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Division of Endocrinology, Children’s Hospital of Philadelphia (S.N.M., C.M., L.S., L.E.L.K., C.A.S.), Philadelphia, Pennsylvania 19104; Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University (S.-L.S.), Portland, Oregon 97239; and Department of Genetics, University of Pennsylvania School of Medicine (A.G.), Philadelphia, Pennsylvania 19104
Address all correspondence and requests for reprints to: Dr. Charles A. Stanley, Division of Endocrinology, Children’s Hospital of Philadelphia, Abramson Research Center, Room 802, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104-4318. E-mail: stanleyc{at}email.chop.edu.
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Abstract |
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Introduction |
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Among the early descriptions of leucine-sensitive hypoglycemia was a case reported by DiGeorge and colleagues in 1960 (7). This boy presented with hypoglycemic seizures in early infancy and was shown to be susceptible to hypoglycemia when given an iv infusion of leucine (7). Recently, a nephew of DiGeorge’s original case presented with neonatal HI, suggesting that leucine-sensitive hypoglycemia in this family might be a dominant form of HI. The purpose of this study was to determine the genetic basis for HI in this family. Functional tests of insulin secretion, mutation analysis, and in vitro expression experiments indicate that this family has a dominantly expressed mutation of the sulfonylurea receptor 1 (SUR1), one of the two genes encoding the pancreatic ß cell KATP channel.
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Subjects and Methods |
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The proband is a 4-yr-old boy (3e in Fig. 1
) who was born at 41 wk gestation, weighing 6.2 kg, by emergency cesarean section for cephalopelvic disproportion and cardiac arrhythmia. He had birth asphyxia and was hypoglycemic with a plasma glucose concentration below 30 mg/dl shortly after delivery. The physical examination was notable for large weight. The proband was admitted to the intensive care unit, where he required mechanical ventilation until 10 d of age. The hypoglycemia and large birth weight were initially attributed to maternal diabetes, because his mother had been diagnosed with gestational diabetes and treated by diet during the pregnancy. However, because of the continuing need for iv dextrose infusions to avoid hypoglycemia, further evaluation was pursued at 33 d of age, which established the diagnosis of HI. The plasma ammonia concentration was normal. Treatment with diazoxide (10 mg/kg/d) successfully controlled hypoglycemia.
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The proband’s mother, 2e, had a birth weight of 3.7 kg, and was not suspected to have hypoglycemia as a child. She was diagnosed with gestational diabetes while pregnant with 3e, but has not subsequently had evidence of diabetes. She reports having episodes of nausea and shakiness, alleviated by eating, with blood glucose levels of 40–50 mg/dl determined by a home glucose meter. Hypoglycemia was not observed during formal fasting tests of up to 21 h.
The proband’s maternal grandparents were both evaluated for leucine-sensitive hypoglycemia when the proband’s uncle (2c) was an infant. The maternal grandmother (1a) was not sensitive to oral leucine. However, the maternal grandfather (1b), now deceased, developed symptomatic hypoglycemia after receiving a submaximal oral dose of leucine, which precluded further testing (7). Apart from this occasion, 1b was never considered to have hypoglycemia. He was subsequently diagnosed with adult-onset diabetes mellitus. Three of the proband’s maternal uncles (2a, 2b and 2d) have adult-onset diabetes mellitus; none has had symptoms of hypoglycemia. One of these (2b) shares the same SUR1 mutation as the proband, and one (2d) does not.
Recently, a child (4a) of a cousin (3d) of the proband was born large for gestational age (4.5 kg) and was found to have hypoglycemia shortly after birth. At 2 months of age, her blood glucose dropped below 70 mg/dl at 6.5 h of fasting, with suppressed levels of plasma ß-hydroxybutyrate and free fatty acids consistent with HI at the end of the fast. Her mother (3d) has no history of hypoglycemic symptoms and did not become hypoglycemic when fasted for 24 h.
AIR tests
The proband and five members of his family were admitted to the General Clinical Research Center at Children’s Hospital of Philadelphia for evaluation. Individuals were studied either before any diazoxide treatment or after having withdrawn diazoxide for at least 5 d. AIR tests were carried out with calcium (2 mg/kg), leucine (15 mg/kg), glucose (0.5 g/kg), and tolbutamide (25 mg/kg) sequentially infused iv at intervals of 1 h. Blood samples were obtained for measurement of glucose and insulin, and the AIR was calculated as the mean increment in insulin levels at 1 and 3 min after infusion. Criteria for abnormal responses in normal subjects are calcium AIR greater than 5 µU/ml and leucine AIR greater than 5 µU/ml (4, 8). In children with HI due to the common recessive SUR1 mutations (g3992–9a and delF1388) (9), the usual tolbutamide AIR is below 5 µU/ml (4, 8, 10). AIR values in groups of these patients and in patients with GDH-HI are shown in Table 1.
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In the postabsorptive state, a protein solution (1 g/kg) was administered orally (Resource Instant Protein Powder, Novartis Pharmaceuticals, East Hanover, NJ). Blood samples for plasma glucose and insulin were obtained at –15, 0, 15, 30, 45, 60, 90, 120, 150, and 180 min. The test was terminated if plasma glucose fell below 50 mg/dl. The normal response was defined as a decrease in plasma glucose of less than 10 mg/dl, with blood glucose remaining greater than 70 mg/dl (11).
Genetic analysis
Peripheral blood was obtained for isolation of genomic DNA from the proband and multiple family members. Direct sequencing of the SUR1 (ABCC8), Kir6.2 (KCNJ11), GDH (GLUD1), and glucokinase coding sequences were performed on the proband. Resulting sequences were analyzed using Sequencher3.1 (Gene Codes Corp., Ann Arbor, MI).
Functional analysis of expressed SUR1 mutant channels
Point mutations of SUR1 were introduced into hamster SUR1 cDNA in the pECE plasmid using the QuikChange site-directed mutagenesis kit (Stratagene, La Jolla, CA) as previously described (12). Mutations were confirmed by DNA sequencing. COSm6 cells were plated onto 35-mm culture dishes and transfected with control or mutant SUR1 and mouse Kir6.2 cDNA (in pCMV6b) using FuGene 6 (Roche Diagnostic Corporation, Indianapolis, IN). For the 86Rb+ efflux assay, cells were incubated for 24 h in culture medium containing 86RbCl (1 µCi/ml) 2–3 d after transfection. Before measurement of 86Rb+ efflux, cells were incubated for 30 min at 25 C in Krebs-Ringer solution with various metabolic inhibitors (2.5 µg/ml oligomycin and/or 0.3–1 mM 2-deoxy-D-glucose). At selected time points, the solution was aspirated from the cells and replaced with fresh solution. At the end of a 40-min period, cells were lysed in 2% sodium dodecyl sulfate-Ringer’s solution. The 86Rb+ in the aspirated solution and the cell lysates was counted. The percent efflux at each time point was calculated as the cumulative counts in the aspirated solution divided by the total counts from the solutions and the cell lysates.
Cell surface expression level of the mutant channels was assessed by Western blot of mutant SUR1 that was tagged with a FLAG epitope (DYKDDDDK in single amino acid code) at the N terminus and by a quantitative chemiluminescence assay as described previously (12). Briefly, cells plated in 35-mm dishes were fixed with 2% paraformaldehyde for 30 min at 4 C 48–72 h after transfection. Fixed cells were preblocked in PBS and 0.1% BSA for 30 min or overnight, incubated in M2 anti-FLAG antibody (10 µg/ml) for 1 h, washed four times for 30 min each time in PBS and 0.1% BSA, incubated in horseradish peroxidase-conjugated antimouse (Jackson ImmunoResearch Laboratories, Inc., West Grove, PA; 1:1000 dilution) for 20 min, and washed again four times for 30 min each time in PBS and 0.1% BSA. The chemiluminescence of each dish was quantified in a TD-20/20 luminometer (Turner Designs, Palo Alto, CA) after 15-sec incubation in Power Signal Elisa Luminol solution (Pierce Chemical Co., Rockford, IL). All steps after fixation were carried out at room temperature.
Patch-clamp recordings were performed in the inside-out configuration as previously described (12). Briefly, COSm6 cells were transfected with cDNA encoding wild-type (WT) or mutant channel proteins as well as cDNA for the green fluorescent protein, which facilitates identification of positively transfected cells. Patch-clamp recordings were made 36–72 h posttransfection. Micropipettes were pulled from nonheparinized Kimble glass (Fisher Scientific, Pittsburgh, PA) with resistance typically approximately 0.5–1 M
. The bath (intracellular) and pipette (extracellular) solution (K-INT) had the following composition: 140 mM KCl, 10 mM K-HEPES, and 1 mM K-EGTA (pH 7.3). ATP and ADP were added as the potassium salt. All currents were measured at a membrane potential of –50 mV (pipette voltage = +50 mV), and inward currents are shown as upward deflections. Data were analyzed using pCLAMP software (Axon Instruments, Union City, CA). Off-line analysis was performed using Excel programs (Microsoft, Redmond, WA). The MgADP or diazoxide response was calculated as the current in a K-INT solution plus 0.1 mM ATP, 0.5 mM ADP, or 0.3 mM diazoxide and 1 mM free Mg2+ relative to that in plain K-INT solution.
For all studies involving human subjects, informed consent was obtained from the subjects. Study protocols were approved by the investigational review board of Children’s Hospital of Philadelphia.
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Results |
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Table 1
shows the results of AIR tests on the proband and his family. At 5 wk of age, while recovering from birth asphyxia, the proband had an abnormal positive response to calcium and an exaggerated tolbutamide AIR. Because these early responses might have been influenced by his severe perinatal stress, he was retested at 10 months of age. This showed an abnormal, positive leucine AIR, an exaggerated response to glucose, and a low normal tolbutamide AIR. AIR tests were also abnormal in four members of the proband’s family who shared the SUR1 R1353H mutation subsequently found in the proband. As shown in Table 1, all four had abnormal positive calcium AIRS, one of four had an abnormal positive leucine AIR, and the tolbutamide AIR was blunted in the one individual who was tested. The positive calcium AIR and decreased tolbutamide AIR pattern is similar to that seen in HI due to recessive mutations of SUR1 (see Table 1). The abnormal positive leucine AIR in the proband and his affected aunt (2f) was consistent with DiGeorge’s report of leucine-sensitive hypoglycemia in this family.
Table 2 shows the results of protein tolerance tests in the proband and other family members who carried the SUR1 R1353H mutation found in the proband. The proband was tested only while receiving diazoxide therapy, but still showed abnormal drops in blood glucose of 9, 10, and 17 mg/dl on three separate occasions. Four of the five other carriers of the proband’s mutation also showed excessive decreases in blood glucose in response to oral protein. The exception (4a) was the affected young baby, who had clear evidence of HI on fasting.
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Genetic analysis
Because the proband’s clinical studies suggested the possibility of either a mutation of GDH or of the KATP channel genes, SUR1 and Kir6.2, his genomic DNA was screened for mutations of these genes as well as for glucokinase. The entire coding regions for all four genes were sequenced. No mutations of GDH, glucokinase, or Kir6.2 were found. However, in SUR1 exon 33, a substitution of G to A at position 4058 was identified, which replaces a histidine for the normal arginine at amino acid position 1353. The arginine residue at position 1353 of SUR1 is conserved across golden hamster, European hamster, rat, mouse, fruit fly, and cricket. This residue is also conserved among SUR proteins 2A and 2B in humans. The mutation destroys an HhaI restriction site that was used to screen genomic DNA from members of the proband’s family. As shown in Fig. 1, the proband (3e), his mother (2e), his affected aunt and uncle (2f and 2c), his asymptomatic uncle and cousin (2b and 3d), and the baby of 3d (4a) were all heterozygous for the R1353H mutation. A sister of 3d (3b) is also a carrier and has symptoms consistent with hypoglycemia, but has not been examined. The maternal grandmother (1b) and the proband’s father (2 g) were negative for the mutation. These results suggested that the R1353H mutation is responsible for HI in this family and is expressed as an autosomal dominant.
Functional analysis of mutant channels
The functional consequences of the R1353H mutation for macroscopic KATP channel activity in intact cells were assessed by the 86Rb+ efflux assay. Before 86Rb+ efflux measurement, cells were incubated with various metabolic inhibitors, which reduce the intracellular ATP/ADP ratio to stimulate channel activity. Four different metabolic states were examined: no metabolic inhibition, partial metabolic inhibition by 0.3 or 1 mM 2-deoxy-D-glucose, and full metabolic inhibition by 1 mM 2-deoxy-D-glucose plus 2.5 µg/ml oligomycin. Representative efflux profiles from the four different metabolic conditions are shown in Fig. 2A. The averaged net efflux (after subtraction of the background efflux measured in control cells not expressing KATP channels) at the end of the 40-min period is significantly lower for the R1353H mutant than for the WT channel in cells that were treated with 0.3 or 1 mM 2-deoxy-D-glucose (P < 0.005 for both; n = 3–4; Table 3). The results indicate that under these metabolic conditions, the R1353H mutant channels do not open as readily as the WT channels. When cells were treated with 1 mM 2-deoxy-D-glucose plus 2.5 µg/ml oligomycin, the difference between the R1353H and WT channels diminished. This is probably because both channels are now maximally stimulated, and the efflux rates are saturated. We also examined the functional consequences of another HI-associated SUR1 mutation at the same amino acid site, the R1353P mutation, identified by Verkarre et al. (14). This mutation acts as a recessive expressed in a focal lesion by loss of heterozygosity for the normal maternal allele. In the efflux assay, the R1353P mutant channels remained mostly inactive even when cell metabolism was maximally inhibited (Fig. 2A). Together, these data provide strong evidence that mutations of R1353 in SUR1 play a causative role in these HI cases.
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). Additional quantitation of the amount of FLAG-tagged SUR1 present on the cell surface using the chemiluminescence assay showed that surface expression of the R1353H mutant is slightly reduced (89.6 ± 6.6% of WT; P < 0.005; n = 10) compared with that of the WT (Table 3). Interestingly, another HI mutation at the same amino acid position, R1353P, dramatically reduced surface expression of the channel (21.5 ± 4.3% of WT; P < 0.001; n = 11). Patch-clamp recording experiments revealed a mild functional defect in the R1353H mutant channel. Compared with WT channels, the R1353H mutant is less active (59.0 ± 5.9% of WT; P < 0.001) at an ADP/ATP ratio of 0.5/0.1 mM (the free Mg2+ concentration is at 1 mM), indicating a reduced response to MgADP stimulation. This reduced response to MgADP is likely to account for the reduced response to metabolic inhibition observed in the 86Rb+ efflux experiments. We also examined the mutant channel response to diazoxide and found it to be slightly reduced compared with that of the WT channel (83.0 ± 5.9% of WT; P < 0.001). |
Discussion |
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There have been two previous descriptions of dominantly inherited SUR1 mutations, E1506K by Huopio et al. (15) and delSer1387 from our institution (16). The E1506K mutation caused HI in seven children within a large pedigree. Four of five patients showed a good response to diazoxide treatment (15). The delSer1387 dominant SUR1 mutation was identified in five members of three generations of a family. Affected individuals had positive AIR to calcium, negative leucine AIR, and protein-sensitive hypoglycemia. Unlike the R1353H and E1506K families, the delSer1387 family members showed only partial diazoxide responsiveness (16). Most other reported SUR1 mutations are recessively expressed, and the heterozygous carriers are both clinically normal and show no evidence of abnormal islet responses to secretagogues (5, 6).
Expression studies of the three dominant SUR1 mutations show a range of abnormalities. In patch-clamp expression studies, E1506K SUR1 formed KATP channels that were sensitive to diazoxide, but not to metabolic inhibition, consistent with partial impairment of function (15). The delSer1387 SUR1 trafficked to the plasma cell membrane normally, but 86Rb+ efflux studies demonstrated complete absence of channel activity (16). Cell surface expression of R1353H showed 86Rb+ efflux intermediate between WT and the completely defective, recessive R1353P SUR1 mutation (14). Patch-clamp studies also indicated decreased, but not absent, sensitivity to MgADP. Thus, the R1353H mutation appears to cause a partial disruption of SUR1 receptor function similar to E1506K, but less severe than delSer1387. The milder impairment of function by R1353H and E1506K compared with delSer1387 correlates with the greater diazoxide responsiveness of patients with these two mutations.
The mechanism for dominant SUR1 disease remains speculative. The KATP channel is formed by four SUR1 subunits combined with four Kir 6.2 subunits. The dominant SUR1 mutations may have a dominant negative effect if channels containing one abnormal SUR1 subunit have loss of function, because only the 1/16th of KATP channels with normal subunits would be functional. Therefore, this fraction of channels function normally and are responsive to diazoxide. This mechanism has been discussed previously (11, 15, 16).
All three families with dominant SUR1 mutations feature carriers who have little or no clinical hypoglycemia (15, 16). In our R1353H family, only the proband (3e), 2c, 2f, and 4a had diagnosed neonatal hypoglycemia. Huopio et al. (15) suggest that this variability might be explained by imprinting, because all of their clinically affected patients inherited the mutation from their mothers. However, neither the R1353H nor delSer1387 pedigrees shows such a parent of origin effect. Variability in clinical expression of hypoglycemia has also been seen in families with HI caused by an activating glucokinase mutation (17) and by GDH mutations (3). In the present R1353H family, even carriers such as 2e and 3d, without clinical hypoglycemia, showed evidence of islet cell dysregulation, as seen by abnormal AIRs and protein sensitivity (Tables 1 and 2).
In our R1353H family, the proband had an exaggerated AIR to tolbutamide at 5 wk of age and to leucine and glucose at 10 months of age, whereas most older affected family members had rather modest responses (Table 2). The greater insulin responses in the proband, particularly at 5 wk of age, might be related to his severe birth asphyxia, similar to the prolonged HI seen in babies with small for gestational age birth weight or birth asphyxia (18, 19). It is also possible that the hypoglycemic effects of KATP channel impairment are more clinically apparent in early infancy than later in life, because other family members (2c, 2f, 2e, and 3d) have had little or no problem with fasting hypoglycemia as adults. Although responsiveness to tolbutamide might seem inconsistent with a SUR1 mutation, this was also seen in two of three delSer1387 mutants studied (16). This is consistent with SUR1 dominant mutants retaining partial function. Recently published data indicated that of nine cases of HI with identified recessive KATP channel mutations, four had positive responses to tolbutamide (20). This suggests that even in those with recessive mutations, the KATP channels may retain some ability to be inhibited by tolbutamide.
Protein-sensitive hypoglycemia was a feature of the HI caused by both the delSer1387 and R1353H dominant SUR1 mutations. However, delSer1387 was not associated with leucine sensitivity on AIR testing (16), and three of five R1353H carriers had negative leucine AIR (Table 1), including patient 2c, who was reported to be leucine sensitive by DiGeorge and his colleagues as an infant (7). The hyperresponsiveness of some R1353H carriers to leucine is probably a consequence of their partial impairment of KATP activity. For example, Fajans et al. (21) noted that leucine sensitivity could be induced in normal adults by prior treatment with tolbutamide. It should be noted that the leucine AIR test used in the present study is quite different from the prolonged iv or oral leucine infusion tests performed previously. Unlike the acute leucine test, the prolonged stimulation with the older tests probably does not act solely through leucine activation of GDH activity.
The lack of correlation in the R1353H between leucine AIR tests and sensitivity to protein-induced hypoglycemia suggests that mixtures of amino acids may stimulate insulin release through pathways other than leucine activation of GDH. We suggest that it is the amino acid mixture in the protein, and not specifically leucine, that is causing hypoglycemia in this family. Li et al. (22) recently reported that glutamine, but not leucine, could stimulate insulin secretion in islets from the SUR1 knockout mouse model of KATP channel HI. This effect occurred under basal conditions only in the SUR1 knockout islets and not in normal islets. It was proposed that glutamine acted by amplifying insulin secretion distal to the steps of ß-cell depolarization and increased intracellular calcium (22). A similar effect due to impaired KATP channel opening may explain the observation of protein sensitivity in the proband and his family.
A notable feature of the R1353H SUR1 mutant carriers was that some, but not all, individuals later developed gestational or adult-onset diabetes mellitus. This was also noted in the family with the dominant E1506K SUR1 mutation described by Huopio et al. (15). Adult-onset diabetes was also reported in a family with HI caused by a dominant glucokinase mutation, but has not been associated with heterozygosity for the recessive SUR1 mutations (10, 17). Based on their observations of subnormal insulin responses to oral and iv glucose and to hyperglycemic clamp studies in adults with the SUR1 E1506K mutations, Huopio et al. (15) suggested that the KATP defect causes diabetes due to ß-cell apoptosis as a result of continuous depolarization and high cytoplasmic calcium concentrations of ß-cells. Supporting this hypothesis is their finding that insulin secretion was lower in older compared with younger E1506K heterozygotes (23). However, an impaired insulin response to glucose is an expected feature of the KATP defect in both humans and mice, and therefore does not necessarily reflect loss of islet mass (10, 24). In fact, adults with the more severe dominant SUR1 delSer1387 mutation have not developed diabetes, but instead have had persistent hypoglycemia (16). Diabetes also was not a consistent feature in the adults of the present family with the R1353H dominant SUR1 mutation. Five of the six known adult R1353H carriers do not have diabetes. It is possible that some of the hyperglycemia seen in adults with dominant SUR1 mutations may represent postprandial glucose intolerance due to their underlying islet cell dysregulation, which causes abnormal insulin responses to both high and low glucose levels.
This case of familial leucine-sensitive hypoglycemia sheds new light on an old diagnosis (25). Leucine-sensitive hypoglycemia is probably a heterogeneous group of disorders not restricted to HI associated with GDH mutations. The identification of the dominant R1353H SUR1 mutation as the cause of hypoglycemia in the present family provides an alternative molecular explanation. This and two other dominant SUR1 mutations that have been identified cause a form of HI that is at least partly responsive to diazoxide. Patients with dominant R1353H and delSer1387 SUR1 mutations appear to be at risk for protein-induced hypoglycemia, but, in contrast to DiGeorge’s observations of hypoglycemia after leucine administration, do not necessarily have exaggerated leucine-stimulated insulin secretion. Dominant SUR1 mutations may be responsible for protein-sensitive HI in other previously reported cases of leucine-sensitive hypoglycemia.
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Acknowledgments |
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Footnotes |
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Abbreviations: AIR, Acute insulin response; FLAG epitope, DYKDDDDK in single amino acid code; GDH, glutamate dehydrogenase; HI, hyperinsulinism; KATP, ATP-dependent potassium channel; SUR1, sulfonylurea receptor 1; WT, wild type.
Received March 8, 2004.
Accepted June 3, 2004.
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