostasis Model Assessment 2 program. Results In total, 569 (333 boys) patients, median 11.5?years of age (range 6-22?years), and median body mass index (BMI) z-score 2.94 (range 1.34-5.54) were included. The mean BMI z-score reduction was 0.31 (�0.46) after 13?months (range 6-18) of treatment. At treatment entry, patients with impaired estimates of glucose metabolism were more obese than normoglycemic patients. Baseline concentration of C-peptide was associated with a lower weight loss during treatment in girls (P?=?.02). Reduction in the insulin concentrations was associated with reduction in BMI z-score in both sexes (P?

The burden of common infections in children and adolescents with diabetes mellitus: A Pediatric Health Information System study

Background People with diabetes mellitus (DM) have increased infection risk. The healthcare utilization of pediatric and adolescent diabetic patients with infection is not well defined. This study evaluates the number of pediatric and adolescent patients with DM that seek medical treatment for infection management and assesses its socioeconomic impact. Methods A retrospective analysis was performed using the Pediatric Health Information System (PHIS) database on children and adolescents with DM who presented to the Emergency Department (ED) or were hospitalized for infection management from 2008 to 2014. The PHIS database collects admission, demographic, and economic data from 44 freestanding children's hospitals across the United States. Results In total, 123?599 diabetic patient encounters were identified (77% type 1 DM, 23% type 2 DM). ED visits and hospitalizations for type 1 DM and type 2 DM increased throughout the study period. Total charges for these encounters were greater than $250 million dollars per year and increased each year. Infection encounters make up more than 30% of that cost while accounting for only 14% of the visits. Respiratory infections were the most common type of infection followed by skin and soft tissue infections for both ED care and inpatient hospitalizations. Patients with infections had longer hospital length of stay and higher cost per day than those without infections. Conclusions Children and adolescents with type 1 and type 2 DM commonly present to the ED and require hospitalization for infection evaluation and management. Encounters with infection make up a large proportion of a growing economic burden on the United States? healthcare system. As the prevalence of DM grows, this burden can be expected to become even more significant. Cost-effective strategies for the prevention of infection in pediatric patients with DM are needed.

A Danish version of self-efficacy in diabetes self-management: A valid and reliable questionnaire affected by age and sex

Background Managing the chronic illness type 1 diabetes (T1D) is extremely demanding, especially during adolescence. Self-efficacy is belief in one?s own capabilities and this is crucial for diabetes management. Having a valid method for measuring self-efficacy is important. Objective Our aims were to psychometrically validate a Danish version of the self-efficacy in diabetes management (SEDM) questionnaire, and to examine the relationship between background variables and self-efficacy. Methods All Danish adolescents with T1D (n?=?1075) were invited to participate in our study. In total, 689 agreed to participate and 602 completed the study. Data were collected using a web-based survey. All participants were asked to provide a blood sample for HbA1c measurement. Graphical log-linear Rasch modeling (GLLRM) was used to validate the questionnaire and its reliability was assessed using Monte Carlo simulation. Results We found the questionnaire to be valid and reliable, but it had a dual structure that suggested a need for 2 separate subscales. One subscale related to practical (SEDM1) and the other to emotional (SEDM2) aspects of diabetes management. Both subscales were targeted toward adolescents with lower self-efficacy and were associated with HbA1c. SEDM1 was influenced by treatment modality and age. In SEDM2 we found an interaction between age and sex. Conclusion The Danish version of the SEDM questionnaire should be divided into two parts, each with a valid and reliable subscale for self-efficacy measurement. The relationship between self-efficacy and age seems to differ between boys and girls.

Genetics of type 1 diabetes

Type 1 diabetes (T1D) results from immune-mediated loss of pancreatic beta cells leading to insulin deficiency. It is the most common form of diabetes in children, and its incidence is on the rise. This article reviews the current knowledge on the genetics of T1D. In particular, we discuss the influence of HLA and non-HLA genes on T1D risk and disease progression through the preclinical stages of the disease, and the development of genetic scores that can be applied to disease prediction. Racial/ethnic differences, challenges and future directions in the genetics of T1D are also discussed.

Achieving ADA/ISPAD clinical guideline goals is associated with higher insulin sensitivity and cardiopulmonary fitness in adolescents with type 1 diabetes: Results from RESistance to InSulin in Type 1 ANd Type 2 diabetes (RESISTANT) and Effects of MEtformin on CardiovasculaR Function in AdoLescents with Type 1 Diabetes (EMERALD) Studies

Objective Most youth with type 1 diabetes do not meet the American Diabetes Association (ADA) and International Society for Pediatric and Adolescent Diabetes (ISPAD) targets for hemoglobin A1c (HbA1c), blood pressure (BP), lipids, and body mass index (BMI). We hypothesized that ISPAD/ADA goal achievement would be associated with better insulin sensitivity (IS) and cardiopulmonary fitness. Methods IS was quantified as glucose infusion rate (GIR) from a hyperinsulinemic-euglycemic clamp in youth with type 1 diabetes from the RESistance to InSulin in Type 1 ANd Type 2 diabetes (RESISTANT) (n = 86) and Effects of MEtformin on CardiovasculaR Function in AdoLescents with Type 1 Diabetes (EMERALD) (n = 41) cohorts (n = 127; age 15.7 � 2.2 years, 52% girls). Cardiopulmonary fitness was measured as peak oxygen consumption (VO2peak/kg) during upright (RESISTANT) or supine (EMERALD) cycle ergometry and were stratified by cycle type. Goal achievement was defined as HbA1c < 7.5%, BP < 90th percentile, LDL-cholesterol < 100 mg/dL, HDL-cholesterol > 35 mg/dL, triglycerides < 150 mg/dL and BMI < 85th percentile. Participants were stratified into 3 groups: achieving 0-3 goals (n = 52), 4 goals (n = 48), and 5-6 goals (n = 27). Differences between groups were examined with generalized linear models. Results IS was lower in youth who met 0-3 goals (5.2 � 3.4 mg/kg/min) vs those who met 4 goals (7.4 � 4.1 mg/kg/min, P = .04) and those who met 5-6 goals (8.5 � 4.3 mg/kg/min, P = .003), and remained significant after adjustments for sex and diabetes duration. Upright VO2peak was lower in youth who met 0-3 goals (25.8 � 4.6 mL/kg/min) vs those who met 4 goals (33.0 � 7.8 mL/kg/min, P = .01) and those who met 5-6 goals (33.2 � 4.4 mL/kg/min, P = .004). Similar and significant relationships were observed in EMERALD participants for supine VO2peak. Conclusions ADA/ISPAD goal achievement was associated with greater IS and cardiopulmonary fitness.

Handgrip strength is associated with insulin resistance and glucose metabolism in adolescents: Evidence from National Health and Nutrition Examination Survey 2011 to 2014

Background Previous studies have reported that handgrip strength, a measure of muscular fitness, is associated with insulin resistance in children and adolescents, with conflicting results. Further, no studies have examined the association between handgrip strength with 2-hour glucose levels. Objective We tested the association of handgrip strength with measures of insulin resistance (fasting insulin and homeostasis model assessment of insulin resistance [HOMA-IR]) and glucose metabolism (fasting and 2-hour glucose levels) in adolescents from the National Health and Nutrition Examination Survey (NHANES) 2011 to 2014. Methods The study included 959 participants aged 12 to 19 years who underwent a handgrip test and a glucose tolerance test. General linear models were used to examine the associations between handgrip strength and the outcome variables. Results After adjustment for age, race, sex, body mass index, and physical activities, handgrip strength was inversely associated with fasting insulin levels (P?=?.017) and HOMA-IR (P?=?.025). Although there was no association between handgrip strength and fasting glucose levels (P?=?.77), handgrip strength was inversely associated with 2-hour glucose levels (P?

Adherence to a lifestyle program for youth with type 2 diabetes and its association with treatment outcome in the TODAY clinical trial

Objective To assess the association of proxies of behavioral adherence to the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) lifestyle program with changes in glycemic control and obesity in a multi-ethnic sample of youth with type 2 diabetes. Methods The TODAY clinical trial included an intensive lifestyle intervention to promote weight reduction. Adherence was assessed with measures of attendance at intervention sessions and rates of self-monitoring of diet and physical activity by participants and their caregivers. The relation between participant characteristics and consistency of proxies of adherence were examined across 3 phases of intervention. Results A total of 234 TODAY youth were randomized to the lifestyle program. Overall rate of session attendance was approximately 60% of planned sessions. Participants with an adequate dose of session attendance (?75% attended) did not differ from those who attended <75% of sessions in glycemic control, but did have significantly greater reductions in percent overweight compared with those who attended fewer than 75% of sessions. Rates of self-monitoring were low and additional analysis was not possible. Conclusions Rates of session attendance were moderate in a lifestyle program for youth with type 2 diabetes, but levels of self-monitoring, considered a key lifestyle change behavior, were low. Glycemic control was not significantly associated with session attendance but reductions in percent overweight were. Given the salience of program attendance and self-monitoring to lifestyle weight management established in other populations, future research is needed to understand, develop, and promote strategies and interventions targeting weight loss to achieve improved glycemic control in youth diagnosed with type 2 diabetes.

Longitudinal follow up of dysglycemia in overweight and obese pediatric patients

Objective To examine factors related to progression of dysglycemia in overweight and obese youth in a large primary care setting. Research design and methods 10- to 18-year-old youth with body mass index (BMI) > 85 percentile and first-time A1c 5.7%-7.9% (39-63 mmol/mol) were identified retrospectively through electronic medical records (EMR). Levels of dysglycemia were defined as low-range prediabetes (LRPD; A1c 5.7%-5.9% [39-41 mmol/mol]), high-range prediabetes (HRPD; A1c 6.0%-6.4% [42-46 mmol/mol]), or diabetes-range (A1c 6.5%-7.9% [48 mmol/mol]). Follow-up A1c and BMI were extracted from the EMR. Follow up was truncated at the time of initiation of diabetes medication. Results Of 11 000 youth, 547 were identified with baseline dysglycemia (mean age 14.5 � 2.2 years, 70% Hispanic, 23% non-Hispanic Black, 7% other). Of these, 206 had LRPD, 282 HRPD, and 59 diabetes. Follow-up A1c was available in 420 (77%), with median follow up of 12-22 months depending on A1c category. At follow-up testing, the percent with diabetes-range A1c was 4% in youth with baseline LRPD, 8% in youth with baseline HRPD, and 33% in youth with baseline diabetes-range A1c. There was a linear association between BMI increase and worsening A1c for LRPD (P < .001) and HRPD (P = .003). Conclusions Most adolescents with an initial prediabetes or diabetes-range A1c did not have a diabetes-range A1c on follow up. Moreover, prediabetes-range A1c values do not all convey equal risk for the development of diabetes, with lower rates of progression for youth with initial A1c <6%. In youth with prediabetes-range A1c, BMI stabilization was associated with improvement of glycemia.

Insulin sensitivity across the lifespan from obese adolescents to obese adults with impaired glucose tolerance: Who is worse off?

Objective Youth type 2 diabetes mellitus (T2DM) occurs decades earlier than adult T2DM and is characterized by high therapeutic failure rates and decreased response to insulin sensitizers suggesting a more severe disease process than in adults. To explain these observations, we hypothesized that insulin resistance is worse in obese youth than adults with impaired glucose tolerance (IGT), a state of high-risk for T2DM. As proof-of-concept, we compared insulin sensitivity between BMI-, sex-, and race-matched obese youth vs adults with IGT. Methods This retrospective analysis of IGT youth and adults included 34 obese adolescents matched (2:1) for BMI, sex, and race to 17 adults. Hepatic and peripheral insulin sensitivity were measured by [6,6-2H2]glucose and hyperinsulinemic-euglycemic clamp. Body composition (DEXA) and serum lipid profile were examined. Results Despite similar percent body fat, obese adolescents had 2-fold higher fasting insulin concentration, lower hepatic (~53%) and peripheral (~42%) insulin sensitivity and lower HDL compared with adults (all P < .01). Surrogate estimate of insulin sensitivity, 1/fasting insulin was lower and HOMA-IR was higher in adolescents vs adults. Adults had a more atherogenic lipid profile with higher total-, LDL-, and non-HDL cholesterol. Conclusions Obese youth and adults with IGT differ in that youth are more insulin resistant than adults in spite of similar adiposity. This could potentially explain the earlier onset of T2DM in youth through an early and amplified burden on a ?-cell destined to decompensate, and explicate their lower therapeutic response to insulin sensitizers.

Effect of obesity and type 2 diabetes, and glucose ingestion on circulating spexin concentration in adolescents

Spexin is a novel peptide that has been reported to be down regulated in obese adults and children and in normoglycemic adults following glucose ingestion. Spexin may therefore have a role in metabolic regulation. The purpose of the current study was to determine the effect of obesity and type 2 diabetes (T2DM), and the effect of glucose ingestion on circulating spexin concentration in adolescents. Boys and girls (mean age 16 years old) classified as healthy normal weight (NW, n = 22), obese (Ob, n = 10), or obese with T2DM (n = 12) completed measurements of body composition, blood pressure, cardiorespiratory fitness, and blood concentrations of glucose, insulin, and lipids. The median fasting serum spexin concentration did not differ between groups (NW: 0.35; Ob: 0.38, T2DM: 0.34 ng/mL, respectively). In 10 NW participants who completed a standard oral glucose tolerance test, spexin concentration was unchanged at 30 and 120 minutes relative to the fasting baseline. Finally, spexin was not significantly correlated with any of the body composition, fitness, or blood biochemical measurements. These data do not support the proposed role of spexin as a metabolic regulator or biomarker of glucose control in adolescents.

Serum and gene expression levels of CT-1, IL-6, and TNF-? after a lifestyle intervention in obese children

Background Inflammation related molecules such as tumor necrosis factor-? (TNF-?), interleukin 6 (IL-6), and cardiotrophin-1 (CT-1) are highly expressed in obese individuals and could partly explain some comorbidities associated to obesity. In obese children, lifestyle interventions are able to lower inflammation and reduce cardiovascular risk factors associated with obesity. The aim of the present work was to study changes in inflammation-related molecules serum and peripheral blood mononuclear cells (PBMC) transcript levels after a 10-week lifestyle intervention in obese children and asses their potential association with glucose metabolism. Methods Twenty-three obese children (mean age 11.5 years; 48% males) underwent a 10-week lifestyle not controlled intervention trial. Anthropometric and biochemical measurements were analyzed. Transcript analysis for CT-1, IL-6, and TNF-? in PBMC were performed by RT-PCR. Serum cytokine levels were also measured at baseline and after 10-weeks. Results Participants achieved a significant reduction in body adiposity (0.34 decrease in body mass index-standard deviation), total cholesterol, and glucose levels after 10-weeks. A Significant decrease in serum TNF-? and C reactive protein (CRP) were observed. CT-1 transcript levels were significantly reduced (P = .005) after lifestyle intervention, and these changes were significantly correlated with changes in serum CT-1 levels (r = 0.451; P = .031). In multiple regression analysis baseline CT-1 transcript levels were positively associated with final insulin (R2 = 0.506; P = .035) and HOMA-IR values (R2 = 0.473; P = .034). Conclusions We reported that serum CRP, TNF-?, as well as PBMC CT-1 transcript levels were reduced after lifestyle intervention in obese children. More studies are needed to clarify the role of inflammation-related molecules in glucose metabolism.

Insulin resistance is higher in prepubertal girls but switches to become higher in boys at age 16: A Cohort Study (EarlyBird 57)

Background The risk of type 2 diabetes is increasing in teenage girls, and is associated with their greater insulin resistance (IR). Hypothesis We hypothesized that the adverse metabolic profile of girls (compared with boys) would persist from childhood through adolescence. Patients and Methods Community-based longitudinal cohort of 292 children (147 boys) studied annually from 9 to 16 years. Measures: IR (homeostasis-model-assessment-2), high-density lipoprotein-cholesterol (HDL-C), triglycerides, % body-fat (dual-energy x-ray absorptiometry), pubertal stage (age at peak height velocity), physical activity (accelerometry). Multi-level modelling established the age-related trends in IR and lipids and the influence of covariates. Results Each year from 9 to 15 years, girls had 21% to 63% higher IR than boys (girls mean IR 0.73-1.33, boys 0.51-0.89, P < .005). At 16 years the gender difference was not significant (girls IR 0.60, boys 0.56, P = .45). Girls had lower HDL-C from 9 to 12 years, higher triglycerides from 9 to 14 years, greater adiposity throughout, and earlier puberty, but boys were more active than girls (all P < .05). After adjustment for %-fat, puberty and activity, the gender difference in IR between girls and boys aged 9 to 15 years became non-significant (IR girls 0.66-1.01, boys 0.65-1.04, P > .07). However, after adjustment at 16 years, girls? IR was 25% lower than boys? (girls 0.44, boys 0.63, P = .001), and they had 22% higher HDL-C (P < .001) and 20% lower triglycerides (P = .003). Conclusions The higher IR of prepubertal and early pubertal girls diminishes during late puberty, and boys begin to exhibit greater metabolic risk. Despite being leaner and more active, boys at 16 years have higher IR than girls, suggesting future higher risk for diabetes, thus we reject our hypothesis.

NIRCa: An artificial neural network-based insulin resistance calculator

Background Direct measurement of insulin sensitivity in children with type 1 diabetes is cumbersome and time consuming. Objective The aim of our study was to develop novel, accurate machine learning-based methods of insulin resistance estimation in children with type 1 diabetes. Methods A hyperinsulinemic hyperglycemic clamp study was performed to evaluate the glucose disposal rate (GDR) in a study group consisting of 315 patients aged 7.6 to 19.7 years. The group was randomly divided into a training and independent testing set for model performance assessment. GDR was estimated on the basis of simple clinical variables using 2 non-linear methods: artificial neural networks (ANN) and multivariate adaptive regression splines (MARSplines). The results were compared against the most frequently used predictive model, based on waist circumference, triglyceride (TG), and HbA1c levels. Results The reference model showed moderate performance ( R 2 = 0.26) with a median absolute percentage error of 49.1%, and with the worst fit observed in young (7-12 years) children ( R 2 = 0.17). Predictions of the MARSplines model were significantly more accurate than those of the reference model (median error 3.6%, R 2 = 0.44 P < .0001). The predictions of the ANN, however, showed significantly lower error than those of the reference model (P < .0001) and MARSplines (P < .0001) and better fit regardless of patient age. ANN-estimated GDRs were within a �20% error range in 75% of cases with a median error of 0.6% and an R 2 = 0.66. The predictive tool is available at http://link.konsta.com.pl/gdr. Conclusions The developed GDR estimation model reliant on ANN allows for an optimized prediction of GDR for research and clinical purposes.

NEUROD1-deficient diabetes (MODY6): Identification of the first cases in Japanese and the clinical features

Aims Only a few families with neuronal differentiation 1 (NEUROD1)-deficient diabetes, currently designated as maturity-onset diabetes of the young 6 (MODY6), have been reported, but mostly in Caucasian, and no mutation has been identified by family-based screening in Japanese. Accordingly, the phenotypic details of the disease remain to be elucidated. Methods We examined a total of 275 subjects having diabetes suspected to be MODY who were negative for mutations in MODY1-5 referred from 155 medical institutions throughout Japan. So as not to miss low penetrant cases, we examined non-obese Japanese patients with early-onset diabetes regardless of the presence of family history by direct sequencing of all exons and flanking regions of NEUROD1 . Large genomic rearrangements also were examined. Results Four patients with 3 frameshift mutations and 1 missense mutation, all of which were heterozygous and 3 of which were novel, were identified. Diabetic ketosis was found occasionally in these patients even under conditions of chronic hyperglycemia, for unknown reasons. Although the capacity of early-phase insulin secretion was low in these patients, the insulin secretory capacity was relatively preserved compared to that in hepatocyte nuclear factor (HNF)1A- and HNF1B-MODY. One of the patients and 2 of their diabetic mothers were found to have some mental or neuronal abnormality. Conclusions This is the first report of NEUROD1 mutations in Japanese, who have a genetic background of intrinsically lower capacity of insulin secretion. NEUROD1-deficient diabetes appears to be low penetrant, and may occur in concert with other genetic factors.

Comprehensive screening for monogenic diabetes in 89 Japanese children with insulin-requiring antibody-negative type 1 diabetes

Background Mutations in causative genes for neonatal diabetes or maturity-onset diabetes of the young have been identified in multiple patients with autoantibody-negative type 1 diabetes (T1D). Objectives We aimed to clarify the prevalence and phenotypic characteristics of monogenic abnormalities among 89 children with autoantibody-negative insulin-requiring T1D. Methods Mutations in 30 genes were screened using next-generation sequencing, and copy-number alterations of 4 major causative genes were examined using multiplex-ligation-dependent probe amplification. We compared the clinical characteristics between mutation carriers and non-carriers. Results We identified 11 probable pathogenic substitutions (6 in INS , 2 in HNF1A , 2 in HNF4A , and 1 in HNF1B ) in 11 cases, but no copy-number abnormalities. Only 2 mutation carriers had affected parents. De novo occurrence was confirmed for 3 mutations. The non-carrier group, but not the carrier group, was enriched with susceptible HLA alleles. Mutation carriers exhibited comparable phenotypes to those of non-carriers, except for a relatively normal body mass index (BMI) at diagnosis. Conclusions This study demonstrated significant genetic overlap between autoantibody-negative T1D and monogenic diabetes. Mutations in INS and HNF genes, but not those in GCK and other monogenic diabetes genes, likely play critical roles in children with insulin-requiring T1D. This study also suggests the relatively high de novo rates of INS and HNF mutations, and the etiological link between autoimmune abnormalities and T1D in the non-carrier group. Carriers of monogenic mutations show non-specific phenotypes among all T1D cases, although they are more likely to have a normal BMI at diagnosis than non-carriers.

Early transition from insulin to sulfonylureas in neonatal diabetes and follow-up: Experience from China

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.

Diagnosis of congenital hyperinsulinism: Biochemical profiles during hypoglycemia

Objectives To define the ranges of biochemical markers during hypoglycemia for the diagnosis of congenital hyperinsulinism (CHI), using high sensitivity insulin assays. Subjects A total of 298 patients with CHI and 58 control patients with non-hyperinsulinemic hypoglycemia, who were diagnosed after 2007. Methods The levels of biochemical markers (glucose, insulin, ?-hydroxybutyrate [BHB], free fatty acids [FFA], lactate, ammonia) at the time of hypoglycemia were analyzed along with the maximal glucose infusion rate (GIR) to maintain euglycemia and clinical outcomes. Results Median levels of blood glucose in patients with CHI and in controls were 30 and 46 mg/dL, while insulin levels were 9.90 and undetectable (<.5) ?U/mL, respectively. Similarly, median levels of BHB were 17.5 and 3745 �mol/L, and those of FFA were 270.5 and 2660 �mol/L, respectively. For patients after 5 months, cutoffs of insulin >1.25 ?U/mL, BHB < 2000 �mol/L, and FFA < 1248 �mol/L predicted CHI with sensitivities of 97.5, 96.2, and 95.2% and specificities of 84.2, 89.3, and 92.3%, respectively. Maximal GIR in the CHI groups tended to decrease with age. In addition, decreased gestational age, low birth weight, and elevated lactate at hypoglycemia were significantly more common in patients who were off treatment within 100 days without pancreatectomy. Conclusions After introduction of high-sensitive assays, the diagnostic value of insulin was improved, allowing for more efficient cutoffs to be set for diagnosis of CHI. Premature birth, low birth weight and elevated lactate might be helpful in predicting early remission of hypoglycemia.

Childhood body mass index in relation to subsequent risk of type 1 diabetes?A Danish cohort study

The incidence of type 1 diabetes (T1D) is increasing, and obesity may be a contributing factor by increasing the risk and accelerating the onset. We investigated the relation between childhood body mass index z-scores (BMIz) and the later risk of T1D, including association with age at onset of T1D. The study included 238 cases and 10 147 controls selected from the Copenhagen School Health Record Register (CSHRR). Cases of T1D were identified in the Danish Registry of Childhood and Adolescent Diabetes and 2 regional studies and linked to CSHRR. Using conditional logistic regression models, the association of childhood prediagnostic BMIz at 7 and 13 years of age and changes between these ages with subsequent risk (odds ratio, OR) of T1D was estimated. A greater BMIz at 7 and 13 years of age was associated with increased risk of T1D with OR of 1.23 (confidence interval, CI 1.09-1.37; P = .0001) and 1.20 (CI 1.04-1.40; P = .016), respectively. The risk was increased by upward changes in z-scores from birth to 7 years (OR=1.21, P = .003) and from 7 to 13 years of age (OR=1.95, P = .023), but in the latter age interval also by a decline in BMIz (OR = 1.91, P = .034). There were no associations between BMIz at 7 and 13 years of age and the age of onset (P = .34 and P = .42, respectively). Increased BMIz is associated with a moderate increase in risk of T1D, but with no relation to age at onset within the analyzed age range. Increased BMIz over time is unlikely to explain the rising incidence of T1D.

Increasing ICA512 autoantibody titers predict development of abnormal oral glucose tolerance tests

Objective Determine if autoantibody titer magnitude and variability predict glucose abnormalities in subjects at risk for type 1 diabetes. Research Designs and Methods Demographic information, longitudinal autoantibody titers, and oral glucose tolerance test (OGTT) data were obtained from the TrialNet Pathway to Prevention study. Subjects (first and second degree relatives of individuals with type 1 diabetes) with at least 2 diabetes autoantibodies were selected for analysis. Autoantibody titer means were calculated for each subject for the duration of study participation and the relationship between titer tertiles and glucose value tertiles from OGTTs (normal, impaired, and diabetes) was assessed with a proportional odds ordinal regression model. A matched pairs analysis was used to examine the relationship between changes in individual autoantibody titers and 120-minute glucose values. Titer variability was quantified using cumulative titer standard deviations. Results We studied 778 subjects recruited in the TrialNet Pathway to Prevention study between 2006 and 2014. Increased cumulative mean titer values for both ICA512 and GAD65 (estimated increase in proportional odds = 1.61, 95% CI = 1.39, 1.87, P < 1 � 10?9 and 1.17, 95% CI = 1.03, 1.32, P = .016, respectively) were associated with peak 120-minute glucose values. While fluctuating titer levels were observed in some subjects, no significant relationship between titer standard deviation and glucose values was observed. Conclusion ICA512 autoantibody titers associate with progressive abnormalities in glucose metabolism in subjects at risk for type 1 diabetes. Fluctuations in autoantibody titers do not correlate with lower rates of progression to clinical disease.

Prediction of type 1 diabetes using a genetic risk model in the Diabetes Autoimmunity Study in the Young

Background Genetic predisposition for type 1 diabetes (T1D) is largely determined by human leukocyte antigen (HLA) genes; however, over 50 other genetic regions confer susceptibility. We evaluated a previously reported 10-factor weighted model derived from the Type 1 Diabetes Genetics Consortium to predict the development of diabetes in the Diabetes Autoimmunity Study in the Young (DAISY) prospective cohort. Performance of the model, derived from individuals with first-degree relatives (FDR) with T1D, was evaluated in DAISY general population (GP) participants as well as FDR subjects. Methods The 10-factor weighted risk model (HLA, PTPN22 , INS , IL2RA , ERBB3 , ORMDL3 , BACH2 , IL27 , GLIS3 , RNLS ), 3-factor model (HLA, PTPN22, INS ), and HLA alone were compared for the prediction of diabetes in children with complete SNP data (n = 1941). Results Stratification by risk score significantly predicted progression to diabetes by Kaplan-Meier analysis (GP: P = .00006; FDR: P = .0022). The 10-factor model performed better in discriminating diabetes outcome than HLA alone (GP, P = .03; FDR, P = .01). In GP, the restricted 3-factor model was superior to HLA (P = .03), but not different from the 10-factor model (P = .22). In contrast, for FDR the 3-factor model did not show improvement over HLA (P = .12) and performed worse than the 10-factor model (P = .02) Conclusions We have shown a 10-factor risk model predicts development of diabetes in both GP and FDR children. While this model was superior to a minimal model in FDR, it did not confer improvement in GP. Differences in model performance in FDR vs GP children may lead to important insights into screening strategies specific to these groups.

Primary islet autoantibody at initial seroconversion and autoantibodies at diagnosis of type 1 diabetes as markers of disease heterogeneity

Objective The relationship between patterns of islet autoantibodies at diagnosis and specificity of the first islet autoantibody at the initiation of autoimmunity was analyzed with the aim of identifying patterns informative of the primary autoantibodies. Methods Information about a single first autoantibody at seroconversion and autoantibody data at diagnosis were available for 128 children participating in the follow-up cohort of the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study. Autoantibody data at diagnosis and genotyping results were also obtained from children in the Finnish Pediatric Diabetes Register (FPDR). Results Insulin autoantibodies (IAA) were the most common primary antibodies (N = 68), followed by those for glutamic acid decarboxylase (GADA; N = 38), IA-2 antigen (IA-2A; N = 13), and zinc transporter 8 (ZnT8A; N = 9), whereas at diagnosis, IA-2A were most frequent (N = 103), followed by IAA (N = 78), ZnT8A (N = 73), and GADA (N = 71). Accordingly, the presence of many specific autoantibodies at diagnosis was due to the secondary antibodies appearing after primary antibodies, and in some cases, the primary autoantibody, most often IAA, had already disappeared at the time of diagnosis. Many of the autoantibody combinations present at diagnosis could be assembled into groups associated with either IAA or GADA as first autoantibodies. These combinations, in children diagnosed below the age of 10 years in the FPDR, were found to be strongly associated with risk genotypes in either INS (IAA first) or IKZF4-ERBB3 (GADA first) genes. Conclusions Autoantibody patterns at diagnosis may be informative on primary autoantibodies initiating autoimmunity in young children developing type 1 diabetes.

Early childhood infections precede development of beta-cell autoimmunity and type 1 diabetes in children with HLA-conferred disease risk

Background The etiology of type 1 diabetes (T1D) is largely unknown. Infections and microbial exposures are believed to play a role in the pathogenesis and in the development of islet autoimmunity in genetically susceptible individuals. Objective To assess the relationships between early childhood infections, islet autoimmunity, and progression to T1D in genetically predisposed children. Methods Children with human leukocyte antigen (HLA)-conferred disease susceptibility (N=790; 51.5% males) from Finland (n = 386), Estonia (n = 322), and Russian Karelia (n = 82) were observed from birth up to the age of 3 years. Children attended clinical visits at the age of 3, 6, 12, 18, 24, and 36 months. Serum samples for analyzing T1D-associated autoimmune markers were collected and health data recorded during the visits. Results Children developing islet autoimmunity (n = 46, 5.8%) had more infections during the first year of life (3.0 vs 3.0, mean rank 439.1 vs 336.2; P = .001) and their first infection occurred earlier (3.6 vs 5.0 months; P = .005) than children with no islet autoimmunity. By May 2016, 7 children (0.9%) had developed T1D (progressors). Compared with non-diabetic children, T1D progressors were younger at first infection (2.2 vs 4.9 months; P = .004) and had more infections during the first 2 years of life (during each year 6.0 vs 3.0; P = .001 and P = .027, respectively). By 3 years of age, the T1D progressors had twice as many infections as the other children (17.5 vs 9.0; P = .006). Conclusions Early childhood infections may play an important role in the pathogenesis of T1D. Current findings may reflect either differences in microbial exposures or early immunological aberrations making diabetes-prone children more susceptible to infections.

Association between interferon-induced helicase (IFIH1) rs1990760 polymorphism and seasonal variation in the onset of type 1 diabetes mellitus

Background Infections, mostly of viral origin, may contribute to the seasonal variation in the onset of type 1 diabetes mellitus (T1DM). The rs1990760 (A>G, Ala946Thr) polymorphism (GG genotype) of the interferon induced helicase (IFIH1), a virus recognition receptor, confers a modest protection for T1DM. The aim of our study was to evaluate a possible association between this IFIH1 polymorphism and the seasonal variation in the onset of T1DM. Materials and Methods The IFIH1 rs1990760 polymorphism was genotyped in 1055 patients of Central-Eastern European ancestry with T1DM (median age at diagnosis: 8.2 [interquartile range, IQR 4.8-11.8] years). T1DM onset was recorded in monthly intervals. Results The IFIH1 genotype distribution was the following: 436 patients (41.3%) had AA genotype, 483 patients (45.8%) had AG genotype, and 136 patients (12.9%) had GG genotype. Significant seasonal variation in manifestation of T1DM (highest rate in winter and lowest rate in summer period) was observed in the total cohort (n = 1055), irrespective of gender. The disease predisposing AA genotype was more frequently found among new cases with onset in summer vs in those with onset in winter (44.3% vs 37.9%); conversely, the protective GG genotype was less frequent (9.3% vs 12.9%, respectively; P = .0268 for trend). Significant effect of genotype (P = .0418) was found on the seasonal variability of T1DM onset in the total cohort. Conclusions The IFIH1 rs1990760 polymorphism seems to be associated with the seasonal manifestation of T1DM. Our findings suggest that this virus receptor gene may contribute to T1DM manifestation primarily in the summer period.