This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Slingerland, A. S. Articles by Hattersley, A. T. Search for Related Content PubMed PubMed Citation Articles by Slingerland, A. S. Articles by Hattersley, A. T. Pubmed/NCBI databases Gene GEO Profiles HomoloGene OMIM UniGene Compound via MeSH Substance via MeSH Medline Plus Health Information Diabetes Related Collections Pediatric Endocrinology Diabetes and Insulin

Activating Mutations in the Gene Encoding Kir6.2 Alter Fetal and Postnatal Growth and Also Cause Neonatal Diabetes

Institute of Biomedical and Clinical Science (A.S.S., A.T.H.), Peninsula Medical School, Exeter EX2 5DW, United Kingdom; and Department of Cardiology (A.S.S.), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

Address all correspondence and requests for reprints to: Professor Andrew T. Hattersley, Peninsula Medical School, Barrack Road, Exeter EX2 5DW, United Kingdom. E-mail: a.t.hattersley{at}ex.ac.uk.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Birth weight is a bioassay for fetal insulin secretion because altered insulin secretion in utero alters insulin-mediated growth. Activating mutations in Kir6.2 are the major cause of neonatal diabetes and reduce insulin secretion by altering the closure of the ß-cell ATP-sensitive potassium channel in the presence of ATP.

Objective: Our objective was to examine fetal and postnatal growth in patients with activating Kir6.2 mutations and identify whether this was modified by severity of mutation or maternal diabetes.

Patients and Methods: We used SD scores (SDS) for birth and postnatal growth in an international series of patients (n = 49) with Kir6.2 mutations and related this to their clinical phenotype.

Results: Birth weight was greatly reduced [–1.73 (–3.68 to 1.41), median (range) SDS], but there was postnatal catch-up because present weight was normal [–0.37 (–4.37 to 2.34) SDS]. Catch-up growth for height and weight was not seen until insulin treatment was started. Birth weight was not influenced by severity of postnatal phenotype but was increased by maternal diabetes –0.12 vs. –1.81 SDS (P = 0.037). Patients with the severe neurological developmental delay, epilepsy, and neonatal diabetes syndrome did not catch up (present weight –2.2 vs. –0.24 SDS (P = 0.003).

Conclusions: Kir6.2 mutations greatly reduce fetal insulin secretion and hence fetal growth, but this is independent of mutation severity. Increased fetal growth in response to maternal diabetes suggests that either the Kir6.2 mutated fetal ß-cell is still glucose responsive or there is a non-insulin-mediated increase in fetal growth. Postnatal catch-up requires insulin treatment but is complete, except in those with epilepsy.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
LOW BIRTH WEIGHT is associated with diabetes mellitus in late adult life. It has been proposed that this may reflect programming of the fetus in utero (1) or alternatively reflect two phenotypes of a single genotype with reduced insulin mediated growth in utero and reduced insulin secretion and/or insulin action (2). One of the arguments used for a genetic hypothesis is that monogenic causes of diabetes frequently have very low birth weight (2, 3, 4, 5). Most causes of monogenic diabetes result in hyperglycemia due to ß-cell dysfunction and hence reduced insulin secretion. In utero insulin is a major growth factor (6), so reduced insulin secretion in utero would result in impaired insulin-mediated fetal growth and hence a low birth weight. Therefore, birth weight can be used as a bioassay for fetal insulin secretion in monogenic diabetes.

Recently activating mutations in the KCNJ11 gene encoding Kir6.2 have been shown to be an important cause of neonatal diabetes because they are the most common, known cause of permanent neonatal diabetes mellitus accounting for 47% of cases and are also a novel cause of transient neonatal diabetes mellitus (TNDM) (5, 7, 8, 9, 10, 11, 12, 13, 14). These mutations have been shown to result in the ATP-sensitive potassium channel (K_ATP) not closing in response to increased ATP (5). This results in reduced insulin secretion in the ß-cell and neurological features from channels affected in brain, muscle, and nerve. The majority of patients have isolated early-onset (before the age of 6 months) diabetes, but neurological features are present in one third of the patients (15). The most severely affected (7%) have severe developmental delay in psychosocial and motor function, epilepsy that results in generalized seizures in the first 2 months, and neonatal diabetes (DEND) syndrome, whereas those with the milder intermediate DEND syndrome have less severe developmental delay and do not have epilepsy (5, 14). Functional studies have shown that the mutations that show a more severe functional deficit in vitro are associated with the most severe clinical phenotype (DEND syndrome) (16), whereas the mutations with the least severe functional deficit in vitro are associated with the least severe clinical phenotype (TNDM syndrome) (13).

Because Kir6.2 mutations result in a fixed defect of K_ATP and hence a fixed defect in ß-cell function, study of the growth in utero and postnatally of these patients will give insights into the relative dependence of growth on insulin. Initial reports suggested that birth weight is reduced in patients with Kir6.2 mutations and in one small study (n = 8) suggested that age of diagnosis is inversely related to birth weight (11). This would be consistent with a more severe phenotype, resulting in not only more severe hyperglycemia and earlier diagnosis but also reduced insulin secretion in utero and hence reduced insulin-mediated growth. Larger studies are needed to assess this finding and examine whether other markers of disease severity (e.g. neurological features) are associated with lower birth weight. Initial reports suggested that there is postnatal catch-up of growth, but the extent, timing, and modifying factors of this are uncertain.

We studied the pre- and postnatal growth in 49 patients with Kir6.2 mutations and related this to the severity of the mutation and the presence of maternal diabetes.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

Sixty-six subjects with a Kir6.2 mutation were identified from published reports (5, 7, 8, 9, 10, 11, 12, 13, 17) and our unpublished series (Flanagan, S., S. Ellard, and A. T. Hattersley, personal communication). We studied 49 patients in whom there were both birth and present weight data. More detailed intermediate growth data from 0 to 2 yr were available in 21 subjects. All patients or their guardians gave written informed consent.

Methods

SD scores (SDS) were determined for their age (or gestational age) using ethnically and sex-matched growth charts (18). In the subgroup on whom we had growth data at intermediate time points, mean SDSs were calculated for all measurements in 3 monthly intervals up to 2 yr. Data on type of mutation, transmission, maternal diabetes, and clinical outcome were recorded.

Calculations and statistics

Measures were expressed as median (range). Comparison between groups of growth data were made using the Mann-Whitney test for independent variables such as subjects born to a diabetic vs. nondiabetic mother or subjects with or without neurological features. For comparing growth data at different ages, we used the Wilcoxon signed-ranks test. To look at the effect of age of diagnosis, the subgroup was split by the median into early vs. late age at diagnosis. Statistical package SPSS (version 11; SPSS, Inc., Chicago, IL) was used for analysis. All tests were two tailed, and significance was defined as P < 0.05.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

Baseline characteristics are presented in Table 1. Six of the 49 subjects were born to diabetic mothers. Thirty-eight subjects were identified with a de novo mutation, whereas 11 were familial cases from nine pedigrees, six were inherited from the mother and three from the father, and two were due to paternal germline mosaicism. Five subjects were diagnosed with TNDM, 44 with permanent neonatal diabetes mellitus, of which 12 had the intermediate DEND and four had full DEND syndrome. Presentation was mainly marked by hyperglycemia (n = 45) and ketoacidosis (n = 9). The most common mutations in Kir6.2 were R201H (n = 17), R201C (n = 4), and V59M (n = 7).

Birth weight was low, with a median birth weight of 2580 g (range 1440–3570 g). This was not a reflection of early delivery because the median gestational age was 39 wk, and only four subjects were born before 37 wk gestation. Mutation carriers are therefore small for gestational age [–1.73 (–3.68 to 1.41) SDS]; this is equivalent to a reduction of birth weight from the general population by approximately 800 g in a term child. Twenty-nine patients (59%) were small for gestational age (below the 10th centile).The distribution of the SDS birth weight is shown in Fig. 1. Length measurements (n = 19) were reduced but to a lesser extent [–1.05 (–2.87 to 2.48) SDS], the equivalent reduction of 2.5 cm in a term child.

View larger version (27K): [in this window] [in a new window]   FIG. 1. Weight distribution of 49 patients with Kir6.2 mutations expressed as SDS at birth and the most recent postnatal measurement. Columns represent all cases, with a value indicated at the bottom of the column ± 0.50 SDS. Birth data are shown in solid columns. Present data are shown in striped columns.

There was clear evidence of postnatal catch-up growth because present median weight (range) was –0.37 (–4.37 to 2.34) SDS and height –0.51 (–2.70 to 3.00) SDSs were close to those in the general population. The distribution of weight had moved from being skewed to the left at birth to a normal distribution postnatally (Fig. 1).

Growth was examined before and after the diagnosis of diabetes, which was made at a median of 6 wk. The relative weight decreased before diagnosis, with weight SDSs falling from –1.73 at birth to –2.35 SDS at diagnosis (P = 0.006). Height SDSs were available in 19 subjects and these also fell, but this was not significant (–1.05 at birth to –1.52 SDS at diagnosis, P = 0.33). After starting insulin treatment, both weight (–2.35 to –0.37 SDS, P < 0.001) and height (–1.52 to –0.51 SDS at diagnosis, P = 0.02) increased.

Impact of maternal diabetic mothers

The six subjects with Kir6.2 mutation born to diabetic mothers were born earlier [38 (32–38.5) vs. 40 (33–42) wk, P = 0.01] and had higher birth weights for their gestational age [–0.12 (–2.40 to 1.41) vs. –1.81 (–3.68 to 0.12) SDS, P = 0.037] (Fig. 2). This impact on fetal growth of having a diabetic mother did not persist postnatally because there was no difference in weight at diagnosis (P = 0.94) (Fig. 2).

View larger version (15K): [in this window] [in a new window]   FIG. 2. Birth weight and the most recent weight in patients with a Kir6.2 mutation born to a diabetic mother (n = 6) and an unaffected mother (n = 43) expressed as SDSs. Birth data are shown in solid columns. Present data are shown in striped columns.

In view of the impact we found of maternal diabetes, all subsequent analyses were performed excluding the six offspring carriers with diabetic mothers.

Age of diagnosis

The 43 subjects not born to diabetic mothers were divided by their median age of diagnosis (6 wk) into early and late-diagnosed groups (diagnosed at 2.3 vs. 11.4 wk). Early diagnosis was not associated with lower birth weight [–1.99 (–3.68 to 0.12) vs. –1.57 (–3.1 to 0.27) (P = 0.44)].

Presentation with diabetic ketoacidosis

Subjects that presented with diabetic ketoacidosis at presentation did not differ in birth weight (P = 0.92).

Severity of neurological phenotype

Subjects showing neurological features showed a similar weight at birth as those without neurological features (P = 0.25). However, at the most recent postnatal measurement, the weight was lower, although this did not quite reach significance [–0.93 (–2.26 to 2.20) SDS vs. – 0.32 (–4.37 to 2.34) SDS, P = 0.051]. Dividing the subjects with neurological features into those with intermediate DEND syndrome (less severe developmental delay without epilepsy) and full DEND syndrome showed that it was the full DEND syndrome patients that did not catch up (Fig. 3). The postnatal SDSs of DEND patients remained low for both weight [–2.20 (–2.26 to –1.98) SDS] and height [–1.95 (–2.70 to –1.27) SDS], which was significantly different when compared with subjects without neurological symptoms (P = 0.003 and P = 0.001, respectively).

View larger version (26K): [in this window] [in a new window]   FIG. 3. Birth weight and the most recent weight in patients with a Kir6.2 mutation without neurological features (n = 33), with intermediate DEND syndrome (neurological features without epilepsy) (n = 12), and with DEND syndrome (neurological features including epilepsy) (n = 4) expressed as SDSs. Birth data are shown in solid columns. Present data are shown in striped columns.

Mutations at V59 were shown to be more severe functional mutations as demonstrated by a higher current over the cell membrane in vitro in Xenopus oocytes and hence showed a greater reduction in ATP sensitivity than mutations at R201 (19). The higher current has also been shown to correlate with the severity of the clinical phenotype at physiological MgATP concentrations (19). We subsequently studied whether the expected greater reduction in ATP sensitivity was also reflected in lower birth weight. Subjects with mutations at V59 (V59M and V59G) had a similar birth weight to those with a mutation at R201 (R201H, R201C, and R201L) (P = 0.49).

Timing of postnatal growth

To see when postnatal catch-up growth occurred and the rate at which it occurred after diagnosis, we used detailed growth data from 21 subjects.

Timing of catch-up growth after initiation of insulin treatment (Fig. 4). Weight and height were plotted using data collected at birth, diagnosis [median 4.57 (0.07–28.00) wk], and then at 3-month intervals. Weight and height SDS decreased from birth to diagnosis but started to increase immediately thereafter (Fig. 4).

View larger version (13K): [in this window] [in a new window]   FIG. 4. Median (interquartile range) weight SDS (top) and height SDS (bottom) from birth to 2 yr in the 21 patients with Kir6.2 mutations in whom full growth data were available. In the 3-month categories, growth data of the 21 patients were averaged, and the group value was calculated.

When, after diagnosis, has growth rate stabilized (Fig. 4)?

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We studied intrauterine growth and postnatal growth in the largest international series of patients with neonatal diabetes resulting from a mutation in the Kir6.2 gene. We identified low birth weight as a consistent phenotypic marker of Kir6.2 patients, but after treatment with insulin, there is marked catch-up, so by 2 yr, growth is similar to the normal population. Interestingly the severity of the mutation was not reflected in the severity of intrauterine growth retardation. The major modifier of birth weight was the presence of maternal diabetes with markedly increased birth weight, and the only modifier of postnatal catch-up was the presence of the severe DEND syndrome, which was associated with low postnatal weight and height.

We found that reduced birth weight was a consistent feature of Kir6.2 mutations, in keeping with previous smaller series and case reports (5, 7, 8, 9, 10, 11, 12, 13). Other ß-cell monogenic disorders resulting in neonatal diabetes also result in reduced insulin secretion and also have reduced birth weight (Table 2) (3, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30). Interestingly birth weights in Kir6.2 mutation carriers are 586-1000 g heavier than the very low birth weights seen in absolute insulin deficiency such as pancreatic agenesis (IPF1, PTF1A) or homozygous glucokinase mutations. This suggests that in Kir6.2 there is some insulin secretion in utero. Low-level insulin secretion postnatally probably also explains why many children with Kir6.2 mutations can survive without insulin treatment for the first month of life and are not diagnosed until a median of 6 wk. In heterozygous mutations of glucokinase, birth weight is reduced by only approximately 500 g, and the level of hyperglycemia postnatally is only modest, with no pharmacological treatment being required (3). The one subgroup in which birth weight does not clearly reflect the severity of the ß-cell defect postnatally is TNDM patients with abnormalities of imprinting of 6q. In these patients the birth weight is similar to the most severely reduced subgroups of neonatal diabetes (–3 SD), but postnatally patients are normoglycemic off insulin within 12 wk of birth. This suggests that ß-cell dysfunction rapidly improves postnatally, but the mechanism for this is unknown (31).

Kir6.2 mutation carriers born to mothers with diabetes were 1.69 SDS (the equivalent of 750 g at term) heavier than offspring born to nondiabetic mothers. They were still not large, compared with the general population, because the mean SDS for birth weight was –0.12, suggesting that the impact of the fetal mutation balanced the impact of the exposure to maternal hyperglycemia. It is well established that the offspring of diabetic mothers are heavier and more likely to be macrosomic than the offspring of nondiabetic mothers (3). Pedersen (32) proposed in 1977 that the increase in birth weight was not the result of a direct increased nutrition transfer but rather the stimulation of fetal insulin secretion that then increased insulin-mediated growth in the fetus. The Pederson hypothesis therefore proposed that the maternal hyperglycemia was sensed by the fetal pancreatic ß-cells, which then increased fetal insulin secretion and hence increased fetal growth. A failure of the ß-cells to respond normally to the prevailing maternal glycemia would therefore mean that fetal growth was reduced. The clearest example of this are heterozygous glucokinase mutations in which a fetal mutation results in a reduction of birth weight of approximately 500 g, whereas the same mutation in the mother will increase maternal glycemia and hence increase the birth weight by approximately 500 g (3). When both the mother and fetus are affected, then the two opposing effects will cancel out and the baby is of normal birth weight.

The situation in Kir6.2 mutations appears to be analogous with the situation in glucokinase with the presence of maternal hyperglycemia as a result of a maternal mutation, counteracting the impact of a fetal mutation. This is very interesting because the Pederson hypothesis would suggest that in the presence of maternal hyperglycemia with glucose values typically ranging between 4 and 10 mmol/liter, a fetus with a Kir6.2 mutation is able to secrete insulin to a similar extent as normal fetus exposed to normal glucoses. This would suggest that the fetal pancreas is able to respond to hyperglycemia with increased insulin release, but studies postnatally have shown no insulin secretion during an iv glucose tolerance test, even when glucose levels exceed 20 mmol/liter (5). Two explanations of this paradox would be that the ß-cell responds differently in utero than postnatally or that there are other stimuli to increase fetal growth in a hyperglycemic environment that are not mediated through fetal insulin secretion. Our study does not allow differentiation between these two possible explanations, and the measurement of cord insulin in offspring born to mothers with Kir6.2 mutations would be of great interest.

Because the Kir6.2 mutation carriers were similar in height and weight to the general population by the time they were 2 yr old, having been born small, they need to show postnatal catch-up growth. This is the first study to examine the timing of this catch-up growth. Relative size continues to fall until diagnosis for both height and weight but is nearly fully restored by the age of 9 months after treatment with insulin. Some of the fall in weight will be due to dehydration related to the hyperglycemia pretreatment, and there may be an increased catabolic state because the glucose toxicity found in most children before the diagnosis of diabetes will further decrease insulin secretion. But the size of the effect, timing of the weight gain after treatment, and the impact on height suggests that this is not the only explanation. The results suggest that normal postnatal growth does not occur in the absence of insulin, even though the main regulation of the IGF axis has switched to GH postnatally. The only exceptions to the catch-up of growth after insulin treatment were the four patients with full DEND syndrome who remained small relative to the general population (present weight –2.20 SDS). In contrast, the children with only moderate DEND showed full catch-up growth (present weight –0.40 SDS) (Fig. 3). Full DEND syndrome is associated with the most functionally severe Kir6.2 mutations, and clinically, compared with moderate DEND, they have more severe developmental delay and epilepsy. Epileptic subjects in general are more likely to show stunted growth, which might be due to the disease in general or to treatment (33, 34, 35).

In conclusion, we show that fetal and postnatal growth is altered in a large cohort of patients with Kir6.2 mutations. These mutations result in reduced fetal growth but to a lesser extent to the rarer genetic causes that cause a complete absence of insulin secretion. There is no evidence to suggest that the functional severity of the mutation alters the extent to which birth weight is reduced. Postnatally catch-up growth does not occur until treatment with insulin commences, but then it is rapid and there appears to be no long-term impact of final growth. The failure of catch-up growth in the subjects with the severe DEND syndrome is probably attributable to their epilepsy or its treatment. Interestingly in the presence of maternal diabetes, fetal growth is increased and the mechanism for this in the presence of a severe fetal ß-cell defect is uncertain. This paradox of the prenatal response of increased fetal growth in subjects with Kir6.2 mutations exposed to maternal hyperglycemia, but the absence of a postnatal response of insulin secretion to marked hyperglycemia is intriguing and needs further investigation.

	Acknowledgments

 
The authors thank all patients and their doctors and all their colleagues at the Peninsula Medical School and elsewhere for their help and ideas, which have contributed considerably to this paper and without whose help the collection of these data would have been impossible.

	Footnotes

 
This work was supported by the Wellcome Trust. The paper was written when A.S.S. visited Exeter, United Kingdom, from the Department of Paediatrics, Division of Diabetes, Erasmus Medical Center-Sophia Children’s Hospital, Rotterdam, The Netherlands, on an International Society for Pediatric and Adolescent Diabetes traveling scholarship. A.T.H. is a Welcome Trust research leave fellow.

Disclosure summary: The authors have nothing to disclose.

First Published Online April 24, 2006

Abbreviations: DEND, Syndrome of developmental delay, epilepsy, and neonatal diabetes; K_ATP, ATP-sensitive potassium channel; SDS, SD score; TNDM, transient neonatal diabetes mellitus.

Received January 30, 2006.

Accepted April 14, 2006.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Barker DJ, Gluckman PD, Godfrey KM, Harding JE, Owens JA, Robinson JS 1993 Fetal nutrition and cardiovascular disease in adult life. Lancet 341:938–941[CrossRef][Medline]
2. Hattersley AT, Tooke JE 1999 The fetal insulin hypothesis: an alternative explanation of the association of low birthweight with diabetes and vascular disease. Lancet 353:1789–1792[CrossRef][Medline]
3. Hattersley AT, Beards F, Ballantyne E, Appleton M, Harvey R, Ellard S 1998 Mutations in the glucokinase gene of the fetus result in reduced birth weight. Nat Genet 19:268–270[CrossRef][Medline]
4. Frayling TM, Hattersley AT 2001 The role of genetic susceptibility in the association of low birth weight with type 2 diabetes. Br Med Bull 60:89–101[Abstract/Free Full Text]
5. Gloyn AL, Pearson ER, Antcliff JF, Proks PG, Bruining GJ, Slingerland AS, Howard N, Srinivasan S, Silva JM, Molnes J, Edghill EL, Frayling TM, Temple IK, Mackay D, Shield JP, Sumnik Z, van Rhijn A, Wales JK, Clark P, Gorman S, Aisenberg J, Ellard S, Njolstad PR, Ashcroft FM, Hattersley AT 2004 Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med 350:1838–1849[Abstract/Free Full Text]
6. Fowden AL, Giussani DA, Forhead AJ 2005 Endocrine and metabolic programming during intrauterine development. Early Hum Dev 81:723–734[CrossRef][Medline]
7. Edghill EL, Gloyn AL, Gillespie KM, Lambert AP, Raymond NT, Swift PG, Ellard S, Gale EA, Hattersley AT 2004 Activating mutations in the KCNJ11 gene encoding the ATP-sensitive K+ channel subunit Kir6.2 are rare in clinically defined type 1 diabetes diagnosed before 2 years. Diabetes 53:2998–3001[Abstract/Free Full Text]
8. Gloyn AL, Cummings EA, Edghill EL, Harries LW, Scott R, Costa T, Temple IK, Hattersley AT, Ellard S 2004 Permanent neonatal diabetes due to paternal germline mosaicism for an activating mutation of the KCNJ11 gene encoding the Kir6.2 subunit of the ß-cell potassium adenosine triphosphate channel. J Clin Endocrinol Metab 89:3932–3935[Abstract/Free Full Text]
9. Sagen JV, Raeder H, Hathout E, Shehadeh N, Gudmundsson K, Baevre H, Abuelo D, Phornphutkul C, Molnes J, Bell GI, Gloyn AL, Hattersley AT, Molven A, Sovik O, Njolstad PR 2004 Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy. Diabetes 53:2713–2718[Abstract/Free Full Text]
10. Vaxillaire M, Populaire C, Busiah K, Cave H, Gloyn AL, Hattersley AT, Czernichow P, Froguel P, Polak M 2004 Kir6.2 mutations are a common cause of permanent neonatal diabetes in a large cohort of French patients. Diabetes 53:2719–2722[Abstract/Free Full Text]
11. Massa O, Iafusco D, D’Amato E, Gloyn AL, Hattersley AT, Pasquino B, Tonini G, Dammacco F, Zanette G, Meschi F, Porzio O, Bottazzo G, Crino A, Lorini R, Cerutti F, Vanelli M, Barbetti F 2004 KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes. Hum Mutat 25:22–27
12. Zung A, Glaser B, Nimri R, Zadik Z 2004 Glibenclamide treatment in permanent neonatal diabetes mellitus due to an activating mutation in Kir6.2. J Clin Endocrinol Metab 89:5504–5507[Abstract/Free Full Text]
13. Gloyn AL, Reimann F, Girard C, Edghill EL, Proks P, Pearson ER, Temple IK, Mackay DJ, Shield JP, Freedenberg D, Noyes K, Ellard S, Ashcroft FM, Gribble FM, Hattersley AT 2005 Relapsing diabetes can result from moderately activating mutations in KCNJ11. Hum Mol Genet 14:925–934[Abstract/Free Full Text]
14. Hattersley AT, Ashcroft FM 2005 Activating mutations in kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy. Diabetes 54:2503–2513[Abstract/Free Full Text]
15. Slingerland AS, Hattersley AT 2005 Mutations in the Kir6.2 subunit of the KATP channel and permanent neonatal diabetes: new insights and new treatment. Ann Med 37:186–195[CrossRef][Medline]
16. Antcliff JF, Haider S, Proks P, Sansom MS, Ashcroft FM 2005 Functional analysis of a structural model of the ATP-binding site of the K(ATP) channel Kir6.2 subunit. EMBO J 24:229–239[CrossRef][Medline]
17. Flanagan SE, Edghill EL, Gloyn AL, Ellard S, Hattersley AT 2006 Mutations in KCNJ11, which encodes Kir6.2, are a common cause of diabetes diagnosed in the first 6 months of life, with the phenotype determined by genotype. Diabetologia 49:1190–1197[CrossRef][Medline]
18. Freeman JV, Cole TJ, Chinn S, Jones PR, White EM, Preece MA 1995 Cross sectional stature and weight reference curves for the UK, 1990. Arch Dis Child 73:17–24[Abstract/Free Full Text]
19. Proks P, Girard C, Ashcroft FM 2005 Functional effects of KCNJ11 mutations causing neonatal diabetes: enhanced activation by MgATP. Hum Mol Genet 14:2717–2726[Abstract/Free Full Text]
20. Schwitzgebel VM, Mamin A, Brun T, Ritz-Laser B, Zaiko M, Maret A, Jornayvaz FR, Theintz GE, Michielin O, Melloul D, Philippe J 2003 Agenesis of human pancreas due to decreased half-life of insulin promoter factor 1. J Clin Endocrinol Metab 88:4398–4406[Abstract/Free Full Text]
21. Njolstad PR, Sovik O, Cuesta-Munoz A, Bjorkhaug L, Massa O, Barbetti F, Undlien DE, Shiota C, Magnuson MA, Molven A, Matschinsky FM, Bell GI 2001 Neonatal diabetes mellitus due to complete glucokinase deficiency. N Engl J Med 344:1588–1592[Free Full Text]
22. Temple IK, Gardner RJ, Mackay DJ, Barber JC, Robinson DO, Shield JP 2000 Transient neonatal diabetes: widening the understanding of the etiopathogenesis of diabetes. Diabetes 49:1359–1366[Abstract]
23. Temple IK, Shield JP 2002 Transient neonatal diabetes, a disorder of imprinting. J Med Genet 39:872–875[Abstract/Free Full Text]
24. Stoffers DA, Zinkin NT, Stanojevic V, Clarke WL, Habener JF 1997 Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet 15:106–110[CrossRef][Medline]
25. Yorifuji T, Kurokawa K, Mamada M, Imai T, Kawai M, Nishi Y, Shishido S, Hasegawa Y, Nakahata T 2004 Neonatal diabetes mellitus and neonatal polycystic, dysplastic kidneys: phenotypically discordant recurrence of a mutation in the hepatocyte nuclear factor-1ß gene due to germline mosaicism. J Clin Endocrinol Metab 89:2905–2908[Abstract/Free Full Text]
26. Hoveyda N, Shield JP, Garrett C, Chong WK, Beardsall K, Bentsi-Enchill E, Mallya H, Thompson MH 1999 Neonatal diabetes mellitus and cerebellar hypoplasia/agenesis: report of a new recessive syndrome. J Med Genet 36:700–704[Abstract/Free Full Text]
27. Sellick GS, Garrett C, Houlston RS 2003 A novel gene for neonatal diabetes maps to chromosome 10p12.1-p13. Diabetes 52:2636–2638[Abstract/Free Full Text]
28. Sellick GS, Barker KT, Stolte-Dijkstra I, Fleischmann C, Coleman RJ, Garrett C, Gloyn AL, Edghill EL, Hattersley AT, Wellauer PK, Goodwin G, Houlston RS 2004 Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nat Genet 36:1301–1305[CrossRef][Medline]
29. Njolstad PR, Sagen JV, Bjorkhaug L, Odili S, Shehadeh N, Bakry D, Sarici SU, Alpay F, Molnes J, Molven A, Sovik O, Matschinsky FM 2003 Permanent neonatal diabetes caused by glucokinase deficiency: inborn error of the glucose-insulin signaling pathway. Diabetes 52:2854–2860[Abstract/Free Full Text]
30. Porter JR, Shaw NJ, Barrett TG, Hattersley AT, Ellard S, Gloyn AL 2005 Permanent neonatal diabetes in an Asian infant. J Pediatr 146:131–133[CrossRef][Medline]
31. Hattersley AT 2004 Unlocking the secrets of the pancreatic ß cell: man and mouse provide the key. J Clin Invest 114:314–316[CrossRef][Medline]
32. Pedersen J 1977 The pregnant diabetic and her newborn: problems and management. Baltimore: William and Wilkins
33. El-Khayat HA, Shatla HM, Ali GK, Abdulgani MO, Tomoum HY, Attya HA 2003 Physical and hormonal profile of male sexual development in epilepsy. Epilepsia 44:447–452[CrossRef][Medline]
34. El-Khayat HA, Abd El-Basset FZ, Tomoum HY, Tohamy SM, Zaky AA, Mohamed MS, Hakky SM, Barbary NS, Nassef NM 2004 Physical growth and endocrinal disorders during pubertal maturation in girls with epilepsy. Epilepsia 45:1106–1115[CrossRef][Medline]
35. Haut SR, Veliskova J, Moshe SL 2004 Susceptibility of immature and adult brains to seizure effects. Lancet Neurol 3:608–617[CrossRef][Medline]

This article has been cited by other articles:

				J. Zhao, M. Li, J. P. Bradfield, K. Wang, H. Zhang, P. Sleiman, C. E. Kim, K. Annaiah, W. Glaberson, J. T. Glessner, et al. Examination of Type 2 Diabetes Loci Implicates CDKAL1 as a Birth Weight Gene Diabetes, October 1, 2009; 58(10): 2414 - 2418. [Abstract] [Full Text] [PDF]

				R. M. Freathy, A. J. Bennett, S. M. Ring, B. Shields, C. J. Groves, N. J. Timpson, M. N. Weedon, E. Zeggini, C. M. Lindgren, H. Lango, et al. Type 2 Diabetes Risk Alleles Are Associated With Reduced Size at Birth Diabetes, June 1, 2009; 58(6): 1428 - 1433. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Slingerland, A. S. Articles by Hattersley, A. T. Search for Related Content PubMed PubMed Citation Articles by Slingerland, A. S. Articles by Hattersley, A. T. Pubmed/NCBI databases Gene GEO Profiles HomoloGene OMIM UniGene Compound via MeSH Substance via MeSH Medline Plus Health Information Diabetes Related Collections Pediatric Endocrinology Diabetes and Insulin