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

Abstract

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.

Fig. 1

Short protocol for switching from insulin to SU. Major steps of the transfer protocol are displayed. Insulin dose (units per kilogram per day) is shown as a dotted line, and glibenclamide dose (milligrams per kilogram per day) is shown as a solid line. Insulin dose was reduced significantly already during the first day of therapy change without glycemia worsening (see also Fig. 2). OGTT, Oral glucose tolerance test.

Fig. 2

First day of switching from insulin to glibenclamide in the SK-1 patient (CGMS data). Glycemia decreased remarkably already after the first glibenclamide dose despite a 60% and 50% reduction of the basal insulin analog and the short acting analog, respectively.

Fig. 3

HbA1c before and after therapy change. After the first month on SU treatment, HbA1c level decreased significantly, and this improvement remained.