The identification of a R201H mutation in KCNJ11, which encodes Kir6.2, and successful transfer to sustained-release sulphonylurea therapy in a subject with neonatal diabetes: evidence for heterogeneity of beta cell function among carriers of the R201H mutation
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The primer set used to amplify KCNJ11, the gene that encodes Kir6.2, with M13 tails
5′–3′ Forward primer
5′–3′ Reverse primer
TGT AAA ACG ACG GCC AGT CCG AGA GGA CTC TGC AGT GA
CAG GAA ACA GCT ATG ACC TAG TCA CTT GGA CCT CAA TGG AG
TGT AAA ACG ACG GCC AGT CTG CTG AGC CCT GTG TCA CC
CAG GAA ACA GCT ATG ACC CAC GCC TTC CAG GAT GAC GAT
TGT AAA ACG ACG GCC AGT CTA CCA TGT CAT TGA TGC TGC CAA
CAG GAA ACA GCT ATG ACC CCA CAT GGT CCG TGT GTA CAC AC
As patients with Kir6.2 diabetes may respond to sulphonylureas, we assessed whether this patient could successfully transfer to sulphonylurea tablets [3, 4]. Glipizide gastrointestinal therapeutic system (GITS), a controlled-release sulphonylurea, was introduced . A dose of 5 mg was administered for 2 days, then 10 mg; insulin was simultaneously slowly withdrawn over a period of 5 days. As the patient experienced a few mild hypoglycaemic episodes during the first 2 days after the discontinuation of insulin the glipizide GITS dose was decreased to 5 mg. While on this dose, a day profile of his capillary glucose concentrations revealed that they were between 4 and 6 mmol/l; a result confirmed by a 72-h record obtained using a continuous glucose monitoring system (Medtronic, Northridge, CA, USA). The IVGTT was repeated 3 weeks after a stable glipizide dose was achieved. At this time the patient’s fasting glucose level was 5.4 mmol/l, and his C-peptide level was 347 pmol/l. The peak increase in insulin concentration during the IVGTT was 197 pmol/l—almost three times higher than that measured prior to sulphonylurea treatment (Fig. 1).
Four individuals on the maternal side of his family had diabetes. The mother developed gestational diabetes at 31 years of age, during her first pregnancy, and remained on insulin until the delivery of the proband. She was also diagnosed with diabetes during her second pregnancy, and an OGTT performed 6 weeks after delivery showed that she remained diabetic. She is treated by diet and does not have type 1 diabetes-related antibodies. Three other distant relatives had typical late-onset type 2 diabetes. These were aged >40 years at diagnosis and do not require insulin treatment. The R201H mutation was not present in the proband’s diabetic mother or in three other family members examined, including one diabetic relative. The proband’s father was not available; however, he is not known to have diabetes. It is therefore likely the proband has a new mutation, as is usually the case with KCNJ11 mutations [3, 4].
Our data support earlier reports suggesting that mutations in Kir6.2 are usually found in patients diagnosed at <3 months of age [3, 4] and that these mutations are uncommon in those aged >6 months . Although the proband had other relatives who had diabetes, these individuals did not have the mutation, thus demonstrating heterogeneity of aetiology in this family. A family history of later-onset diabetes should not influence the decision to test for Kir6.2 mutations. The R201H mutation found in this Polish child has previously been described in neonatal diabetes, and has been shown to reduce the response of the Kir6.2 channel to ATP in functional studies [3, 4]. Despite having a low birthweight and a similar age at diagnosis (<6 months) there are some striking differences between our patient and the previously reported cases. Our patient’s insulin requirement was substantially lower than in ten previously reported R201H carriers (0.25 vs ≥0.6 U/kg) [3, 4]. In keeping with this, both his basal C-peptide concentration (443 vs <20 pmol/l) and his peak increase in insulin response during an IVGTT before treatment with sulphonylureas (70 vs <3 pmol/l) were considerably higher than those in the other R201H carriers [3, 4]. These results are consistent with our patient having greater endogenous beta cell function than others with the same mutation, supporting the presence of phenotypic heterogeneity. Its cause is not known, but it could represent polygenic or environmental factors. These might include the allele status at other KCNJ11 polymorphic sites, since, surprisingly, the proband was a homozygote for the K allele at residue 23 of the protein, which predisposes to type 2 diabetes . Interestingly, the five R201H carriers with the more severe beta cell defect carried at least one E variant [3, and E. E., S. E. and A. H. unpublished data]. Further studies are needed to determine whether the interaction between the R201H mutation and the variant at residue 23 influence the severity of beta cell dysfunction.
In summary, we have described the successful initial transfer of a patient with Kir6.2 mutation from insulin to a sustained-release sulphonylurea. The lowest adult dose of glipizide (5 mg) resulted in a markedly increased acute insulin response to an IVGTT, despite the fact that the last dose was administered 24 h before the investigation. The heterogeneity of beta cell function in association with the R201H mutation suggests that the response to sulphonylurea treatment may vary considerably between individuals even if they have the same mutation.
T. Klupa and E. L. Edghill contributed equally to this work. We thank A. Gloyn for her considerable assistance with this project, including setting up the sequencing of KCNJ11 in Exeter. M. T. Malecki is supported by the National Institutes of Health Fogarty International Research Collaboration Award (Grant no. 1 R03 TW01351-01) and the Jagiellonian University (Medical College Grant no. 501/KL/439/L). E. L. Edghill and A. T. Hattersley are supported by the Wellcome Trust. A. T. Hattersley is a Wellcome Trust Research Leave Fellow.
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