the pancreatic beta - cell atp - sensitive potassium ( k - atp ) channels play a critical role in regulation of 
 glucose - induced insulin secretion to maintain glucose homeostasis . the k - atp channel is a hetero - octameric 
 complex composed of two types of subunits : four sulfonylurea receptor 1 ( sur1 ) subunits and four 
 inward - rectifying potassium channel pore - forming ( kir6.2 ) subunits encoded by the genes abcc8 
 and kcnj11 , respectively . increased blood glucose ( bg ) levels lead to a high atp / adp ratio and 
 k - atp channel closure in pancreatic beta cells , resulting in cell membrane depolarization , which then triggers 
 the opening of voltage - gated calcium channels , calcium influx and a rise in intracellular calcium concentration , 
 thereby resulting in exocytosis of insulin granules ( 1 , 2 ) . inactivating mutations in abcc8 or 
 kcnj11 cause congenital hyperinsulinism ( chi ) characterized by hypoglycemia with 
 inappropriate insulin secretion in infancy ( 3,4,5,6 ) . however , patients with chi due to 
 abcc8/kcnj11 mutations are not always responsive to medical treatment and 
 sometimes require pancreatectomy , resulting in a high incidence of diabetes mellitus . on the other hand , 
 abcc8 inactivating mutations in nonpancreatectomized patients have recently been reported to 
 be involved in the development of diabetes mellitus due to impaired insulin secretion later in life ( 7,8,9,10 ) . reactive ( or postprandial ) hypoglycemia is a symptomatic hypoglycemia that occurs a few hours after eating 
 ( especially a high carbohydrate meal or oral glucose load ) , and the symptoms are improved by intake of glucose . the etiology of reactive hypoglycemia includes dumping syndrome after stomach resection , nesidioblastoma , 
 insulinoma , impaired glucose tolerance / early diabetes mellitus , drugs or other rare mechanisms ( 11 ) . here we described a compound heterozygous mutation in abcc8 in a japanese girl who was born 
 macrosomic with transient hypoglycemia and thereafter developed diabetes mellitus accompanied by repeated 
 reactive hypoglycemia in childhood . in addition , the patient was successfully treated by nateglinide , which 
 stimulated early insulin secretion . she was large for her gestational age , with a birth weight of 3,384 g and a height of 49.0 
 cm , respectively . on the second day of age , she suffered severe symptomatic hypoglycemia ( a blood glucose level 
 below the detection range ) . brain mri 
 findings were compatible with periventricular leukomalacia . her cousin on her father s side , now 10 yr old , was 
 also born macrosomic at 36 wk of gestation , with a birth weight of 4,244 g. although he suffered 
 hyperinsulinemic hypoglycemia during his infancy , hypoglycemia spontaneously improved without diazoxide or other 
 medication . no other family members reported any hypoglycemic episodes or a diabetes mellitus history . during her infancy , although the 
 episodes of hypoglycemia gradually decreased after 6 yr of age , she again suffered repeated symptomatic 
 aketogenic hypoglycemia in the late morning or early evening from 10 yr of age , and the frequency was increased . she was investigated for hypoglycemia at 11 yr of age when her growth was normal , with a weight of 50.8 kg ( bmi 
 21.6 ) and a height of 153.2 cm ( + 1.25 sd ) . her physical findings were not remarkable except for mild 
 macroglossia , and she was not mentally retarded . she developed symptomatic aketogenic hypoglycemia almost every 
 day ( bg levels were between 4176 mg / dl ) in the late morning ( 10:0011:00 ) or early evening ( 16:0017:00 ) and 
 often required oral glucose or glucose infusion , although her bg level was not low at night or in the early 
 morning ( table 1a ) . an oral glucose tolerance test ( ogtt ) revealed a 
 high bg level at 120 min ( 248 mg / dl ) due to poor early insulin response , which was followed by hypoglycemia due 
 to delayed prolonged insulin secretion ( bg was 44 mg / dl at 270 min ) ( table 
 2a , fig . 1afig . , the ogtt revealed hyperglycemia ( glucose level at 120 min was 248 mg / dl ) due to poor 
 early insulin secretion ( insulin level at 120 min was 28.6 u / ml ) , followed by hypoglycemia ( glucose level 
 at 270 min was 44 mg / dl ) due to delayed prolonged insulin secretion ( insulin level at 270 min was 8.2 
 u / ml).b . after treatment with -gi and nateglinide , the peak of insulin secretion was earlier and lower 
 compared with before treatment and hypoglycemia was improved . ) . hba1c was elevated ( 6.8% , ngsp ) , and anti - gad antibody and 
 anti - insulin antibody were negative . abdominal ct showed no obvious pancreatic lesion , and brain mri showed no 
 new abnormal findings except for pvl . table 1   circadian changes in blood glucose , serum iri and iri / bsat breakfast2 h after breakfastat lunch2 h after lunch17:00at dinner2 h after dinnerat bedtimea one day before treatmentbs ( mg / dl)10715310519149249iri ( u / ml)819.58.217.46iri / bs0.070.130.080.090.12b one day after treatment with -gibs ( mg / dl)1101459212666136170c one day after treatment with -gi and nateglinidebs ( mg / dl)12211411014311593iri ( u / ml)9.338.711.115.39.37iri / bs0.0760.3400.1010.1070.0810.075blood glucose levels during hypoglycemia are underlined . 
 table 2   oral glucose tolerance testtime ( min ) 0306090120150180210240270a before treatment bs ( mg / dl ) 851582082462482051761237644 iri ( u / ml ) 6.417.320.621.628.639.137.525.113.28.2 cpr ( ng / ml ) 1.52.53.84.26.06.67.05.13.92.8 iri / bs 0.0750.1090.0990.0880.1150.1910.2130.2040.1740.186b after taking medicines ( one year later ) bs ( mg / dl ) 781491781891871351281179280 iri ( u / ml ) 7.220.615.121.525.419.919.614.59.59.1 cpr ( ng / ml ) 1.442.582.493.263.773.33.432.82.342.02 iri / bs 0.0920.1380.0850.1140.1360.1470.1530.1240.1030.114blood glucose , serum iri and c - peptide ( cpr ) levels were measured until 270 min after glucose load . the ogtt revealed hyperglycemia ( glucose level at 120 min was 248 mg / dl ) due to poor 
 early insulin secretion ( insulin level at 120 min was 28.6 u / ml ) , followed by hypoglycemia ( glucose level 
 at 270 min was 44 mg / dl ) due to delayed prolonged insulin secretion ( insulin level at 270 min was 8.2 
 u / ml ) . b. after treatment with -gi and nateglinide , the peak of insulin secretion was earlier and lower 
 compared with before treatment and hypoglycemia was improved . blood glucose , serum iri and c - peptide ( cpr ) levels were measured until 270 min after glucose load . we first started medical therapy with an alpha - glucosidase inhibitor ( -gi ; voglibose ) before each meal ( 0.6 mg 
 per day ) to control postprandial hyperglycemia and subsequent reactive hypoglycemia by slowing the digestion and 
 absorption of carbohydrates and preventing prolonged insulin secretion . however , it was not effective enough for 
 reactive hypoglycemia , although postprandial hyperglycemia was slightly improved ( table 1b ) . then we added nateglinide before breakfast and lunch ( 30 mg per day ) to 
 control reactive hypoglycemia by stimulating early insulin secretion close to normal insulin kinetics . nateglinide successfully decreased the frequency of hypoglycemia from almost everyday to a few times a month 
 ( table 1c ) . one year later , we reexamined the ogtt just after 
 taking nateglinide and voglibose . the peak of insulin secretion after oral glucose load was earlier and lower 
 compared with the previous one , and hypoglycemia was improved , although hyperglycemia was still recognized 
 ( table 2b , fig . she is now 12 yr old , and her quality of life has been improved , 
 although she occasionally suffers mild hypoglycemia and needs supplementary food . we analyzed genes involved in beta - cell functions , abcc8 , kcnj11 , and 
 hnf4. genomic dna was extracted from peripheral blood leukocytes of the patient , her parents 
 and her cousin . all 
 coding exons and exon / intron boundaries of abcc8 , kcnj11 and 
 hnf4 were pcr amplified and directly sequenced as previously reported ( 12 ) . abcc8 analysis identified a compound heterozygous mutation , 
 c.4259g > a ( p.r1420h ; exon35 ) and c.1773delc ( p.f591fs604x ; exon12 ) . no mutation was found in 
 kcnj11 and hnf4. her father and her cousin on her father s side carried a 
 heterozygous c.4259g > a mutation , and her mother carried a heterozygous c.1773delc mutation ( fig . subjects indicated by a black dot within the symbol 
 were heterozygous for mutations but had no clinical manifestations . the patient ( indicated by the arrow ) 
 carried a compound heterozygous abcc8 mutation , c4259g > a ( p.r1420h ; exon 35 , paternal ) 
 and c1773 delc ( p.f591fs604x ; exon 12 , maternal ) . her cousin on her father s side carried a heterozygous 
 c.4259g > a mutation . ) . subjects indicated by a black dot within the symbol 
 were heterozygous for mutations but had no clinical manifestations . the patient ( indicated by the arrow ) 
 carried a compound heterozygous abcc8 mutation , c4259g > a ( p.r1420h ; exon 35 , paternal ) 
 and c1773 delc ( p.f591fs604x ; exon 12 , maternal ) . her cousin on her father s side carried a heterozygous 
 c.4259g > a mutation . the characteristic clinical course in our case is that a patient carrying a compound heterozygous 
 abcc8 mutation ( r1420h / f591fs604x ) was born macrosomic with severe hypoglycemia in the 
 neonatal period followed by development of diabetes mellitus accompanied by repeated reactive hypoglycemia in 
 childhood . although we could not determine her insulin level during hypoglycemia in the neonatal period , we 
 presumed that she developed hyperinsulinemic hypoglycemia in the neonatal period because she was born 
 macrosomic , suggesting intrauterine fetal hyperinsulinism . recently , there have been some reports of late - onset diabetes mellitus in nonpancreatectomized patients after 
 chi in infancy due to abcc8 inactivated mutations . reported that 
 a heterozygous e1506k mutation in abcc8 caused chi in infancy , loss of insulin secretory 
 capacity in early childhood and diabetes mellitus in middle age ( 7 , 13 ) . vieira et al . also reported a patient carrying the same 
 mutation who developed gestational diabetes and diabetes mellitus in adulthood after mild hypoglycemia in 
 infancy ( 10 ) . on the other hand , abdulhadi - atwan et al . reported diabetes mellitus development at 10.5 yr after mild hypoglycemia during infancy in a patient carrying a 
 heterozygous r370s mutation in abcc8 ( 8) . reported development of glucose metabolism impairment from glucose intolerance to 
 insulin - dependent diabetes mellitus in 3 nonpancreatectomized patients with compound heterozygous 
 abcc8 mutations ( 9 ) . all 3 patients presented 
 persistent hyperinsulinemic hypoglycemia in infancy unresponsive to diazoxide , and ogtts were performed . patient 
 1 had a diabetic ogtt response with hypoglycemic episodes at 22 yr of age , followed by overt insulin - dependent 
 diabetes mellitus without hypoglycemia at the age of 25 yr . in patient 2 , who was 17 yr of age , diabetic ogtt 
 responses and hyperglycemic and hypoglycemic episodes were observed from 10 yr of age despite normal hba1c 
 values . in patient 3 , who was 24 yr of age , intolerant ogtt responses furthermore , there is a report that the acute insulin response to glucose was blunted in nonpancreatectomized 
 children with diffuse hyperinsulinism , suggesting the increased risk of diabetes mellitus later in life ( 14 ) . however , the precise mechanism of transition with age from 
 hyperinsulinemic hypoglycemia to hypoinsulinemic hyperglycemia due to abcc8 mutation is not 
 known . in k - atp channel ko mice ( kir6.2 and sur1 ) or transgenic mice expressing a 
 dominant - negative form of kir6.2 , hypoglycemia with hyperinsulinemia occurs in neonates followed by 
 hyperglycemia with insulin secretory failure in adults ( 15,16,17,18 ) . it was also shown that disruption of the k - atp channel induced elevation of the basal calcium 
 concentration and apoptosis in beta cells ( 15 , 19 ) . therefore , it has been speculated that the chronic elevation of the intracellular 
 calcium concentration due to mutant k - atp channel closure induces apoptosis in pancreatic beta cells , resulting 
 in loss of beta - cell mass and decreased insulin secretion ( 18 , 20 ) . indeed persistent increased beta - cell apoptosis was also observed in 
 pancreases from chi patients ( 21 ) . the patient we described carried a compound heterozygous abcc8 mutation , c4259g > a ( r1420h ; 
 exon 35 , paternal ) and c1773 delc ( f591fs604x ; exon 12 , maternal ) . r1420 is located in the second nucleotide 
 binding fold ( nbf2 ) of sur1 , and homozygous missense mutation r1420c is reported in japanese chi siblings ( 22 ) . although they were born macrosomic and developed hypoglycemia soon after 
 birth , hypoglycemia resolve spontaneously after 3 mo of age . functional analysis of the mutant r1420c sur1 
 showed lower expression of the mutant channel and reduced affinity of nfb2 for mgadp that might lead to the 
 enhanced insulin secretion ( 23 ) . although the substituted amino acid was 
 different and the mutation was compound heterozygous in our case , the r1420h mutation may also impair k - atp 
 channel activity . however , it is unknown why the patient s father is healthy and her cousin developed 
 hypoglycemia in infancy despite carrying the same heterozygous mutation . on the other hand , we presume that the 
 f591fs604x mutation from the maternal allele is also pathogenic because it is a frameshift mutation leading to 
 truncated protein , which might be nonfunctional . our patient developed diabetes mellitus accompanied by repeated reactive hypoglycemia , and it was hard to 
 control not only hyperglycemia but also reactive hypoglycemia . reactive hypoglycemia usually occurred in the 
 late morning or early evening , and not at night . not only taking supplementary food for reactive hypoglycemia 
 and subsequently dinner but also the secretions of counter - regulatory hormones triggered by hypoglycemia might 
 prevent reactive hypoglycemia after dinner . the ogtt before treatment showed that hyperglycemia developed due to 
 delayed early insulin response to an elevation of blood glucose levels and that reactive hypoglycemia developed 
 due to delayed suppression of insulin secretion in response to a fall in blood glucose levels . therefore , it is 
 suggested that the response to glucose metabolic change was impaired in the mutant k - atp channel . in our case , 
 we could not control reactive hypoglycemia with only an alpha - glucosidase inhibitor , which is described as 
 effective for reactive hypoglycemia ( 24 , 25 ) . however , the combination of -gi and nateglinide could obviously decrease episodes of reactive 
 hypoglycemia , although this combination has not been reported to be effective for reactive hypoglycemia . nateglinide is a d - phenylalanine derivative antihyperglycemic drug that stimulates early insulin secretion , and 
 it has a shorter duration of action than sulfonylurea . considering its action , it has been expected that 
 nateglinide is effective for diabetes mellitus with reactive hypoglycemia by inducing early insulin secretion 
 and preventing delayed prolonged insulin secretion ( 26 ) . in fact , we 
 could control not only hyperglycemia but also reactive hypoglycemia with the combination of -gi and 
 nateglinide . in conclusion , our case showed that a sur1 mutation in chi could alter regulation of insulin secretion with 
 advancing age , leading to diabetes mellitus with reactive hypoglycemia from hyperinsulinism . therefore , we think 
 that long - term follow - up and periodic ogtts are important for early detection of insulin dysregulation in chi 
 patients carrying a sur1 mutation , even though hypoglycemia resolves spontaneously without pancreatectomy during 
 infancy . furthermore , nateglinide may be useful therapeutically in the treatment of reactive hypoglycemia with 
 impaired glucose tolerance / early diabetes mellitus .
abcc8 encodes the sulfonylurea receptor 1 ( sur1 ) subunits of the beta - cell atp - sensitive 
 potassium ( k - atp ) channel playing a critical role in the regulation of insulin secretion , and inactivating 
 mutations in abcc8 cause congenital hyperinsulinism . 
 recently , abcc8 
 inactivating mutations were reported to be involved in the development of diabetes mellitus later in life . 
 we 
 report a girl who was born macrosomic with transient hypoglycemia and thereafter developed diabetes mellitus 
 accompanied by severe reactive hypoglycemia at the age of 11 yr . an ogtt ( oral glucose tolerance test ) 
 revealed hyperglycemia due to poor early insulin response and subsequent hypoglycemia due to delayed prolonged 
 insulin secretion . 
 hypoglycemia was improved by the combination of nateglinide , which stimulates early insulin 
 secretion , and an alpha - glucosidase inhibitor , voglibose . 
 sequencing of the abcc8 identified 
 a compound heterozygous mutation ( r1420h / f591fs604x ) , suggesting that this mutation may alter regulation of 
 insulin secretion with advancing age , leading to diabetes mellitus with reactive hypoglycemia from 
 hyperinsulinism . therefore , 
 long - term follow - up and periodic ogtts are important for early detection of 
 insulin dysregulation in congenital hyperinsulinism patients carrying the abcc8 mutation , 
 even though hypoglycemia resolves spontaneously during infancy . 
 furthermore , nateglinide may be useful 
 therapeutically in the treatment of not only diabetes mellitus but also reactive hypoglycemia .