Meglitinide (repaglinide) therapy in permanent neonatal diabetes mellitus: two case reports.

BACKGROUND: Permanent neonatal diabetes mellitus (PNDM) presents with dehydration and hyperglycemia, which usually occurs during the first 12 months of life. Activating mutations of beta-cell adenosine triphosphate-sensitive potassium [KATP] channel subunits that cause opening of the channel are associated with PNDM. Some patients with PNDM respond to administration of a sulfonylurea derivative, which has long action on blood glucose even during hypoglycemia and has an apoptotic effect on beta cells. However, there have been no reports regarding treatment with meglitinide (repaglinide), which has rapid and short duration of action during the rise in blood glucose after meals that is more similar to beta cell function. It has no effects during hypoglycemia, so it does not cause neurological damage, and has no apoptotic effect on beta cells. We report herein the effects of repaglinide administration in the management and clinical outcome of two patients with PNDM during 9 and 10 years of follow-up. CASE PRESENTATION: Two Iranian infants were brought to our institution with poor general condition, dehydration, lethargy, and poor feeding. They had diabetic ketoacidosis at 52 days and 3.5 months of age, respectively. Their genetic analysis revealed mutations in the KCNJ11 gene encoding KIR6.2, so they both had PNDM. After treatment of diabetic ketoacidosis with insulin, they responded to sulfonylurea (glibenclamide) treatment, but were switched to repaglinide because of blood sugar fluctuations in terms of hyper- and hypoglycemia. Repaglinide was administered with the dosage of 0.04 mg/kg/day divided before every meal. RESULTS: The patients were 10 and 9 years old at the last visit, with normal growth parameters. The values of self-monitored blood glucose were well-controlled, and the hemoglobin A1C (HbA1C) levels ranged from 3.6 to 6.4% during the follow-up period. There was no complication of diabetes, neurological disorder, or adverse effects related to repaglinide. CONCLUSION: In every neonate or infant < 6 months of age with diabetes mellitus, PNDM should be considered. A trial of oral repaglinide can be performed and substituted for glibenclamide for prevention of hypoglycemia, neurological damage, and apoptosis of beta cells during long-term administration.

Identification of a novel nonsense mutation and a missense substitution in the AGPAT2 gene causing congenital generalized lipodystrophy type 1.

Congenital generalized lipodystrophy (CGL) is an autosomal recessive disease characterized by the generalized scant of adipose tissue. CGL type 1 is caused by mutations in gene encoding 1-acylglycerol-3-phosphate O-acyltransferase-2 (AGPAT2). A clinical and molecular genetic investigation was performed in affected and unaffected members of two families with CGL type 1. The AGPAT2 coding region was sequenced in index cases of the two families. The presence of the identified mutations in relevant parents was tested. We identified a novel nonsense mutation (c.685G>T, p.Glu229*) and a missense substitution (c.514G>A, p.Glu172Lys). The unaffected parents in both families were heterozygous carrier of the relevant mutation. The results expand genotype-phenotype spectrum in CGL1 and will have applications in prenatal and early diagnosis of the disease. This is the first report of Persian families identified with AGPAT2 mutations.