There is an increase in the incidence of type 2 diabetes in children and adolescents. Absence of known diabetes autoimmune markers is sometimes required to confirm the diagnosis.
To identify clinical ...and autoimmune characteristics of type 2 diabetes in a pediatric population.
We report an analysis of 48 children and adolescents with type 2 diabetes, compared with 39 randomly selected children with type 1 diabetes, diagnosed and followed at the Loma Linda University Pediatric Diabetes Center. Ethnic, familial, seasonal, and autoimmune marker characteristics are outlined. To determine the reliability of antibody testing in confirming the type of diabetes at diagnosis, we studied the incidence of positive islet cell antibodies (ICAs), glutamic acid decarboxylase antibodies (GADs), and insulin autoantibodies (IAAs) at diagnosis in both groups. ICA512, GADs, and IAAs were measured by radioimmunoassay.
The cohort with type 2 diabetes had a similar gender distribution as the group with type 1 diabetes but a significantly higher age at diagnosis. Ethnic background was significantly different between the 2 groups, predominantly Hispanic in type 2 and white in type 1. Body mass index was significantly higher in type 2 diabetes (mean = 31.24 kg/m(2)). Among the patients with type 2 diabetes, 33% presented in diabetic ketoacidosis, random blood glucose at diagnosis ranged from 11.4 to 22.25 mmol/L (228-445 mg/dL), fasting C-peptide levels ranged from 0.89 to 2.7 nmol/L (2.7-8.2 ng/mL; normal: <1.36 nmol/L), and hemoglobin A(1C) was 10.8 +/- 3.5% (normal: <6.6%). None of these parameters was significantly different from the type 1 diabetes group. Although the incidence of diabetes antibody markers was significantly lower in type 2 versus type 1 diabetes, 8.1% of patients with type 2 diabetes had positive ICAs, 30.3% had positive GADs, and 34.8% had positive IAAs without ever being treated with insulin. In the type 2 diabetes group, none of the Hispanic patients had ICAs. However, there was no significant correlation between any of the diabetes antibodies and obesity, presence of acanthosis nigricans, or family history of diabetes. The frequency of thyroid antibodies was not significantly different from the group with type 1 diabetes. Daily insulin requirements 1 year after diagnosis were significantly lower in type 2 diabetes, ranging from 0 to 1.2 U/kg with a mean of 0.33.
Absence of diabetes autoimmune markers is not a prerequisite for the diagnosis of type 2 diabetes in children and adolescents.
Background: Over the past decade, there has been a worldwide largely unexplained increase in the incidence of type 1 diabetes in young children. This study explores the quantitative role of exposure ...to specific air pollutants in the development of type 1 diabetes in children.
Methods: A total of 402 children were retrospectively studied. Zip code‐related, time‐specific birth‐to‐diagnosis exposure to five ambient air pollutants was obtained for 102 children with type 1 diabetes and 300 healthy children receiving care at a single hospital. Pollution exposure levels were created by summing up zip code‐specific pollution data and dividing by months of exposure from birth to diagnosis. Analysis employed χ2, two‐tailed independent sample t‐test and unconditional logistic regression.
Results: Odds ratio (OR) was significantly high for cumulative exposure to ambient ozone (O3) and sulfate (SO4) in cases compared with controls, OR = 2.89 95% confidence interval (CI) = 1.80–4.62 and OR = 1.65 (CI = 1.20–2.28), respectively, even after adjustment for several potential confounders. Passive smoking was more frequent in children with diabetes (30 vs. 10%, p = 0.001). Attending day care and breast feeding in infancy were less frequent in children with diabetes (14 vs. 23%, p = 0.025; 59 vs. 78%, p = 0.001). Family history of diabetes, autoimmune disease and drug abuse was more frequent in cases (p < 0.01).
Conclusion: Cumulative exposure to ozone and sulfate in ambient air may predispose to the development of type 1 diabetes in children. Early infant formula feeding and passive smoking in the household may precipitate or accelerate the onset of type 1 diabetes.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
KCNJ11 mutations cause permanent neonatal diabetes through pancreatic ATP-sensitive potassium channel activation. 90% of patients successfully transfer from insulin to oral sulfonylureas with ...excellent initial glycaemic control; however, whether this control is maintained in the long term is unclear. Sulfonylurea failure is seen in about 44% of people with type 2 diabetes after 5 years of treatment. Therefore, we did a 10-year multicentre follow-up study of a large international cohort of patients with KCNJ11 permanent neonatal diabetes to address the key questions relating to long-term efficacy and safety of sulfonylureas in these patients.
In this multicentre, international cohort study, all patients diagnosed with KCNJ11 permanent neonatal diabetes at five laboratories in Exeter (UK), Rome (Italy), Bergen (Norway), Paris (France), and Krakow (Poland), who transferred from insulin to oral sulfonylureas before Nov 30, 2006, were eligible for inclusion. Clinicians collected clinical characteristics and annual data relating to glycaemic control, sulfonylurea dose, severe hypoglycaemia, side-effects, diabetes complications, and growth. The main outcomes of interest were sulfonylurea failure, defined as permanent reintroduction of daily insulin, and metabolic control, specifically HbA1c and sulfonylurea dose. Neurological features associated with KCNJ11 permanent neonatal diabetes were also assessed. This study is registered with ClinicalTrials.gov, number NCT02624817.
90 patients were identified as being eligible for inclusion and 81 were enrolled in the study and provided long-term (>5·5 years cut-off) outcome data. Median follow-up duration for the whole cohort was 10·2 years (IQR 9·3–10·8). At most recent follow-up (between Dec 1, 2012, and Oct 4, 2016), 75 (93%) of 81 participants remained on sulfonylurea therapy alone. Excellent glycaemic control was maintained for patients for whom we had paired data on HbA1c and sulfonylurea at all time points (ie, pre-transfer for HbA1c, year 1, and most recent follow-up; n=64)—median HbA1c was 8·1% (IQR 7·2–9·2; 65·0 mmol/mol 55·2–77·1) before transfer to sulfonylureas, 5·9% (5·4–6·5; 41·0 mmol/mol 35·5–47·5; p<0·0001 vs pre-transfer) at 1 year, and 6·4% (5·9–7·3; 46·4 mmol/mol 41·0–56·3; p<0·0001 vs year 1) at most recent follow-up (median 10·3 years IQR 9·2–10·9). In the same patients, median sulfonylurea dose at 1 year was 0·30 mg/kg per day (0·14–0·53) and at most recent follow-up visit was 0·23 mg/kg per day (0·12–0·41; p=0·03). No reports of severe hypoglycaemia were recorded in 809 patient-years of follow-up for the whole cohort (n=81). 11 (14%) patients reported mild, transient side-effects, but did not need to stop sulfonylurea therapy. Seven (9%) patients had microvascular complications; these patients had been taking insulin longer than those without complications (median age at transfer to sulfonylureas 20·5 years IQR 10·5–24·0 vs 4·1 years 1·3–10·2; p=0·0005). Initial improvement was noted following transfer to sulfonylureas in 18 (47%) of 38 patients with CNS features. After long-term therapy with sulfonylureas, CNS features were seen in 52 (64%) of 81 patients.
High-dose sulfonylurea therapy is an appropriate treatment for patients with KCNJ11 permanent neonatal diabetes from diagnosis. This therapy is safe and highly effective, maintaining excellent glycaemic control for at least 10 years.
Wellcome Trust, Diabetes UK, Royal Society, European Research Council, Norwegian Research Council, Kristian Gerhard Jebsen Foundation, Western Norway Regional Health Authority, Southern and Eastern Norway Regional Health Authority, Italian Ministry of Health, Aide aux Jeunes Diabetiques, Societe Francophone du Diabete, Ipsen, Slovak Research and Development Agency, and Research and Development Operational Programme funded by the European Regional Development Fund.
Little is known about auxologic, autoimmune, and HLA characteristics specific to children with early-onset diabetes (EOD). HLA subtypes have been shown to play an important part in the determination ...of islet-cell autoimmunity and in the pace and intensity of the beta-cell destructive process.
Our goals were to: 1) outline auxologic, autoimmune, and HLA class II characteristics of children diagnosed with type 1 diabetes before 5 years of age (EOD); 2) evaluate differences between EOD and later-onset or non-age-stratified type 1 diabetes; and 3) investigate the relation between type 1 diabetes-related HLA subtypes and markers of diabetic autoimmunity in EOD.
Forty children with EOD were studied. Auxologic and antibody radioimmunoassay data were obtained by retrospective analysis of records. HLA diabetes-related class II alleles were typed by polymerase chain reaction using sequence-specific primers.
At diagnosis, the average age of the EOD study patients was 2.6 years, body mass index was 16.9 kg/m2, and weight was 106% of average weight for height. When compared with a matched subgroup of children with later-onset type 1 diabetes, preschoolers did not significantly differ in terms of birth weight or body mass index. The frequency of positive islet cell antibodies 512 and glutamic acid decarboxylase 65 antibodies was significantly less in EOD (28.6% and 31.6%, respectively). There were significant differences in the frequencies of some diabetes-related HLA alleles and haplotypes between the early-onset group and a large non-age-stratified type 1 diabetes group. None of the patients with EOD had either of the protective DRB1*1501 or DQB1*0602 alleles. There was a negative correlation between glutamic acid decarboxylase and the predisposing haplotype DR3/DQ2.
Children diagnosed with type 1 diabetes before 5 years of age may have different diabetes-related autoimmune and genetic characteristics from those diagnosed at a later age.
To determine the effect of insulin glargine on glycemic control in pediatric type 1 and 2 diabetes, a retrospective repeated-measure analysis of variance was performed of hemoglobin A1C (HbA1C), ...frequency of hypoglycemia and hyperglycemia, mean blood glucose, body mass index (BMI), and daily weight-adjusted insulin dosage before and after institution of glargine therapy in 72 children and adolescents with diabetes. At glargine start, age range was 1.2-19.6 years, mean age was 12.5 +/- 4.6 years, BMI was 22.48 +/- 6.3 kg/m(2), and mean HbA1C was 9.7 +/- 1.9%. Mean duration of diabetes was 3.58 years, and mean baseline insulin dose was 0.93 U/kg/day. Gender breakdown was 60% female, and the majority (83%) had type 1 diabetes. Average HbA1C decreased from 9.5% pre-glargine to 8.6% post-glargine (p < 0.001). HbA1C decrease was significant in both types of diabetes without a concomitant increase in frequency of hypoglycemia, BMI, or weight-adjusted insulin dose. Hypoglycemia decreased significantly in type 1 diabetes. Thus, glargine therapy may decrease HbA1C and frequency of hypoglycemia in toddlers, children, and adolescents with diabetes, without an increase in BMI or insulin requirements.
A retrospective analysis of 381 pediatric heart‐transplant recipients was performed to determine the frequency, characteristics, and risk factors for post‐transplant diabetes. The rate of ...post‐transplant diabetes was 1.8% with antithymocyte globulin, cyclosporine and azathioprine as primary immunosuppressive therapy. Time from transplant to diabetes was 0.25–13 years. Diabetes was characterized by reversibility, and lack of insulinopenia and autoimmunity. The post‐transplant diabetes rate in tacrolimus‐converted children (n = 45) was 8.8%. In tacrolimus‐converted children, age at transplant, mean and maximum tacrolimus blood levels, and first‐year rejection episodes were higher in the post‐transplant diabetes group, which also consistently had DR‐mismatched transplants and HLA DR3/DR4 haplotypes. Body mass index was not different between diabetic and control tacrolimus‐converted children. In conclusion, pediatric post‐transplant diabetes may be related to reversible insulin resistance. Tacrolimus levels, HLA DR mismatch, and older age at transplant may predispose to post‐transplant diabetes.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
: Objective: To assess the role of ambient air pollutants in type 1 diabetes in children.
Design and methods: Prediagnosis exposure to five air pollutants was studied in two subgroups with onset of ...type 1 diabetes before and after 5 yr of age, and two matched subgroups of healthy children. Zip codes and dates of residence from birth to diagnosis were used to obtain geographic‐ and time‐specific air concentrations of SO2, NO2, ozone (O3), SO4, and particulate matter < 10 µm in diameter (PM10). Prediagnosis time‐adjusted pollutant exposure levels were created by summing up zip code‐specific pollution data and dividing by months of exposure from birth to diagnosis. Two‐tailed t‐test and logistic regression were used to evaluate relative effects and test data between cases and controls.
Results: Prediagnosis average O3 exposure was significantly higher in children with type 1 diabetes than in healthy controls. Prediagnosis PM10 exposure was significantly higher in children diagnosed before 5 yr of age, when compared with healthy controls. SO2 exposure was significantly higher in children with later‐onset diabetes compared with those with early‐onset diabetes (EOD). NO2, SO2 and SO4 exposure was significantly lower in children diagnosed after 5 yr of age, when compared with healthy controls. O3, NO2, SO4 and PM10 levels did not significantly differ between the two diabetic subgroups.
Conclusion: Increased ozone exposure may be a contributory factor to the increased incidence of type 1 diabetes. PM10 may be a specific contributory factor to the development of type 1 diabetes before 5 yr of age.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
To test the hypothesis that insulin regulates leptin, we measured the
plasma leptin concentration before and during treatment of diabetic
ketoacidosis (DKA), a condition characterized by extreme ...insulin
deficiency. The study included 17 patients with type 1 diabetes (7
males and 10 females), aged 10 ± 1 yr (mean ±
se), with a body mass index of 17.6 ± 1.9
kg/m2. Patients were treated with continuous insulin
infusion and fluid and electrolyte replacement. Plasma leptin was
measured every 6 h in the first 24 h, during which patients
received a total insulin dose of 0.6–2.0 U/kg. Plasma leptin
concentrations were also measured in a control group of 29
stable type 1 diabetic children (12 males and 17 females) and 25
healthy children (11 males and 14 females), aged 11 ± 1 yr, with
a body mass index of 18.5 ± 1.1 kg/m2. Before
treatment, plasma leptin concentrations were significantly lower in
patients with DKA than those in diabetic and healthy controls (4.9±
1.2 vs. 9.0 ± 1.8 and 11.2 ± 2.1 ng/mL,
respectively; P < 0.05). In the DKA patients,
plasma leptin increased to 6.4 ± 1.5, 7.5 ± 1.9, 9.1±
2.7, and 8.9 ± 2.5 at 6, 12, 18, and 24 h, respectively,
after starting treatment (P = 0.001). Thus, leptin
levels increased by 38 ± 10% and 92 ± 38% within 6 and
24 h of starting treatment. There was no difference in the change
in plasma leptin by 24 h between subjects who could eat (n =
7) and those who could not (n = 10). The plasma leptin increase
was paralleled by a rise in insulin level and a decline in glucose and
cortisol levels at 6 and 24 h. In conclusion, DKA was associated
with decreased plasma leptin concentrations. Treatment resulted in a
significant increase in plasma leptin, which may be due to the effect
of insulin on leptin production. Our data lend support to the
hypothesis that insulin is the link between caloric intake and plasma
leptin.
The proband, a 9-year-old Hispanic female, presented with hair loss, strabismus, and weight gain. On magnetic resonance imaging (MRI) she was found to have severe primary hypothyroidism and a large ...pituitary mass. In addition, acanthosis nigricans, obesity, and hyperinsulinism were observed. Findings were similar in three of four siblings. Thyroid peroxidase antibodies were detected in the father and three of four siblings. Although all family members were obese, and hyperinsulinemia with high proinsulin and C-peptide was found in all except one sibling, only the mother and one child had overt type 2 diabetes mellitus. Because of the unusual association of autoimmune thyroid disease, insulin resistance and obesity rather than insulin deficiency, we searched for possible genetic abnormalities. The HLA haplotypes did not cosegregate with autoimmune thyroid disease or insulin resistance. Mutational analysis of known obesity genes was done. Leptin was not deficient, and sequencing of the proband's DNA showed no mutations in the perixisome proliferator activated receptor (PPAR)-gamma, PPAR-gamma(2), PPAR-alpha or melanocortin 4 receptor genes. Maternally inherited diabetes and deafness was ruled out since no mutations were found in mitochondria DNA. Insulin receptor antibodies were not detected. In conclusion, the remarkably high incidence of childhood autoimmune hypothyroidism, pituitary enlargement, insulin resistance and obesity in this family is not linked to known HLA types or known gene defects.
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