Clinical Care/Education/Nutrition/Psychosocial Research ORIGINAL ARTICLE

Effective Treatment With Oral Sulfonylureas in Patients With Diabetes Due to 1 (SUR1) Mutations

1,2 1 MEENA RAFIQ, SIAN ELLARD, PHD, MRCPATH of all cases of (9) and 1 1 SARAH E. FLANAGAN, BSC ANDREW T. HATTERSLEY, FRCP, DM frequently cause transient neonatal dia- 1 ANN-MARIE PATCH, PHD THE NEONATAL DIABETES INTERNATIONAL 1 betes (3,9,10). BEVERLEY M. SHIELDS, PHD COLLABORATIVE GROUP* In the normal pancreatic ␤-cell, me- tabolism results in increased cellular ATP, which binds to Kir6.2 to close the potas- OBJECTIVE — Neonatal diabetes can result from mutations in the Kir6.2 or sulfonylurea sium channel and hence depolarizes the ϩ receptor 1 (SUR1) subunits of the ATP-sensitive K channel. Transfer from insulin to oral membrane and, through increased cal- sulfonylureas in patients with neonatal diabetes due to Kir6.2 mutations is well described, but cium entry, initiates insulin release less is known about changing therapy in patients with SUR1 mutations. We aimed to describe the (11,12). Conversely, increased cellular response to sulfonylurea therapy in patients with SUR1 mutations and to compare it with Kir6.2 ADP acts on SUR1 to open the channel mutations. and prevent insulin release (11). Activat- RESEARCH DESIGN AND METHODS — We followed 27 patients with SUR1 muta- ing mutations in these channels reduces tions for at least 2 months after attempted transfer to sulfonylureas. Information was collected on sensitivity to the inhibitory actions of ATP clinical features, treatment before and after transfer, and the transfer protocol used. We com- and increases sensitivity to the stimula- pared successful and unsuccessful transfer patients, glycemic control before and after transfer, tory actions of ADP (2,9). This causes the ϩ and treatment requirements in patients with SUR1 and Kir6.2 mutations. ATP-sensitive K channel to remain open, even in the presence of glucose, RESULTS — Twenty-three patients (85%) successfully transferred onto sulfonylureas with- therefore preventing insulin release. out significant side effects or increased hypoglycemia and did not need insulin injections. In Sulfonylureas act by an ATP-indepen- these patients, median A1C fell from 7.2% (interquartile range 6.6–8.2%) on insulin to 5.5% dent mechanism to close these channels (5.3–6.2%) on sulfonylureas (P ϭ 0.01). When compared with Kir6.2 patients, SUR1 patients needed lower doses of both insulin before transfer (0.4 vs. 0.7 units kgϪ1 dayϪ1; P ϭ 0.002) even when mutations are present (2,9,13). and sulfonylureas after transfer (0.26 vs. 0.45 mg kgϪ1 dayϪ1; P ϭ 0.005). They result in insulin release and are there- fore a potential treatment option in neonatal CONCLUSIONS — Oral sulfonylurea therapy is safe and effective in the short term in most diabetes caused by mutations in these chan- patients with diabetes due to SUR1 mutations and may successfully replace treatment with nels. The effective replacement of insulin insulin injections. A different treatment protocol needs to be developed for this group because treatment by high-dose sulfonylureas has they require lower doses of sulfonylureas than required by Kir6.2 patients. been shown to be successful in 90% of pa- tients with Kir6.2 mutations and results in Diabetes Care 31:204–209, 2008 improved glycemic control in a series of 49 patients described by Pearson et al. (14). ctivating mutations in the Kir6.2 ported in the KCNJ11 and are There is far less information on sulfo- and sulfonylurea receptor 1 (SUR1) thought to account for between 25 and nylurea use in patients with SUR1 muta- subunits of the pancreatic ATP- 55% of all cases of neonatal diabetes tions. Successful transfer from insulin to A ϩ sensitive K channel, coded for by the (1,4–6). ABCC8 gene mutations may be oral sulfonylureas has been described in KCNJ11 and ABCC8, are recently either dominantly or recessively acting, eight patients with neonatal diabetes due to identified major causes of both transient and ϳ40 different mutations have been SUR1 mutations (9,10,15–17). This study and permanent neonatal diabetes (1–3). reported in patients with neonatal dia- will examine the treatment response to sul- To date, over 40 different heterozygous betes (7,8). Mutations in the ABCC8 fonylureas in a cohort of 27 patients with activating mutations have been re- gene are thought to account for ϳ10% diabetes due to SUR1 mutations to identify ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● whether they can be used effectively and how their transfer and treatment differ from From the 1Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, U.K.; and 2St. George’s University of London, London, U.K. that in Kir6.2 patients. Address correspondence and reprint requests to Professor Andrew T. Hattersley, Peninsula Medical School, Barrack Road, Exeter, EX2 5DW, U.K. E-mail: [email protected]. RESEARCH DESIGN AND Received for publication 11 September 2007 and accepted in revised form 12 November 2007. Published ahead of print at http://care.diabetesjournals.org on 19 November 2007. DOI: 10.2337/dc07- METHODS — We studied an interna- 1785. tional series of 27 patients with ages rang- *A full list of authors who contributed to this paper from the Neonatal Diabetes International Collabo- ing from 2 months to 46 years, with a rative Group can be found in the APPENDIX (alphabetical by author). genetic diagnosis of diabetes due to an Abbreviations: SUR1, sulfonylurea receptor 1. ABCC8 gene mutation (or mutations), © 2008 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby identified by sequencing in Exeter, U.K. marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Genetic information on 23 of these muta-

204 DIABETES CARE, VOLUME 31, NUMBER 2, FEBRUARY 2008 Rafiq and Associates

Table 1—Clinical characteristics of patients with SUR1 mutations according to success of treatment with sulfonylureas

Patients with successful sulfonylurea Patients with unsuccessful sulfonylurea Characteristic All patients treatment treatment P* n 27 23 4 Mutation (number of NA V86G†, P45L/G1401R- (2)†, D209E F132L (2)†, F132V†, and N72S† NA patients) (3)†, T229I/V1523L†, Q211K†, (mosaic). V86A (2)†, E1507G, V215I/V607M, E208K/Y263D†, R1380L (2)‡, D212I (3)§, T229I/T229I‡, R1183W§, L225P†, R826W, and D209N Classification: TNDM 2/6/17/2 2/6/13/2 0/0/4/0 NA initial/TNDM relapse/ PNDM/non-neonatal diabetes Neurological features 6 (22) 4 (17) 2 (50) 0.20 Male sex 10 (37) 8 (35) 2 (50) 0.61 Birth weight (g) 2,675 (1,470–3,870) 2,675 (1,470–3,500) 2,670 (2,440–3,870) Birth weight (SD score) Ϫ1.3 (Ϫ2.8 to 0.64) Ϫ1.3 (Ϫ2.8 to Ϫ0.1) Ϫ1.1 (Ϫ1.4 to 0.64) 0.22 Age at diagnosis (weeks) 6 (0–30) 5 (0–30) 17 (5–26) 0.046 Age at start of 7.8 (0.2–46.5) 7.1 (0.2–46.5) 14.9 (0.4–28.5) 0.52 sulfonylurea treatment (years) A1C before sulfonylurea 7.5 (5.0–21.0) 7.1 (5.0–21.0) 10.0 (7.5–12.0) 0.11 treatment (%) Insulin dose (units kgϪ1 0.5 (0.2–1.2) 0.4 (0.2–0.9) 0.8 (0.4–1.2) 0.097 dayϪ1) Equivalent dose of 0.28 (0.07–2.80) 0.26 (0.07–2.80) 1.00 (1.00–1.12) NA glyburide (mg kgϪ1 dayϪ1) Data are median (range), n (%), or n unless otherwise indicated. Percentages are rounded up to the nearest whole number. *P values are for comparison of the patients with a successful switch with patients with an unsuccessful switch and were calculated by the Mann-Whitney U test or Fisher’s exact test for categorical data. †Reported in Ellard et al., 2007 (ref. 7); ‡reported in Patch et al., 2007 (ref. 8); §reported in Flanagan et al., 2007 (ref. 3). NA, not applicable. tions has previously been published (3,7) Switch to sulfonylureas the sulfonylurea dose as a percentage of (Table 1). Most patients were referred For this study, clinicians were provided the maximum recommended dose (ac- based on membership in the International with two recommended protocols for the cording to the British National Formulary Society of Pediatric and Adolescent Dia- transfer to the sulfonylurea glyburide 2007) and converting this to an equiva- betes. All of the patients attempted trans- (also known as glibenclamide) as used for lent dose of glyburide. Transfer was con- fer from treatment with insulin to a Kir6.2 patients (see www.diabetesgene- sidered a success if the patient was able to sufficient dose of sulfonylureas except s.org and 14). One was for a rapid inpa- completely stop insulin at any dose of sul- two, who were initially on no treatment tient transfer, where the glyburide dose fonylurea and was considered unsuccess- Ϫ1 Ϫ1 and then treated with sulfonylureas when was increased by 0.2 mg kg day ful if insulin was still required with a dose every day and the other for a slower out- of sulfonylurea equivalent to at least 0.6 treatment was required. The dose of sul- Ϫ Ϫ patient transfer, where the glyburide dose mg kg 1 day 1 glyburide. fonylurea was considered to be sufficient Ϫ Ϫ was increased by 0.2 mg kg 1 1 if equivalent to at least 0.6 mg kg body day Information was collected from clini- Ϫ Ϫ every week. Both involved the gradual cians regarding treatment before and after wt 1 day 1 of glyburide use; this is the withdrawal of insulin as sulfonylurea was transfer, clinical features, and details of highest reported dose required in previ- introduced depending on blood glucose. the transfer. Clinical features were com- ously published cases with patients with These protocols were modified by the pared between patients who successfully ABCC8 gene mutations (9). No other se- treating clinicians. In seven patients, as a transferred onto sulfonylureas and pa- lection criteria were applied, and all pa- result of physician choice, the recom- tients whose transfer was unsuccessful. tients were included when there was mended sulfonylurea, glyburide, was not Fisher’s exact test for categorical data and outcome data for the attempted transfer. used: three patients used gliclazide, three the Mann-Whitney U test for continuous The observation period was at least 2 used glipizide, and one used tolbutamide. data were used because the data were not months after commencing sulfonylureas For these patients, equivalent doses of normally distributed. Glycemic control in all patients. Treatment details for two glyburide were calculated to allow inclu- before and after sulfonylurea therapy was patients have been described previously sion of these results. This, as previously compared by analyzing the A1C values (8,15,17). described (14), was done by expressing using Wilcoxon’s signed-rank test. Doses

DIABETES CARE, VOLUME 31, NUMBER 2, FEBRUARY 2008 205 Sulfonylurea use in SUR1 diabetes of insulin and sulfonylurea used in Kir6.2 and SUR1 patients who successfully transferred from insulin to sulfonylurea therapy were compared using the Mann- Whitney U test. All tests were two sided. Data are expressed as median (range). Dif- ferences with a P value Ͻ0.05 were con- sidered statistically significant. This study was conducted in accor- dance with the Declaration of Helsinki as revised in 2000. Informed consent was obtained from all participating patients, with parental consent given on behalf of children.

RESULTS

Successful transfer Of the 27 patients who attempted transfer onto sulfonylureas at an adequate dose, 23 (85%) were successful in being able to be treated with sulfonylureas alone. Suc- cessful transfer occurred with all the dif- ferent sulfonylureas used, suggesting that choice of agent was not critical. The clin- ical characteristics of these patients are shown in Table 1. The ages of these pa- tients at transfer ranged from 2 months to 46 years. All eight patients with transient neonatal diabetes were successfully treated with sulfonylureas: six were treated having relapsed, and two were treated in the initial diabetic phase before they went into remission ϳ11 months af- ter transfer. Four patients with neurolog- ical features successfully transferred onto sulfonylureas; all of these had develop- mental delay, and one also had general- ized seizures. Median A1C level dropped from 7.2% (interquartile range 6.6–8.2) on insulin to 5.5% (5.3–6.2) on sulfonyl- ureas (P ϭ 0.011) (see Fig. 1A) in the 10 Figure 1—Initial reduction in A1C levels following transfer from insulin to sulfonylurea. patients in whom A1C measurements were available before and at least 4 weeks peptide levels following the transfer, but patient had mild transitory diarrhea on after transfer (median 15 weeks). it was decided that the response was in- glyburide, which has been previously In the five patients for whom fol- sufficient to discontinue insulin. Two of reported (15), but when transferred to low-up data were available for Ͼ6 the patients had neurological features, in- tolbutamide, another sulfonylurea, no months following transfer onto sulfonyl- cluding one patient who had severe devel- further side effects were experienced. urea, glycemic control continued to im- opmental delay, epilepsy, and neonatal Another patient had morning nausea prove despite decreasing sulfonylurea diabetes (2). while on glyburide, which may have doses, with a mean drop in A1C levels of Clinical features of the patients ac- been a side effect of the sulfonylurea 1.86% (95% CI 0.2- 3.5) from after trans- cording to whether transfer was success- therapy but resolved without discon- fer to the most recent value (Fig. 1B). ful are shown in Table 1. Unsuccessful tinuing treatment. Transitory nausea patients were diagnosed as diabetic later: has been previously reported in patients Unsuccessful transfer median age at diagnosis 17 weeks (range on glyburide (18). One severe hypogly- 5–26) compared with 5 weeks (0–30) cemic episode (grade three in the Inter- Four patients were unable to completely ϭ stop treatment with insulin despite re- (P 0.046). national Society of Pediatric and ceiving an adequate dose of at least 1 mg Adolescent Diabetes 2000 consensus Ϫ Ϫ kg 1 day 1 of sulfonylurea (Table 1). Side effects guidelines) was reported in a patient, Two of these patients with F132V and Three patients reported side effects dur- requiring a reduction in dosage of sul- F132L mutations had increased C- ing treatment with sulfonylureas. One fonylureas. This patient also experi-

206 DIABETES CARE, VOLUME 31, NUMBER 2, FEBRUARY 2008 Rafiq and Associates

Table 2—Comparison of clinical characteristics of patients with SUR1 and Kir6.2 mutations Lower doses of sulfonylureas were who successfully transferred from insulin to sulfonylureas needed in the SUR1 patients compared with the Kir6.2 patients. This meant that SUR1 patients with Kir6.2 patients with doses were closer to those used in type 2 successful sulfonylurea successful sulfonylurea diabetic patients if calculated as dose cor- Characteristic treatment treatment* P† rected for body weight, while those used in patients with Kir6.2 mutations were n 21 44 considerably higher. It is likely that this Neurological features 4 (19) 6 (14) 0.72 reduced dose of sulfonylureas repre- Male sex 8 (38) 24 (55) 0.16 sented increased endogenous insulin se- Birth weight (g) 2,700 (1,470–3,500) 2,740 (1,871–3,570) 0.27 cretion, as the patients also required less Ϫ Ϫ Ϫ Ϫ Ϫ Birth weight (SD score) 1.3 ( 2.79 to 0.1) 1.0 ( 3.7 to 1.3) 0.46 insulin before transfer. Further support Age at diagnosis (weeks) 5 (0–30) 6 (0–152) 0.52 that the degree of endogenous insulin se- Age at start of sulfonylurea 7.2 (0.2–46.5) 6 (0.2–36.0) 0.55 cretion determines the sulfonylurea dose treatment (years) came from the four patients with excellent Days to transfer 3.5 (1–107) 12 (0–170) 0.12 control on insulin (A1C Ͻ7%), who all A1C before sulfonylurea 7.1 (5.0–21.0) 8.1 (6.3–13.1) 0.062 required very low doses of sulfonylureas treatment (%) Ϫ1 Ϫ1 Ϫ Ϫ (Ͻ0.1 mg kg day ). The lower sul- Insulin dose (units kg 1 day 1) 0.4 (0.2–0.9) 0.7 (0.1–1.2) 0.002 fonylurea requirements suggest that a dif- Equivalent dose of glyburide 0.26 (0.07–2.8) 0.45 (0.05–1.5) 0.005 Ϫ Ϫ ferent protocol for transfer onto (mg kg 1 day 1) sulfonylureas is needed for SUR1 patients Data are median (range) or n (%) unless otherwise indicated. Data from the Kir6.2 patients are taken from ref. 14. *Data from Pearson et al. (ref. 14). †P values are for comparison of the patients with SUR1 mutations with than for Kir6.2 patients. We suggest that patients with Kir6.2 mutations and were calculated by the Mann-Whitney U test or Fisher’s exact test for in SUR1 patients, the gradual increase in categorical data. glyburide dose recommended during in- Ϫ patient transfer should be 0.1 mg kg 1 Ϫ day 1, which is one-half the increase per enced abdominal discomfort, which CONCLUSIONS — We found that day used for Kir6.2 patients. Particular started before the transfer but may have the majority of patients (85%) with dia- care should be taken when attempting worsened during treatment with gly- betes due to ABCC8 gene mutations could transfer in patients with evidence of exist- buride. No other severe hypoglycemic be successfully treated with oral sulfonyl- ing endogenous insulin secretion. These episodes were reported before or after urea treatment even if they had previously patients are likely to already have good glycemic control, with A1C levels Ͻ7%, the transfer onto sulfonylureas in any been treated with insulin. As with those Ϫ Ϫ patients, and no other side effects were with Kir6.2 mutations (14), patients who insulin doses Ͻ0.5 units kg 1 day 1, reported. transferred from insulin showed mark- and measurable C-peptide. It is likely that edly improved glycemic control, and the these patients will need lower doses of Comparison with patients with good control was maintained over the first sulfonylureas; they should be monitored Kir6.2 mutations who successfully year. There was no evidence that despite closely to avoid hypoglycemic episodes, transferred to sulfonylureas the improved control, there was an in- and an even slower increase in glyburide Our SUR1 patients who successfully crease in hypoglycemia. should be considered. Despite this, some transferred from insulin to sulfonylureas were compared with the previously pub- lished series of patients with Kir6.2 mu- tations published by Pearson et al. (14) (Table 2). Comparison of treatment in SUR1 patients with Kir6.2 patients showed different treatment requirements (Fig. 2). The SUR1 patients needed a lower dose of insulin before transfer (me- Ϫ Ϫ dian of 0.4 units kg 1 day 1 ([0.2– 0.9]) compared with that in Kir6.2 Ϫ Ϫ patients (0.7 units kg 1 day 1 [0.1 -1.2]) (P ϭ 0.002). SUR1 patients also required a lower dose of sulfonylurea after Ϫ transfer, with a median of 0.26 mg kg 1 Ϫ day 1 (0.07–0.63) compared with 0.45 Ϫ Ϫ mg kg 1 day 1 (0.05–1.50) in Kir6.2 patients (P ϭ 0.005). In four SUR1 pa- tients, the dose of sulfonylurea required Ϫ1 Ϫ1 Figure 2—Lower treatment doses are needed in patients with SUR1 mutations compared with was less than 0.1 mg kg day , and those with Kir6.2 mutations f. Median insulin and sulfonylurea doses are shown for 21 patients these patients all had A1C levels on insu- with SUR1 mutations and 44 with Kir6.2 mutations who successfully transferred from insulin to lin treatment Ͻ7%. sulfonylurea therapy.

DIABETES CARE, VOLUME 31, NUMBER 2, FEBRUARY 2008 207 Sulfonylurea use in SUR1 diabetes patients may still need high doses of sul- was performed in multiple centers kum, Berlin, Germany; Mathias Herr, fonylureas, particularly if transferred out- throughout the world; hence, it is not Charitie Campus Virchow Klinikum, Ber- side childhood. possible to ensure a standard protocol, as lin, Germany; Khalid Hussain, Great Or- The prevalence of side effects was shown by the choice of medication vary- mond Street Hospital for Children, low. There was only one severe hypogly- ing. Finally, it is not possible to be certain London, U.K.; Laurent Legault, Montreal cemic episode reported in our cohort, but about the prevalence of hypoglycemia be- Children’s Hospital, Montreal, Canada; this is further evidence that caution and fore and after transfer, as this were not Maciek Malecki, Jagiellonian University, close blood glucose monitoring is needed formally studied using techniques such as Krakow, Poland; Magdalena Paskova, during transfer to avoid hypoglycemic ep- 24-h glucose monitoring. Children’s University Hospital, Kosice, isodes. Despite this, sulfonylurea use in We conclude that most patients with Slovakia; Ewan Pearson, University of this group appears to be safe, with the ABCC8 gene mutations can successfully Dundee, Dundee, U.K.; Christine Rodda, only other side effects reported being transfer onto sulfonylureas. This treat- Monash Medical Centre, Victoria, Austra- mild transitory diarrhea, morning nausea, ment has been shown to be safe and lia; Anya Rothenbuhler, Hopital Saint and abdominal discomfort. Sulfonylurea achieve improved glycemic control in the Vincent de Paul, Paris, France; Juan Ϫ Ϫ doses of over 1 mg kg 1 day 1 were short term. Long-term follow up is Sanchez, Rilex Hospital for Children, In- used in this study with no reported ad- needed in a large cohort of patients to see dianapolis, Indiana, U.S.; Julian Shield, verse effects. Continued close follow-up is whether trends in improved glycemic Bristol Children’s Hospital, Bristol, U.K.; recommended in view of the high doses control and decreased sulfonylurea dose Ra`ceala`-Motoc Stanca, Pediatrics Hospi- used. continue. In comparison with Kir6.2 pa- tal of Sibiu, Sibiu, Romania; John Van der Four patients in our study were un- tients, lower doses of both insulin and Meulen, McMaster Children’s Hospital, able to completely stop insulin and suc- sulfonylurea were found in SUR1 pa- Ontario, Canada. cessfully transfer onto sulfonylureas. tients, suggesting that they have greater Patients who could not transfer were di- endogenous insulin secretion. We recom- agnosed with diabetes later in life than mend that patients with diabetes diag- References those who did transfer. This might sug- nosed before 6 months of age should 1. Gloyn AL, Pearson ER, Antcliff JF, Proks gest that in addition to the characteristics undergo genetic testing for ABCC8 gene P, Bruining GJ, Slingerland AS, Howard of the mutation, exposure before diagno- mutations if they do not have a KCNJ11 N, Srinivasan S, Silva JM, Molnes J, Edghill EL, Frayling TM, Temple IK, sis of the pancreatic islet to untreated hy- mutation encoding Kir6.2 and if positive Mackay D, Shield JP, Sumnik Z, van Rhijn perglycemia might alter response to transfer onto oral sulfonylureas be at- A, Wales JK, Clark P, Gorman S, Aisen- sulfonylureas. Two of the patients who tempted but using a different protocol berg J, Ellard S, Njolstad PR, Ashcroft FM, could not transfer also have neurological than that for Kir6.2 patients. Hattersley AT: Activating mutations in the complications, including one case of de- gene encoding the ATP-sensitive potassi- velopmental delay, epilepsy, and neonatal um-channel subunit Kir6.2 and perma- diabetes, which is the most severe form of Acknowledgments— We acknowledge nent neonatal diabetes. N Engl J Med 350: neonatal diabetes (DEND syndrome). funding from the Wellcome Trust (to M.R.). 1838–1849, 2004 Previous studies have shown that patients We also acknowledge funding from the Sir 2. Proks P, Arnold AL, Bruining J, Girard C, with neurological complications and Graham Wilkins studentship (to SE.F.). This Flanagan SE, Larkin B, Colclough K, Hat- study was funded by the Wellcome Trust and tersley AT, Ashcroft FM, Ellard S: A het- Kir6.2 mutations are less likely to success- was supported by the European Union (Inte- erozygous activating mutation in the fully transfer onto sulfonylureas (14). grated Project EURODIA LSHM-CT-2006- sulphonylurea receptor SUR1 (ABCC8) This can be explained by in vitro studies 518153 in the Framework Programme six of causes neonatal diabetes. Hum Mol Genet that found that mutations associated with the European Community). A.T.H. is a Well- 15:1793–1800, 2006 neurological symptoms are less respon- come Trust Research Leave Fellow. 3. Flanagan SE, Patch AM, Mackay DJ, sive to sulfonylureas as well as respond- The authors thank all of the families for par- Edghill EL, Gloyn AL, Robinson D, Shield ticipating in this study. Our thanks go to the JP, Temple K, Ellard S, Hattersley AT: Mu- ing less to ATP (19,20). Despite this, ϩ four patients in our study who had neu- many referring clinicians. tations in ATP-sensitive K channel genes rological features successfully trans- cause transient neonatal diabetes and per- ferred onto sulfonylureas. This APPENDIX manent diabetes in childhood or adult- hood. Diabetes 56:1930–1937, 2007 indicates that presence of neurological 4. Massa O, Iafusco D, D’Amato E, Gloyn complications in patients with diabetes Contributing clinicians: AL, Hattersley AT, Pasquino B, Tonini G, due to SUR1 mutations should not act as a Chandar Batra, Batra Hospital, New Dammacco F, Zanette G, Meschi F, Porzio barrier to attempting sulfonylurea ther- Delhi, India; Jan Bruining, Sophia Chil- O, Bottazzo G, Crino A, Lorini R, Cerutti apy. dren’s Hospital, Rotterdam, Holland; F, Vanelli M, Barbetti F: KCNJ11 activat- Our study had some limitations. At Dennis Carson, Royal Belfast Hospital for ing mutations in Italian patients with per- present, it is only possible to comment Sick Children, Belfast, Northern Ireland; manent neonatal diabetes. Hum Mutat 25: that transfer to sulfonylureas is successful Ethel Codner, University of Chile, San- 22–27, 2005 in the short term, as we do not have fol- tiago, Chile; Elizabeth Cummings, IWK 5. Vaxillaire M, Populaire C, Busiah K, low-up data outside the immediate start- Health Centre, Nova Scotia, Canada; Jac- Cave H, Gloyn AL, Hattersley AT, Czer- nichow P, Froguel P, Polak M: Kir6.2 ing of sulfonylurea treatment. It is queline Curran, University of Western mutations are a common cause of per- encouraging that the few patients with Australia, Perth, Western Australia; Eliz- manent neonatal diabetes in a large co- data over the first year maintained excel- abeth Davis, Princess Margaret Hospital hort of French patients. Diabetes 53: lent glycemic control despite a decreasing for Children, Perth, Australia; Dorothee 2719–2722, 2004 sulfonylurea dose over time. The transfer Deiss, Charitie Campus Virchow Klini- 6. Flanagan SE, Edghill EL, Gloyn AL, Ellard

208 DIABETES CARE, VOLUME 31, NUMBER 2, FEBRUARY 2008 Rafiq and Associates

S, Hattersly AT: Mutations in KCNJ11, natal diabetes and clinical features. Diabe- McKnight H, Stanley CA, Nichols CG: A which encodes Kir6.2, are a common tes 56:1737–1741, 2007 mutation in the TMD0–L0 region of sul- cause of diabetes diagnosed in the first 6 11. Tucker SJ, Gribble FM, Zhao C, Trapp S, fonylurea receptor-1 (L225P) causes per- months of life with the phenotype deter- Ashcroft FM: Truncation of Kir6.2 pro- manent neonatal diabetes mellitus mined by genotype. Diabetologia 49: duces ATP-sensitive Kϩ channels in the (PNDM). Diabetes 56:1357–1362, 2007 1190–1197, 2006 absence of the sulphonylurea receptor. 17. Stanik J, Gasperikova D, Paskova M, 7. Ellard S, Flanagan SE, Girard CA, Patch Nature 387:179–183, 1997 Barak L, Javorkova J, Jancova E, Ciljakova AM, Harries LW, Parrish A, Edghill EL, 12. Gloyn AL, Siddiqui J, Ellard S: Mutations M, Hlava P, Michalek J, Flanagan SE, Mackay DJG, Proks P, Shimomura K, in the genes encoding the pancreatic beta- Pearson E, Hattersley AT, Ellard S, Klimes Haberland H, Carson DJ, Shield JPH, Hat- cell KATP channel subunits Kir6.2 I: Prevalence of permanent neonatal dia- tersley AT, Ashcroft FM: Permanent neo- (KCNJ11) and SUR1 (ABCC8) in diabetes betes in Slovakia and successful replace- natal diabetes caused by dominant, mellitus and hyperinsulinism. Hum Mutat ment of insulin with sulfonylurea therapy recessive, or compound heterozygous 27:220–231, 2006 in KCNJ11 and ABCC8 mutation carriers. SUR1 mutations with opposite functional 13. Ashcroft FM, Gribble FM: Tissue-specific J Clin Endocrinol Metab 92:1276–1282, effects. Am J Hum Genet 81:375–382, effects of sulfonylureas: lessons from 2007 2007 studies of cloned K(ATP) channels. J Dia- 18. Malecki MT, Skupien J, Klupa T, Wanic 8. Patch AM, Flanagan SE, Boustred C, Hat- betes Complications 14:192–196, 2000 K, Mlynarski W, Gach A, Solecka I, Si- tersley AT, Ellard S: Mutations in the 14. Pearson ER, Flechtner I, Njolstad PR, Ma- eradzki J: Transfer to sulphonylurea ther- ABCC8 gene encoding the SUR1 subunit lecki MT, Flanagan SE, Larkin B, Ashcroft apy in adult subjects with permanent of the KATP channel cause transient neo- FM, Klimes I, Codner E, Iotova V, Sling- neonatal diabetes due to KCNJ11-activat- natal diabetes, permanent neonatal diabe- erland AS, Shield J, Robert JJ, Holst JJ, ing mutations: evidence for improvement tes or permanent diabetes diagnosed Clark PM, Ellard S, Sovik O, Polak M, in insulin sensitivity. Diabetes Care outside the neonatal period. Diabetes Obes Hattersley AT: Switching from insulin to 30:147–149, 2007 Metab 9 (Suppl. 2):28–39, 2007 oral sulfonylureas in patients with diabe- 19. Proks P, Antcliff JF, Lippiat J, Gloyn AL, 9. Babenko AP, Polak M, Cave H, Busiah K, tes due to Kir6.2 mutations. N Engl J Med Hattersley AT, Ashcroft FM: Molecular Czernichow P, Scharfmann R, Bryan J, 355:467–477, 2006 basis of Kir6.2 mutations associated with Aguilar-Bryan L, Vaxillaire M, Froguel P: 15. Codner E, Flanagan SE, Ugarte F, Garcı´a neonatal diabetes or neonatal diabetes Activating mutations in the ABCC8 gene H, Vidal T, Ellard S, Hattersley AT: Sulfo- plus neurological features. Proc Natl Acad in neonatal diabetes mellitus. N Engl J Med nylurea treatment in young children with SciUSA101:17539–17544, 2004 355:456–466, 2006 neonatal diabetes: dealing with hypergly- 20. Trapp S, Proks P, Tucker SJ, Ashcroft FM: 10. Vaxillaire M, Dechaume A, Busiah K, cemia, hypoglycemia, and sick days (Let- Molecular analysis of ATP-sensitive K Cave H, Pereira S, Scharfmann R, de Nan- ter). Diabetes Care 30:e28–e29, 2007. channel gating and implications for chan- clares GP, Castano L, Froguel P, Polak M: DOI: 10.2337/dc06-2134 nel inhibition by ATP. J Gen Physiol 112: New ABCC8 mutations in relapsing neo- 16. Masia R, De Leon DD, MacMullen C, 333–349, 1998

DIABETES CARE, VOLUME 31, NUMBER 2, FEBRUARY 2008 209