| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Original Article |
Departments of Pediatrics (H.H., J.J., J.K., R.V.) and Medicine (R.M., P.K., M.L.), Kuopio University Hospital, FIN-70211 Kuopio; Department of Pediatrics (P.T.), Oulu University Hospital, FIN-90029 Oulu; and Transplantation Laboratory, Haartman Institute, and the Hospital for Children and Adolescents (T.O.), University of Helsinki, FIN-00014 Helsinki, Finland
Address all correspondence and requests for reprints to: Hanna Huopio, M.D., Department of Pediatrics, Kuopio University Hospital, P.O. Box 1777, Fin-70211 Kuopio, Finland. E-mail: hanna.huopio{at}uku.fi.
Abstract
Mutations in genes encoding the two subunits of the ß-cell ATP-sensitive potassium channel (KATP) channel (SUR1 and Kir6.2) are the major cause of congenital hyperinsulinism (CHI). In this study, the KATP channel genes were screened in a population-based study that included all verified Finnish CHI patients (n = 43) in a 27-yr period. Seven different mutations were identified, which accounted for 60% of all cases. The functional consequences of the major missense mutations were studied in vivo by determining acute (1–3 min) plasma insulin and C-peptide responses to calcium (n = 18), glucose (n = 12), and tolbutamide (n = 11) in those CHI patients who were able to take part in these studies. C-peptide and insulin responses to calcium were significantly higher in the patients with SUR1-E1506K mutation, compared with patients without KATP channel mutations. The patients with SUR1-V187D mutation showed a reduced response to tolbutamide but unexpectedly did not show any response to calcium stimulation. A compound heterozygous patient with Kir6.2-(-54)/K67N mutations responded to calcium but also to tolbutamide. In conclusion, our results show that a positive response in the calcium test is indicative of a KATP channel mutation, but all mutations cannot be identified with this method. The insulin response to tolbutamide in patients with SUR1 mutations is impaired to different extents, depending on the genotype. The combination of calcium and tolbutamide tests is a useful tool for the detection of CHI patients with KATP channel dysfunction. Our results, however, also demonstrate the complexity of these responses and the difficulties in their interpretation.
CONGENITAL HYPERINSULINISM (CHI) is characterized by inappropriate insulin secretion, leading to persistent and recurrent hypoglycemia in infancy (1). Although the incidence of CHI is only about 1 in 42,000 in Finland, as in most populations studied (2, 3), it is a major cause of neurological damage and lifelong handicap if not treated adequately (4).
The most common known causes of CHI are mutations in the genes encoding the ß-cell ATP-sensitive potassium channel (KATP) subunits, sulfonylurea receptor 1 (SUR1) and inward rectifier K+ channel (Kir6.2) (5, 6, 7, 8). In the normal ß-cell, the increase in cytosolic ATP/ADP ratio leads to the closure of the KATP channels and depolarization of the cell membrane. This, in turn, opens the voltage-gated Ca2+channels and allows an influx of extracellular calcium and exocytosis of insulin. In the case of the mutant KATP channels, this mechanism is impaired, leading to chronic depolarization of the ß-cell membrane and continuous insulin secretion (9). KATP channel antagonists, like sulfonylureas, increase the rate of insulin secretion, but KATP channel agonists, such as diazoxide, decrease insulin release (10). The majority of CHI cases show diffuse involvement of all pancreatic ß-cells, whereas focal adenomatous hyperplasia is present in up to 30% of cases, with loss of maternal alleles, allowing the penetrance of a paternal SUR1 mutation (11, 12).
Considering the specific features of Finnish population genetics (13), it was assumed that few mutations would account for the major proportion of CHI in Finland. Indeed, the previously reported SUR1 mutations V187D (3) and E1506K (14) are the cause of most genetically characterized CHI cases. The mutation SUR1-V187D leads to total loss of function of KATP channels and severe drug-resistant phenotype. In contrast, the dominantly inherited mutation SUR1-E1506K associates with milder diazoxide-responsive form of CHI. In the present study, we report additional KATP channel mutations detected in single cases in the Finnish population. Previous reports of CHI patients have suggested that patients with KATP channel mutations exhibit impaired responses to tolbutamide, but that elevation of extracellular calcium directly stimulates insulin release by enhancing calcium influx through voltage-gated calcium channels that are constantly open (15, 16). The existence of two founder mutations in Finland makes it possible to study the correlation between genotype and phenotype more reliably. Therefore, in the present study, we investigated the acute ß-cell responses to calcium, glucose, and tolbutamide in vivo in Finnish patients with different genotypes.
Patients and Methods
Patients
All patients diagnosed with CHI at the Departments of Pediatrics of the five University Central Hospitals of Finland since 1972 were included in the genetic part of the study (age at the time of DNA sampling ranging from 1 wk to 27 yr). These patients are likely to represent all affected individuals diagnosed during that time, but the possibility of single undiagnosed cases cannot be excluded. CHI was diagnosed using generally accepted criteria including nonketotic hypoglycemia, inappropriately elevated insulin levels, and an increased need for glucose administration to prevent hypoglycemia (1, 4). The study protocol had been approved by the Ethics Committee of Kuopio University Hospital. Informed consent was given by all subjects studied.
Acute insulin response (AIR) tests were performed in all CHI patients who were able and willing to participate, except those who were diabetic and required more than 0.5 U/kg insulin per day. The first study group consisted of five patients (aged 2–26 yr) in which no KATP channel gene mutations have been identified despite two separate screening processes of SUR1 and Kir6.2 genes. The second group consisted of a single 8-yr-old patient with two different Kir6.2 mutations (paternally inherited Kir6.2-K67N and maternally inherited C to T substitution 54 bases proximal of the translation initiation site). He had been treated with subtotal pancreatectomy at the age of 11 d. The third group consisted of six patients (aged 6–27 yr) carrying the dominant SUR1-E1506K mutation. The oldest patient in this group had been treated with subtotal pancreatectomy at the age of 3.5 yr and had diabetes. The fourth group was composed of one homozygous and five compound heterozygote patients with the mutation SUR1-V187D (aged 1–14 yr). Five of the six had undergone subtotal pancreatectomy as infants, and four had diabetes treated with insulin at the time of investigation. The patients with paternal SUR1-V187D and maternal SUR1-A1457T (n = 1) or SUR1-V1550D (n = 1) were excluded from AIR tests because of the requirement of insulin more than 0.5 U/kg per day. The two compound heterozygotes with paternal L1551V were not willing to participate in the study. All pancreatectomized patients who were included in AIR tests had the diffuse form of CHI as judged by histopathological examination (no KATP channel mutation, n = 1; Kir6.2-(-54)/K67N, n = 1; SUR1-E1506K, n = 1; SUR1-V187D, n = 5). The major clinical characteristics of the patients are shown in Table 1
.
|
Peripheral blood samples were collected from all patients, and DNA was prepared from blood leukocytes by proteinase K-phenol-chloroform extraction. The immediate promoter region of SUR1 (220 bp upstream from the transcription start site), all 39 SUR1 exons and flanking introns, and the single exon of Kir6.2 were investigated using the primers designed by us according to the reported sequences of SUR1 and Kir6.2 genes or synthesized as previously reported (17, 18, 19). The PCR-SSCP was performed as previously reported (14, 20).
Direct sequencing
Variant forms of DNA detected by SSCP analysis were identified by direct sequencing (Thermo Sequenase radiolabeled terminator cycle sequencing kit, USB Corp., Cleveland, OH) and verified by restriction fragment length polymorphism analysis on a 9% polyacrylamide gel stained in ethidium bromide and photographed.
Detection of the novel mutations in KATP channel genes
The primers and conditions for PCRs and the restriction endonucleases used in detecting novel mutations are shown in Table 2.
|
Patients who participated in acute ß-cell response tests were admitted to the pediatric ward of Kuopio University Hospital. Patients on diazoxide treatment came to the hospital 6 d before and the patient on octreotide treatment 2 d before the tests for discontinuation of the medication. Patients with diabetes (daily dose of insulin < 0.5 U/kg) had their last sc insulin injection in the morning of the day before the tests. A stable insulin infusion was started (Actrapid, 0.5 U/ml NaCl 0.9% at the rate of 0.025 U/kg per hour, Novo Nordisk, Gentofte, Denmark) in the same evening and was maintained until the end of the calcium stimulation test. The plasma glucose was 4.8 mmol/liter ± 1.5 (SD), range 2.7–7.1 mmol/liter in patients who were not diagnosed with diabetes and 5.2 mmol/liter ± 1.6 (SD), range 2.4–6.9 mmol/liter in diabetic patients before the start of the stimulation tests.
The study protocol consisted of an iv calcium stimulation test (15) in all patients (n = 18) and it was followed by iv glucose tolerance and tolbutamide tests (16) in nondiabetic subjects (n = 12). An iv catheter was placed in the antecubital vein for the infusion of calcium, glucose, and tolbutamide. Another cannula was inserted in the contralateral antecubital vein for the blood sampling. All patients were monitored carefully for 24 h after the tests.
Calcium stimulation test
After a baseline blood collection, a bolus of elemental calcium (2 mg/kg; Sandoz Pharmaceuticals Corp., Novartis, Switzerland) was infused within 60 sec to evaluate the insulin response to an acute elevation of plasma calcium level. Samples for the measurement of blood glucose, plasma insulin, plasma C-peptide, and plasma calcium were drawn at -5, 0, 1, 3, and 5 min. In addition, the blood glucose level was measured at 15 and 30 min after the calcium bolus.
Intravenous glucose tolerance test (IVGTT)
One hour after the calcium stimulation test, patients who were not diagnosed with diabetes underwent an IVGTT to determine the first-phase insulin secretory capacity. After baseline blood collection (-5 and 0 min), a bolus of glucose (0.5 g/kg, maximum 20 g, in a 20% solution) was injected within 2 min to increase the blood glucose level acutely. Samples for the measurement of blood glucose, plasma insulin, and plasma C-peptide were drawn at 1, 3, and 5 min from the end of the glucose infusion.
Tolbutamide test
Nondiabetic subjects also underwent a tolbutamide test to investigate the ß-cell response to the KATP channel antagonist tolbutamide. This was performed 60 min after the IVGTT. A bolus of tolbutamide (25 mg/kg, maximum dose 1000 mg; Orinase Diagnostic, Pharmacia & Upjohn, Kalamazoo, MI) was injected within 1 min and venous blood collected at -5, 0, 1, 3, and 5 min. A maintenance glucose infusion was then started to prevent the development of hypoglycemia. In one patient (case 3) the tolbutamide test was interrupted because of dizziness and nausea 1 min after the tolbutamide bolus.
Assays and calculations
For the determination of plasma insulin and C-peptide, blood was collected into EDTA tubes. After centrifugation, the plasma for the determination of insulin and C-peptide was stored at -20 C until the analysis. Plasma insulin and C-peptide were determined by RIA (Phadeseph insulin RIA 100, Pharmacia Diagnostics AB, Uppsala, Sweden, and C-peptide RIA, INCSTAR Corp., Stillwater, MN, respectively). This insulin assay also detects proinsulin and its conversion products, with a cross-reactivity of 47%. The incremental insulin and glucose areas under the curve were calculated by the trapezoidal method.
The AIRs to calcium, glucose, and tolbutamide were calculated as the means of the increments in insulin and C-peptide concentrations measured 1 and 3 min after the stimulation.
Statistical analysis
All calculations were performed with the SPSS, Inc. for Windows software (SPSS, Inc., Chicago, IL.). Data are shown as the mean ± SEM in the text and as the median results in Table 3. Differences among the different variables in two groups were analyzed using the nonparametric Kruskal-Wallis and Mann-Whitney tests.
|
Detection of novel KATP channel mutations
PCR-SSCP analysis revealed three novel mutations in the second nucleotide-binding fold of SUR1. The mutation A1457T in exon 36 was found to be maternally inherited in one compound heterozygote patient with the paternally inherited mutation SUR1-V187D (case 19). The mutation V1550D in exon 39 of SUR1 was maternally inherited in one individual who also had paternally inherited SUR1-V187D (case 20). The SUR1 mutation L1551V in exon 39 was detected heterozygously in two sisters, and we were unable to detect any mutation in the other SUR1 allele (cases 21 and 22). Two different Kir6.2 mutations were identified in the same patient (case 6): K67N was inherited paternally and the substitution C-to-T 54 bases proximal of the translation initiation site, which leads to a formation of a new start codon (ATG) and a frame shift, was inherited maternally. None of these novel mutations were detected in 100 chromosomes from unrelated healthy Finnish volunteers.
Despite two separate screening processes of the KATP channel genes, we were not able to identify another SUR1 mutation in the five SUR1-V187D compound heterozygote patients who were tested with the AIR tests. This can be explained in two ways: either the patients are compound heterozygotes, or they have a paternally inherited mutation with focal HI (21). In these cases it must be assumed that the patients are compound heterozygotes on the basis of the following reasons. First, three of the patients (cases 14, 17, and 18) had inherited the V187D mutation from their mother, which is inconsistent with focal disease. Second, the histological analysis of the resected pancreases in cases 14, 15, 17, and 18 revealed diffuse pathology.
Acute ß-cell responses to calcium and tolbutamide stimulation in CHI subjects.
The mean increments in serum-ionized calcium concentration during the calcium stimulation test were comparable in all study groups: 0.19 mmol/liter in CHI patients without KATP mutations, 0.23 mmol/liter in the patient with both Kir6.2 mutations, 0.17 mmol/liter in SUR1-E1506K patients, and 0.23 mmol/liter in SUR1-V187D patients. The acute plasma C-peptide response to calcium was significantly increased in patients with SUR1-E1506K (159 ± 28 pmol/liter), compared with either patients without KATP channel mutations (33 ± 25 pmol/liter) (P < 0.05) or SUR1-V187D carriers (41 ± 15 pmol/liter) (P < 0.05). The response to calcium was not significantly different between the SUR1-V187D carriers and patients without KATP channel mutations.
It is obvious that the subjects with SUR1-V187D have very little remaining ß-cell function after the subtotal pancreatectomy and that this is maximally stimulated even under basal conditions. This is supported by the fact that four of six of these subjects were already diabetic and that the responses to tolbutamide and glucose were severely impaired even in the older, now 8-yr-old nondiabetic subject (case 16). Because it is difficult to evaluate the results of diabetic patients, only the results of the nondiabetic patients are shown in Table 3
.
The plasma insulin and C-peptide responses to tolbutamide appeared to be lower in subjects with SUR-V187D and SUR-E1506K channel mutations, compared with the subjects without KATP channel mutations, but the differences were not statistically significant because of the small number of observations. One of four patients with SUR1-E1506K showed a clear response to tolbutamide, but the response was low in all other cases. Interestingly, the patient with mutations in Kir6.2 had a normal response to tolbutamide (Table 3).
All nondiabetic subjects without KATP channel mutations as well as the patient with two Kir6.2 mutations exhibited normal AIR to glucose. It was clearly subnormal in the prepubertal SUR1-V187D homozygous patient (case 16) and in the postpubertal SUR1-E1506K heterozygotes.
Discussion
Mutations in genes encoding the ß-cell KATP channels, SUR1 and Kir6.2, are the major cause of CHI in the Finnish population. Altogether, seven different mutations in these genes are associated with 60% of all cases. The two previously reported founder SUR1 mutations, V187D (3) and E1506K (14), account for 88% of the genetically characterized cases. The other five SUR1 or Kir6.2 mutations have been detected in only single cases.
Correlation between genotype and phenotype
The verified compound heterozygote subjects (A1457T/V187D and V1550D/V187D) show a very severe and drug-resistant disease phenotype. This is likely to be due to the total loss of channel activity by both of the novel mutations because we have shown that the mutation V187D alone does not cause any impairment of insulin secretion in heterozygous carriers (22). Both these patients were diabetic and had no intrinsic insulin secretion, and therefore, we were not able to perform the AIR tests in these patients.
The two subjects who were heterozygous for the SUR1 mutation L1551V had a milder form of CHI, which was responsive to diazoxide. No AIR tests could be performed in these patients to study the functional consequences of this mutation in detail. Because no other mutations were detected in this family, the possibility remains that this diazoxide-responsive mutation could be inherited dominantly, analogous with the E1506K mutation (14). Further studies are needed to verify or exclude this possibility.
The compound heterozygote subject carrying two different Kir6.2 mutations was treated with octreotide without significant response and underwent subtotal pancreatectomy at the age of 11 d. He has not subsequently required treatment, either for insulin deficiency or excess. One of the mutations located in the translation initiation site is predicted to lead to a novel start codon and a scrambled sequence. This is expected to lead to a reduced number of KATP channels. This should not, on its own, result in clinical CHI. The other mutation in the coding sequence (K67N) is predicted to also affect channel function. Because of the combination of these two mutations, the channels expressed in this patient are predicted to contain only wild-type SUR1 and Kir6.2-K67N. The positive response to the calcium stimulation test suggests that this patient has depolarized ß-cells at fasting plasma glucose concentrations, which is consistent with KATP channel dysfunction. The strong responses of the subject to the glucose and tolbutamide stimulation tests may be a consequence of the function of these mutant channels. It is possible that the ß-cells are only partially depolarized, leaving capacity for additional stimulation by glucose or tolbutamide. Furthermore, glucose and tolbutamide may act through KATP-independent pathways because these agents have been shown to enhance insulin secretion or exocytosis directly (23, 24).
Correlation between genotype and the results of clinical stimulation tests
The severity of CHI, as well as the therapy needed, varies according to the genotype. To date, four different genes are known to cause CHI, but no genetic etiology has been determined for as many as 60% of cases (8). Previous studies have shown that the most severe CHI cases are associated with mutations in KATP channel genes. This is in agreement with our results, which demonstrate that all subjects with recessive KATP channel mutations have severe, early-onset CHI, which has necessitated pancreatectomy in most patients. In contrast, all patients without KATP channel mutation responded well to conservative treatment, except for case 4 who had been treated with pancreatectomy according to the treatment policy of that time. It is presumable that they have CHI because of some other gene defect than KATP channel defect. This assumption is supported by the fact that despite the two screening processes of whole SUR1 and Kir6.2, no mutations were identified in them. The development of clinical tests to distinguish different types of CHI, without requiring full genotyping of each patient, would be of significant diagnostic and therapeutic value. It has been suggested that the calcium and tolbutamide stimulation tests might provide such a clinical tool.
Previous studies have suggested that children with hyperinsulinism caused by KATP channel gene defects hyper-respond to calcium because of constant activation of ß-cell voltage-gated calcium channels (15). Consistent with this idea, subjects with SUR1-E1506K and the Kir6.2 mutations showed a significant response to calcium. The patient with Kir6.2 mutation showed a huge response, compared with the other groups or with the patients included in the study of Ferry et al. (15). The result also supports the previous finding that in the case of diffuse CHI, the abnormal insulin response persists despite the subtotal pancreatectomy (15). In accordance with previous studies (15), none of the patients without KATP channel mutations responded to the calcium challenge. Unexpectedly, subjects with SUR1-V187D did not respond to calcium stimulation. This might be explained by the very low and chronically maximally stimulated residual ß-cell function of these patients. Our results, thus, demonstrate that a positive response in the calcium test strongly suggests that the hyperinsulinism is due to a mutation in one of the KATP channel genes; a negative result does not rule out this possibility.
Mutations in the KATP channel genes can lead to a reduction or a complete loss of action of the channel antagonist tolbutamide (9). This could also be used for the differential diagnosis of CHI patients. Previous studies have suggested that in focal CHI, the response to tolbutamide stimulation is normal, whereas it is impaired in the diffuse form (16). All pancreatectomized subjects in our study had a diffuse form of CHI. The C-peptide response to tolbutamide was severely decreased in SUR1-V187D subjects. This finding is in agreement with the previous results of ion channel recordings of ß-cells isolated from a SUR1-V187D homozygous patient. Unlike control cells that were activated by diazoxide and inhibited by tolbutamide, no actions of KATP channel agonists diazoxide or octreotide were seen in the cells with SUR1-V187D mutation (3). A diminished response to tolbutamide was also seen in the oldest SUR1-E1506K subjects, which may at least partly be explained by the natural course of E1506K-associated CHI. The two youngest prepubertal patients with normal response to iv glucose also responded to tolbutamide. According to the recombinant KATP channel studies of the dominant SUR1-E1506K, the mutated channels were partially activated by diazoxide and further blocked by tolbutamide (14). Although the cases are too few for statistical comparison, the results clearly support the idea that a low response to tolbutamide is consistent with a SUR1 mutation. However, the high response in our single case with Kir6.2 mutations and the variable response of SUR1-E1506K cases suggest that these patients would not be detected by this test alone.
In summary, our results support the previous findings of the usefulness of the calcium and tolbutamide stimulation tests in the differential diagnosis of CHI patients. The results show, however, that a negative response to calcium stimulation does not exclude the possibility that a subject has a KATP channel mutation, as clearly demonstrated by the major Finnish SUR1 mutation V187D. An impaired response in the tolbutamide test is characteristic for KATP channel mutations but does not appear in all cases. In conclusion, the combined calcium and tolbutamide test is a useful diagnostic tool in CHI, but our results also demonstrate the complexity of these responses and the difficulties in their interpretation.
Acknowledgments
We are grateful to Prof. Jacques Rahier for the histopathological reexamination of the Finnish cases. Sirpa Järveläinen is thanked for excellent technical assistance.
Footnotes
This work was supported by the Foundation for Pediatric Research in Finland (to H.H. and T.O.), Finnish Cultural Foundation (to H.H.), and the concerted action Network for Research into Hyperinsulinism in Infancy (ENRHI) supported by the European Union (QLG1-CT-2000-00513).
Abbreviations: AIR, Acute insulin response; CHI, congenital hyperinsulinism; IVGTT, iv glucose tolerance test; KATP, ATP-sensitive potassium channel; Kir6.2, inward rectifier K+ channel; PCR-SSCP, single-strand conformation polymorphism analysis; SUR1, sulfonylurea receptor 1.
Received March 11, 2002.
Accepted July 12, 2002.
References
This article has been cited by other articles:
 |
|
 |
|
  S. E. Calvo, D. J. Pagliarini, and V. K. Mootha Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans PNAS, May 5, 2009; 106(18): 7507 - 7512. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K Mazor-Aronovitch, D Gillis, D Lobel, H J Hirsch, O Pinhas-Hamiel, D Modan-Moses, B Glaser, and H Landau Long-term neurodevelopmental outcome in conservatively treated congenital hyperinsulinism Eur. J. Endocrinol., October 1, 2007; 157(4): 491 - 497. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Hussain, M. Seppanen, K. Nanto-Salonen, N. S. Adzick, C. A. Stanley, P. Thornton, and H. Minn The Diagnosis of Ectopic Focal Hyperinsulinism of Infancy with [18F]-Dopa Positron Emission Tomography J. Clin. Endocrinol. Metab., August 1, 2006; 91(8): 2839 - 2842. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Marthinet, A. Bloc, Y. Oka, Y. Tanizawa, B. Wehrle-Haller, V. Bancila, J.-M. Dubuis, J. Philippe, and V. M. Schwitzgebel Severe Congenital Hyperinsulinism Caused by a Mutation in the Kir6.2 Subunit of the Adenosine Triphosphate-Sensitive Potassium Channel Impairing Trafficking and Function J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5401 - 5406. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Henwood, A. Kelly, C. MacMullen, P. Bhatia, A. Ganguly, P. S. Thornton, and C. A. Stanley Genotype-Phenotype Correlations in Children with Congenital Hyperinsulinism Due to Recessive Mutations of the Adenosine Triphosphate-Sensitive Potassium Channel Genes J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 789 - 794. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Westlake, L. Payen, M. Gao, S. P. C. Cole, and R. G. Deeley Identification and Characterization of Functionally Important Elements in the Multidrug Resistance Protein 1 COOH-terminal Region J. Biol. Chem., December 17, 2004; 279(51): 53571 - 53583. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Giurgea, K. Laborde, G. Touati, C. Bellanne-Chantelot, M.-C. Nassogne, C. Sempoux, F. Jaubert, N. Khoa, V. Chigot, J. Rahier, et al. Acute Insulin Responses to Calcium and Tolbutamide Do Not Differentiate Focal from Diffuse Congenital Hyperinsulinism J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 925 - 929. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Stanley, P. S. Thornton, A. Ganguly, C. MacMullen, P. Underwood, P. Bhatia, L. Steinkrauss, L. Wanner, R. Kaye, E. Ruchelli, et al. Preoperative Evaluation of Infants with Focal or Diffuse Congenital Hyperinsulinism by Intravenous Acute Insulin Response Tests and Selective Pancreatic Arterial Calcium Stimulation J. Clin. Endocrinol. Metab., January 1, 2004; 89(1): 288 - 296. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. DUNNE, K. E. COSGROVE, R. M. SHEPHERD, A. AYNSLEY-GREEN, and K. J. LINDLEY Hyperinsulinism in Infancy: From Basic Science to Clinical Disease Physiol Rev, January 1, 2004; 84(1): 239 - 275. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Otonkoski, N. Kaminen, J. Ustinov, R. Lapatto, T. Meissner, E. Mayatepek, J. Kere, and I. Sipila Physical Exercise-Induced Hyperinsulinemic Hypoglycemia Is an Autosomal-Dominant Trait Characterized by Abnormal Pyruvate-Induced Insulin Release Diabetes, January 1, 2003; 52(1): 199 - 204. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
