Permanent diabetes mellitus in the first year of life

Abstract

Aims/hypothesis. The pathogenesis of permanent diabetes mellitus diagnosed early in life is heterogeneous and, in most cases, not known. We aimed at identifying markers differentiating between non-autoimmune and autoimmune diabetes. Methods. The clinical, genetic and epidemiological features of 111 diabetic patients (62 males) who received insulin within 12 months of life were studied. Results. The epidemic curve by age of diabetes onset revealed two subsets of patients at a cutoff of 180 days. In the group with diabetes onset before 180 days ("early onset" permanent diabetes) the analysis of HLA susceptibility heterodimers (available for 21 individuals) showed that 76% had a "protective" HLA genotype for Type I (insulin-dependent) diabetes mellitus as compared to 11.9% (5/42) of the later onset group. Accordingly, "early onset" children were less likely to have autoimmunity markers (4 out of 26 tested) than children with onset after 180 days (13 out 20 tested) (15.4% vs. 65.0%, p<0.01). Of note, 19 out of 20 (or the 95%) patients who were born on the island of Sardinia, an Italian region where the incidence of Type I diabetes is six times higher than continental Italy (33/100000/year vs 5/100000/year), were included in the later onset group (>180 days). Small-for-date birthweight, a possible sign of reduced foetal insulin secretion, was more common in the "early onset" group (OR=9.9, 95%-CI 2.6-38.6). Conclusion/interpretation. These results, obtained in the largest population-based cohort of diabetic infants hitherto reported, suggest that "early onset" permanent diabetes cases differ from later onset cases and that most of them do not have an autoimmune pathogenesis. [Diabetologia (2002) 45:798-804]

Mutations in KCNJ11, which encodes Kir6.2, are a common cause of diabetes diagnosed in the first 6 months of life, with the phenotype determined by genotype

“…Only those diagnosed in the first 3 months have previously been classified as having neonatal diabetes, and this result confirms that a broader definition is needed when considering KCNJ11 mutations [4]. A cut-off point at 6 months is consistent with previous work looking at autoantibodies and HLA suggesting that type 1 diabetes is rare in those aged below 6 months [22]. Our study would not support testing for KCNJ11 mutations in patients diagnosed after 6 months, although relatives of probands with transient neonatal diabetes have been diagnosed at 3, 5, 22 and 26 years [2,3].…”

Activating Mutations in Kir6.2 and Neonatal Diabetes

“…Permanent neonatal diabetes due to homozygous glucokinase mutations (46) or pancreatic aplasia due to homozygous IPF1 mutations (47,48) results in a more severe insulin deficiency as shown by a lower birth weight and a younger age at diagnosis. In keeping with pancreatic autoantibodies being rare in patients who are diagnosed with diabetes before 6 months (45), no patients with Kir6.2 mutations have pancreatic autoantibodies, but these are found in patients with FOXP3 mutations leading to IPEX syndrome (45). Transient neonatal diabetes resulting from the common abnormalities of the imprinted region on 6q24 differs from transient neonatal diabetes caused by Kir6.2 mutations.…”

HLA Genotyping Supports a Nonautoimmune Etiology in Patients Diagnosed With Diabetes Under the Age of 6 Months

“…A recent Italian study suggested that children diagnosed with diabetes before 6 months of age do not have the genetic characteristics of autoimmune diabetes (15). Many patients from this cohort have since been diagnosed with KCNJ11 mutations (10), but the etiology of diabetes in the remainder is uncertain.…”