Early Postnatal Use of Glibenclamide in Permanent Neonatal Diabetes Secondary to Antenatally Diagnosed KJCN11 Mutation.

INTRODUCTION: Heterozygous activating mutations in KCNJ11 cause both permanent and transient neonatal diabetes. A minority of patients also have neurological features. Early genetic diagnosis has important therapeutic implications as treatment with sulfonylurea provides good metabolic control and exerts a protective effect on neuromuscular function. CASE PRESENTATION: A term female infant with normal birth weight (2.73 kg, z-score: -1.69) was admitted to the Neonatal Unit at Addenbrookes Hospital. She had been antenatally diagnosed with KCNJ11 mutation-R201C inherited from her glibenclamide-treated mother who continued sulfonylurea treatment throughout pregnancy. A continuous glucose-monitoring system inserted at 20 h of age showed progressive rise of blood glucose concentrations, prompting treatment with glibenclamide on day 2 of life. Initial attempts to treat with an extemporaneous solution of glibenclamide (starting dose 0.2 mg/kg/day) resulted in inconsistent response and significant hypoglycaemia and hyperglycaemia. A licenced liquid formulation of glibenclamide (AMGLIDIA) at a starting dose of 0.05 mg/kg/day was used with stabilization of blood glucose profile within 24 h. Other than a mild transient elevation in transaminase, treatment was well tolerated. At most recent review (age 12 months), the patient remains well with age-appropriate neurodevelopment. Overall glucose control is reasonable with estimated HbA1c of 7.6% (59.9 mmol/mol). CONCLUSION: Early postnatal glibenclamide treatment of insulin-naive patients with KATP-dependent neonatal diabetes is safe, provides good metabolic control, and has a potential protective effect on neurological function. The formulation of the medicine needs to be carefully considered in the context of the very small doses required in this age group.

Long-term DHEA replacement in primary adrenal insufficiency: a randomized, controlled trial.

CONTEXT: Dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) are the major circulating adrenal steroids and substrates for peripheral sex hormone biosynthesis. In Addison's disease, glucocorticoid and mineralocorticoid deficiencies require lifelong replacement, but the associated near-total failure of DHEA synthesis is not typically corrected. OBJECTIVE AND DESIGN: In a double-blind trial, we randomized 106 subjects (44 males, 62 females) with Addison's disease to receive either 50 mg daily of micronized DHEA or placebo orally for 12 months to evaluate its longer-term effects on bone mineral density, body composition, and cognitive function together with well-being and fatigue. RESULTS: Circulating DHEAS and androstenedione rose significantly in both sexes, with testosterone increasing to low normal levels only in females. DHEA reversed ongoing loss of bone mineral density at the femoral neck (P < 0.05) but not at other sites; DHEA enhanced total body (P = 0.02) and truncal (P = 0.017) lean mass significantly with no change in fat mass. At baseline, subscales of psychological well-being in questionnaires (Short Form-36, General Health Questionnaire-30), were significantly worse in Addison's patients vs. control populations (P < 0.001), and one subscale of SF-36 improved significantly (P = 0.004) after DHEA treatment. There was no significant benefit of DHEA treatment on fatigue or cognitive or sexual function. Supraphysiological DHEAS levels were achieved in some older females who experienced mild androgenic side effects. CONCLUSION: Although further long-term studies of DHEA therapy, with dosage adjustment, are desirable, our results support some beneficial effects of prolonged DHEA treatment in Addison's disease.