Diabetic autoimmune markers in children and adolescents with type 2 diabetes.

BACKGROUND: 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. OBJECTIVE: To identify clinical and autoimmune characteristics of type 2 diabetes in a pediatric population. METHOD: 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. RESULTS: 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. CONCLUSION: Absence of diabetes autoimmune markers is not a prerequisite for the diagnosis of type 2 diabetes in children and adolescents.

Diabetic autoimmunity in infants and pre-schoolers with type 1 diabetes.

The incidence of type 1 diabetes is increasing most rapidly in children under 5 yrs of age, a group where the disease appears to be more accelerated than traditional type 1 diabetes. Little is known about demographics, and markers of diabetes autoimmunity, in infants and pre-schoolers with type 1 diabetes. We report an analysis of 47 children diagnosed with type 1 diabetes prior to 5 yrs of age compared with a representative cohort (n=49) diagnosed after 5 yrs of age, and all were followed at Loma Linda University (LLU) Children's Hospital. Ethnic, familial, seasonal, and autoimmune marker characteristics are outlined. To determine the prevalence of diabetes autoimmune markers, ICA512, GAD65 and insulin autoantibodies (IAA) antibodies were measured. Children with early-onset diabetes had a significantly higher incidence of viral illness symptoms (p=0.005) and diabetic ketoacidosis (DKA; p=0.017) at the time of diagnosis. However, hemoglobin A1C (HbA1c) levels at diagnosis were significantly higher in the later-onset group (p=0.001). A honeymoon period was reported in 14.8% of children diagnosed before 5 yrs of age compared with 42.1% in those diagnosed over 5 yrs of age (p=0.038). Islet-cell antibodies (ICAs) and glutamic acid decarboxylase (GAD) antibody titers were significantly different between early- and later-onset groups. ICA titers were positive in 35.29%, and GAD in 41.38% of the early-onset group versus 70.83 and 71.74% in children with later-onset disease, (p=0.001 and 0.009, respectively). IAA titers, drawn after instituting insulin therapy, were not significantly different between the two groups. GAD and ICA512 antibody results suggest a relative lack of diabetes immune markers in infants and toddlers with new-onset diabetes. This finding, and the apparent shorter pre-clinical phase reflected in the lower HbA1c values, may indicate age-related differences in type 1 diabetes autoimmunity or the existence of non-autoimmune diabetogenic mechanisms in younger children.

Changes in plasma leptin during the treatment of diabetic ketoacidosis.

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.

Normal growth despite GH, IGF-I and IGF-II deficiency.

A 6.5-year-old male with normal linear growth, despite septo-optic dysplasia, panhypopituitarism and a deficient GH/IGF axis, is presented. In addition to measuring IGF-I, IGF-II and IGFBP-3, serum IGFBP-1, -2, -4 and -5 were measured. A human osteosarcoma cell line was used to assess growth-promoting activity in the patient's serum. The role of leptin in linear growth in this case was investigated. There was no evidence for hyperinsulinism or hyperandrogenism. GH was undetectable upon multiple stimulation. GHBP was elevated. Serum IGF-I (25 microg/l), IGF-II (194 microg/l), IGFBP-3 (0.4 mg/l), and IGFBP-5 (87 microg/l) levels were low compared to age-matched prepubertal children. Serum IGFBP-4 level was normal. Molecular size of IGF-II in the patient's serum was normal, suggesting normal IGF-II bioavailability. Human osteosarcoma cell proliferation in response to the patient's serum was similar to sera from age-matched normal controls. Leptin levels were markedly elevated. Osteoblast cell proliferation was not stimulated by leptin. The data demonstrate that normal growth and osteoblast cell proliferation in this patient is not mediated by GH, total IGFs, insulin, or leptin, and suggest the presence of a yet unidentified growth factor or mechanism. The case offers a detailed picture of binding proteins in a case of growth without GH. It introduces osteoblast cell proliferation as a method of assessing serum growth-promoting activity in such cases. It adds IGF-II and leptin to the list of excluded growth-promoting candidates in GH-independent growth, and further demonstrates our incomplete understanding of the phenomenon of growth.

Association of terminal chromosome 1 deletion with sertoli cell-only syndrome.

We report on del(1)(q44), developmental delay, cryptorchidism, and seizure disorder in a 19-year-old man. Endocrinologic evaluation showed delayed puberty and elevated gonadotropins. Testicular biopsy was consistent with Sertoli cell-only syndrome. The case illustrates a previously an unreported manifestation in males with del(1)(q44), and suggests a link between the development of germinal epithelium and genes in the 1q44 area.

Hemifacial microsomia and abnormal chromosome 22.

We report on partial dup(22q), growth deficiency, and the facioauriculovertebral sequence including hemifacial microsomia, cleft lip and palate, preauricular tags, and hearing loss in one patient. No endocrine or systemic cause for growth deficiency was identified. The case illustrates applicability of chromosome analysis in syndrome-associated growth failure, and a previously unreported associated chromosome abnormality.