Prevalence of permanent neonatal diabetes in Slovakia and successful replacement of insulin with sulfonylurea therapy in KCNJ11 and ABCC8 mutation carriers.

CONTEXT: Mutations in the KCNJ11 and ABCC8 genes encoding the pancreatic beta-cell K(ATP) channel have recently been shown to be the most common cause of permanent neonatal diabetes mellitus (PNDM). Information regarding the frequency of PNDM has been based mainly on nonpopulation or short-term collections only. Thus, the aim of this study was to identify the incidence of PNDM in Slovakia and to switch patients to sulfonylurea (SU) where applicable. DESIGN: We searched for PNDM patients in the Slovak Children Diabetes Registry. In insulin-treated patients who matched the clinical criteria for PNDM, the KCNJ11 or ABCC8 genes were sequenced, and mutation carriers were invited for replacement of insulin with SU. RESULTS: Eight patients with diabetes onset before the sixth month of life without remission were identified since 1981, which corresponds to the PNDM incidence in Slovakia of one case in 215,417 live births. In four patients, three different KCNJ11 mutations were found (R201H, H46Y, and L164P). Three patients with the KCNJ11 mutations (R201H and H46Y) were switched from insulin to SU, decreasing their glycosylated hemoglobin from 9.3-11.0% on insulin to 5.7-6.6% on SU treatment. One patient has a novel V86A mutation in the ABCC8 gene and was also substituted with SU. CONCLUSIONS: PNDM frequency in Slovakia is much higher (one in 215,417 live births) than previously suggested from international estimates (about one in 800,000). We identified one ABCC8 and four KCNJ11 mutation carriers, of whom four were successfully transferred to SU, dramatically improving their diabetes control and quality of life.

Screening detected celiac disease in children with type 1 diabetes mellitus: effect on the clinical course (a case control study).

OBJECTIVE: To investigate clinical and metabolic characteristics of diabetic children with screening detected celiac disease in a multicenter case-control study. CASES: 98 diabetic patients were diagnosed as having silent celiac disease by screening with endomysial antibodies and subsequent biopsy. CONTROLS: two controls in the same center were chosen, (stratified by age and age-at-diabetes onset) who were negative for endomysial antibodies (n = 195). Height, weight, HbA1c, insulin dosage and acute complications were documented for at least 1 year of follow up. RESULTS: Mean age of diabetes manifestation was 6.5 +/- 4.1 years and diagnosis of celiac disease was made at 10.0 +/- 5.4 years. Biopsy showed total or subtotal mucosal atrophy in 74 patients. The mean observation period after the diagnosis of celiac disease was 3.3 +/- 1.9 years. Mean HbA1c levels were similar between cases and controls (8.63% +/- 1.45% versus 8.50% +/- 1.39%; P = 0.35). There was also no difference in the frequency of severe hypoglycemia, ketoacidosis and the applied insulin dosage (P = 0.45). Body mass index-standard deviation score at celiac disease diagnosis (0.57 +/- 1.24 versus 0.52 +/- 1.07) and height-standard deviation score (0.14 +/- 1.13 versus 0.30 +/- 0.95) did not differ between cases and controls. After diagnosis of celiac disease, weight gain was diminished in boys with celiac disease compared with their controls (P < 0.05). Female cases also had a lower body mass index than female controls (P = 0.067). CONCLUSION: In a cohort of diabetic children, silent celiac disease had no obvious effect on metabolic control but negatively influenced weight gain.

Continued growth hormone (GH) treatment after final height is necessary to complete somatic development in childhood-onset GH-deficient patients.

Lean body mass (LBM), fat mass (FM), and total bone mineral content are significantly reduced in adult GHD subjects who had received pediatric GH. To test the hypothesis that continued GH therapy after final height is necessary to attain adult body composition, we performed a prospective, multinational, randomized, controlled, 2-yr study in patients who completed pediatric GH treatment at final height. Patients were randomized to GH at 25.0 microg/kg x d (pediatric dose; n = 58) or 12.5 microg/kg x d (adult dose; n = 59) or no GH treatment (control; n = 32). LBM and FM were measured by dual energy x-ray absorptiometry and were centrally evaluated. IGF-I, IGF-binding protein-3, and lipid concentrations were also measured centrally. During the 2 yr, GH-treated patients gained a significant amount of LBM compared with controls (P < 0.001), but the change with the higher pediatric dose (14.2 +/- 11.7%) was not different from that seen with the lower adult dose (12.7 +/- 9.4%; P = 0.970). Similarly, the decrease in FM was significantly (P = 0.029) influenced by treatment, but with no dose effect (adult dose, -7.1 +/- 22.8%; pediatric dose, -6.0 +/- 26.6%; P = 0.950). When the GH treatment effect was analyzed by gender, males gained 15.6 +/- 9.8% and 14.3 +/- 11.7% LBM (P = 0.711) and lost 12.4 +/- 22.2% and 11.0 +/- 27.1% FM (P = 0.921) with the low and high doses, respectively. Females gained 8.3 +/- 7.3% and 12.5 +/- 12.8% LBM with the two doses (P = 0.630), but increased their FM by 3.5 +/- 16.2% with the lower dose and lost only 1.2 +/- 23.2% FM with the higher dose (P = 0.325). A similar pattern was seen in IGF-I sd score; the 2-yr GH dose response was significantly higher with the pediatric than with the adult dose in females (P = 0.008), but not males (P = 0.790). The divergent pattern of change in LBM and FM in males and females is consistent with normal developmental sexual dimorphism and indicates that GH-dependent progress to target body composition continues after the age at which GH treatment is usually terminated. Dose requirements may have to be adjusted by gender, with females requiring a higher dose than males.