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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 2 925-929
Copyright © 2004 by The Endocrine Society

Acute Insulin Responses to Calcium and Tolbutamide Do Not Differentiate Focal from Diffuse Congenital Hyperinsulinism

Irina Giurgea, Kathleen Laborde, Guy Touati, Christine Bellanné-Chantelot, Marie-Cecile Nassogne, Christine Sempoux, Francis Jaubert, Nguyen Khoa, Valerie Chigot, Jacques Rahier, Francis Brunelle, Claire Nihoul-Fékété, Mark J. Dunne, Charles Stanley, Jean-Marie Saudubray, Jean-Jacques Robert and Pascale de Lonlay

Departments of Pediatrics (I.G., G.T., M.-C.N., J.-M.S., J.-J.R., P.d.L.), Physiology (K.L.), Pathology (F.J.), Biochemistry A (N.K.), Radiology (V.C., F.B.), and Pediatric Surgery (C.N.-F.), Hôpital Necker Enfants Malades, 75743 Paris, France; Department of Biology (C.B.-C.), Hôpital Saint-Antoine, 75012 Paris, France; Department of Pathology (C.Se., J.R.), Université de Louvain, B-1349 Louvain-La-Neuve, Belgium; Division of Physiology and Pharmacology (M.J.D.), School of Biological Science, The University of Manchester, M-139 PL Manchester, United Kingdom; and Department of Pediatrics (C.St.), The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104-4399


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Congenital hyperinsulinism (CHI) is related to two main histological pancreas anomalies: focal adenomatous hyperplasia and diffuse ß-cell hypersecretion. Pharmacological tests to measure acute insulin responses (AIR) to peripheral iv injections of glucose, calcium, and tolbutamide have been reported as potential means to distinguish between these histological forms. In patients with defects in ATP-sensitive potassium channels, tolbutamide will fail to induce insulin release in affected portions of the pancreas, whereas calcium gluconate will enhance insulin release through spontaneously active voltage-gated Ca2+ channels. Consequently, in focal CHI patients, calcium should promote AIRs from the lesion, whereas tolbutamide should act to promote insulin secretion from the healthy region of the pancreas (outside the focal hyperplasia). We therefore studied AIRs to calcium and tolbutamide stimulation tests in 16 children with focal (n = 9) or diffuse (n = 7) CHI before pancreatic surgery. We found hypervariable AIRs to glucose and calcium stimulation in both focal and diffuse CHI patients. AIRs to tolbutamide stimulation were found modest in focal CHI patients, which might account for ß-cell quiescence in the healthy portion of the pancreas of these patients. We conclude that AIRs to calcium and tolbutamide stimulation tests are not sufficient to differentiate the focal from the diffuse CHI patients.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
CONGENITAL HYPERINSULINISM (CHI) (OMIM 256450), previously named persistent hyperinsulinemic hypoglycemia of infancy, is characterized by profound hypoglycemia related to inappropriate insulin secretion (1, 2, 3). CHI can be related to two distinct histological anomalies: focal adenomatous hyperplasia and diffuse pancreatic insulin hypersecretion (4, 5, 6). Focal CHI (adenomatous hyperplasia of pancreatic islet cells) has been ascribed to loss of heterozygosity for paternally inherited mutations in the ATP-sensitive potassium (KATP) channel genes encoding the sulfonylurea receptor (ABCC8 or SUR1) or the inwardly rectifying potassium channel subunit (KCNJ11 or Kir6.2). This loss of heterozygosity is due to a partial aneusomy for maternal chromosome 11p15.1 in the pancreatic lesion (6, 7, 8). By contrast, diffuse CHI is due to functional abnormalities of islets throughout the whole pancreas (4). In diffuse CHI, several genes are involved with autosomal recessive or, less frequently, dominant inheritance, namely SUR1; Kir6.2 (9, 10, 11); glucokinase (12); glutamate dehydrogenase (with associated hyperammonemia) (13); and most recently, short-chain L-3-hydroxyacyl-Coenzyme A dehydrogenase (14).

CHI aggressive treatment is necessary to prevent irreversible brain damage (15, 16). Focal and diffuse forms (5, 6) share a similar clinical presentation but require a different treatment. The distinction between focal and diffuse lesions is crucial because neonatal hyperinsulinemic hypoglycemia is mostly resistant to medical therapy and surgically treated. Diffuse CHI requires near-total pancreatectomy with a high risk of iatrogenic diabetes and pancreatic insufficiency, whereas focal CHI can be cured by partial pancreatectomy limited to the focal somatic lesion (5, 17). The reference technique for the preoperative diagnosis and localization of focal forms is the functional study of insulin secretion by selective pancreatic venous sampling (PVS) (18, 19). However, because this method is technically challenging and requires that the patient be maintained in a hypoglycemic state under general anesthesia throughout the investigation, continuing efforts are needed to define alternative tests to diagnose focal CHI.

Pharmacological tests to measure acute insulin responses (AIRs) to peripheral iv injections of glucose, calcium, and tolbutamide appeared to be a promising method to distinguish focal and diffuse CHI (20, 21). In normal ß-cells, glucose-dependent increases in the cytosolic ATP:ADP ratio leads to the closure of the KATP channels and a depolarization of the cell membrane. This opens the voltage-gated Ca2+ channels and allows the influx of extracellular calcium and the exocytosis of insulin. In patients with nonfunctional KATP channels, AIRs to calcium stimulation have been explained by enhances in calcium influx through spontaneously open voltage-gated Ca2+ channels (20). Previous reports of CHI patients with abnormal KATP channels showed that diffuse and focal CHI responded favorably to calcium stimulation (20). Tolbutamide inhibits ß-cell KATP channels and stimulates insulin release in normal ß-cells. In patients with diffuse CHI as a result of defects in KATP channels, tolbutamide fails to alter intracellular Ca2+ levels (21) and has no effect on insulin release in vitro and in vivo (20, 21). Based on these findings and the morphofunctional architecture of focal CHI, it has been hypothesized that tolbutamide should stimulate insulin secretion in the healthy portions of pancreas, i.e. outside the focal hyperplasia, and that this could be used in the diagnosis of focal vs. diffuse CHI (20). However, to date, this hypothesis has not been studied in focal CHI.

The aim of this study was to investigate whether focal and diffuse CHI can be distinguished on the basis of AIRs to tolbutamide and calcium stimulation tests before surgery.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

In this study, 16 patients with CHI were investigated at Necker-Enfants Malades Hospital before pancreatic surgery. The clinical characteristics of the patients are summarized in Table 1Go. The subjects were aged from 1 to 40 months at the time of the study. The disease had neonatal onset in 14 children (NN, neonatal) and occurred after 2 months of life for the other two patients (INF, infants). The medical sensitivity to diazoxide, reported in Table 1Go, was defined as the complete normalization of blood glucose (>3 mmol/liter), measured before and after each meal, in patients fed normally, after iv glucose and any other medication had been stopped for at least 5 consecutive days. Resistance to medical treatment was defined as two confirmed blood glucose measurements lower than 3 mmol/liter in a 24-h period. According to these criteria, all the patients were diazoxide resistant.


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  		TABLE 1. Clinical characteristics of patients

 
The differential diagnosis between the focal and diffuse forms were performed by PVS (18, 19, 22) and/or by pancreatic arterial calcium stimulation (PACS) (23, 24) combined with preoperative histological examination of frozen sections (5, 25). Nine patients had a suspected focal CHI (patients 1–9), and seven had a diffuse CHI (patients 10–16) on PVS and/or PACS. Thirteen of these patients underwent a pancreas surgery, which confirmed the histological diagnosis by conventional microscopy (4, 5). Three patients had a typical pattern of diffuse insulin secretion in the whole pancreas at PVS, but the suspected diffuse CHI was not confirmed by conventional microscopy because they were treated medically by octreotide (Table 1Go). One of these untreated patients (patient 14) had an elder affected brother with a histologically proven diffuse CHI.

Twelve patients were related to SUR1/Kir6.2 genes (Table 1Go). It was not possible to genotype the other four patients (two focal and two diffuse CHI) because DNA was not available to us. However, all four patients had severe neonatal hypoglycemia resistant to diazoxide treatment, strongly suggesting a KATP channel defect. Patients with hyperinsulinism/hyperammonemia syndrome were excluded from the study.

Study design

All investigations were performed before surgery. All medical treatments, such as glucagon, octreotide, and diazoxide, were stopped 5 d before the tests. The blood glucose level was maintained between 3.3 and 5 mmol/liter by iv dextrose infusion. The tests were performed after 6 h of fasting. Each patient had two peripheral venous catheters: one for infusion and the other for blood sampling. The tests were always performed in the same order. The first test was an acute insulin response to peripheral iv calcium gluconate stimulation (CaAIR) (20): 2 mg elemental calcium/kg injected iv over 1 min. The second test was an iv glucose tolerance test (IVGTT): 0.5 g/kg glucose (30% dextrose) injected iv over 2–3 min. All other infusion of glucose was stopped during the IVGTT. This test was made 60 min or more after the calcium injection. The third test was a tolbutamide test: 25 mg/kg tolbutamide or 1-butyl-3-tolylsulfonyl urea monosodium (Orinase Diagnosis, Pharmacia/Upjohn, Kalamazoo, MI) was given iv over 1 min (21). This test was initiated after a minimum period of 20 min after the IVGTT.

For each of the three tests, blood was taken at times: 5 min prior the injection, 0 min (at the end of the injection), 1 min, 3 min (and additionally at 5, 10, 15, 30, and 60 min for infants older than 6 months) for determination of glucose, insulin, and C-peptide levels. The calcium level was measured only in the CaAIR test.

Assays and statistical analysis

Plasma insulin was determined by a radioenzymatic method (Insulin IMX, Abbott Division Diagnostic, Abbott Park, IL). Plasma C-peptide was determined by RIA (Specific C-peptide RIA, Sanofi Diagnostic, Pasteur, Paris, France).

Insulin response to glucose stimulation was measured as the early insulin peak, the sum of plasma insulin levels at 1 + 3 min of an IVGTT.

The insulin and C-peptide responses to calcium and tolbutamide stimulation were calculated as the mean of plasma insulin levels at 1 and 3 min after the iv injection. All results are shown as the difference ({Delta}) between the mean peak values and the mean baseline levels (mean of -5 min and 0 min). Previous publications defined AIRs to calcium or tolbutamide as positive if {Delta} was more than 5 µU/ml (20, 21). Additionally, because the insulin and C-peptide baseline levels were variable among the patients, insulin and C-peptide responses to calcium and tolbutamide stimulation were also calculated as the ratio between the peak and baseline levels. With regard to previously published control data (20, 21), we defined: 1) insulin response to peripheral calcium stimulation as positive when the ratio was increased 2-fold, and 2) insulin response to peripheral tolbutamide stimulation as positive when the ratio was increased 4-fold. The calcium stimulation test was interpreted only if a 0.2 mmol/liter rise in serum calcium occurred after the calcium injection.

For statistical analyses, the Mann-Whitney rank sum test was used for comparison among the different groups. P < 0.05 was considered as significant.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
The results are shown in Tables 2Go, 3Go, and 4Go.


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  		TABLE 2. IVGTT

 

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  		TABLE 3. Acute insulin response to peripheral iv tolbutamide stimulation

 

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  		TABLE 4. Acute insulin response to peripheral iv calcium stimulation

 
IVGTT

The IVGTT was performed in 15 subjects, nine focal and six diffuse CHI. The injection of iv glucose led to a hypervariable increase in insulin secretion, whatever the histological form of hyperinsulinism. The mean insulin response was not significantly different between the two CHI forms, with a large range of insulin responses in the two forms of hyperinsulinism (Table 2Go).

Tolbutamide test

The tolbutamide test was carried out in 14 subjects: eight focal CHI and six diffuse CHI. Plasma insulin responses after tolbutamide infusion did not increase at all in three of eight focal CHI patients and in two of six diffuse CHI patients. The increase was modest (less than 15 µU/ml) in two focal and two diffuse CHI patients. The peak:baseline ratio was greater than 2 in four focal and two diffuse CHI patients and greater than 4 in one diffuse CHI patients but in no focal CHI patients (Table 3Go). Two patients have not been studied with the tolbutamide test because of difficulties obtaining the tolbutamide drug.

Peripheral iv CaAIR

Plasma insulin responses to the calcium test increased by less than 5 µU/ml in three of nine focal CHI patients and two of four diffuse CHI patients. The increase was modest (5–15 mmol/liter) in two focal and two diffuse CHI patients and greater in four focal patients. The peak:baseline ratio was greater than 2 in six of nine focal and one diffuse CHI patient after calcium stimulation (Table 4Go). Three patients were excluded from this study because plasma calcium level did not increase after calcium infusion.

For all three pharmacological tests, there was no significant difference between the two diverse CHI forms, focal and diffuse, and between the SUR1-mutated patients and patients with no molecular basis. The C-peptide responses gave similar results (Tables 2–4GoGoGo).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
An ability to distinguish between the two histologically diverse forms of CHI, focal and diffuse, is now considered an essential prerequisite to surgical treatment and long-term clinical outcome of the patient. To date, only the selective PVS and PACS have been proposed to identify diffuse insulin secretion of the whole pancreas (diffuse CHI) or localized insulin hypersecretion, suggesting focal CHI. However, these tests are difficult to perform and require that the child be maintained under general anesthesia (PVS and PACS) and at hypoglycemic levels (PVS). The previously published pharmacological tests with iv injections of calcium, glucose, and tolbutamide seemed to offer promise as diagnostic utilities and are far simpler to undertake than PVS and PACS (20, 21). Tolbutamide, an insulin secretagogue that inhibits ß-cell KATP channels in normal ß-cells has been shown to be ineffective at promoting insulin release from patients with diffuse CHI because abnormalities affect the entire pancreas (26). Because children with focal CHI also have a subpopulation of normal ß-cells outside their focal lesion, these patients would be expected to retain an AIR to tolbutamide, enabling diagnosis of focal CHI to be defined. However, in our study, AIRs to tolbutamide infusion were very similar in both focal and diffuse CHI patients, and the overall responses indicated only a modest positive tolbutamide AIR response in focal CHI. Considering the molecular origins of focal CHI, these observations were surprising and unexpected. One possible explanation is that otherwise healthy ß-cells located outside the lesion are quiescent in patients with focal CHI because of a negative feedback as a result of insulin hypersecretion. This is supported by histological data that indicate that the healthy portion of the pancreas of focal CHI patients has the appearance of resting tissue with a condensed cytoplasm (5). Furthermore, the transient hyperglycemia frequently observed in the first few days after partial pancreatectomy of focal CHI supports this suggestions because the quiescence of the pancreas requires a defined period of time to disappear. It generally takes a few days before the patients recover full glycemic control (17).

Our data with the AIR to calcium stimulation indicated that responses of patients were highly variable in both subject groups. The rationale for a positive calcium AIR is that patients with diffuse or focal CHI have spontaneously active voltage-gated Ca2+ channels and that high extracellular calcium raises intracellular Ca2+ as a direct consequence (23). This is supported by in vitro data obtained from CHI patients (21, 23) and, in vivo, in previously studied patients with either focal or diffuse CHI because of mutations in the SUR1 gene (20). We found that the responses of CHI patients were less discriminating than predicted. Indeed, some patients with focal and diffuse forms of CHI had a very poor response to calcium stimulation. This remains difficult to interpret because the calcium-induced increase of plasma insulin levels is comparatively weak. These results and those showing that some patients with a diffuse CHI curiously responded to tolbutamide clearly suggest that the relationship between genotype and function at the level of the ß-cell is not entirely predictable and that the AIR response to tolbutamide and calcium depends largely on the downstream consequences after the loss of KATP channels as recently suggested (27, 28).

This study also revealed that, as in control subjects (29), plasma insulin responses to iv glucose stimulation exhibited marked patient-to-patient variability and that there was no overall significant difference between the two patient groups, focal and diffuse. AIRs to glucose stimulation in patients with defective KATP channels arises as a result of the KATP channel-independent or amplification pathways of regulated insulin release, suggesting that these pathways play an important role in stimulating insulin secretion in vivo. This assumption confirms previous functional studies of control human islets and islets from CHI patients that described the KATP channel-independent pathways of glucose-induced insulin release in vitro (26).

In conclusion, our results clearly show that AIRs to calcium and tolbutamide stimulation tests are not sufficient to differentiate focal from diffuse CHI and that other diagnostic tests have to be found.


   Acknowledgments
 
We thank the patients and their families for their participation and the nurses for their expert work and great patience.


   Footnotes
 
Address all correspondence and requests for reprints to: Dr. Pascale de Lonlay, Fédération de Pédiatrie, Hôpital Necker–Enfants Malades, 149 rue de Sèvres, 75743 Paris cedex 15, France. E-mail: pascale.delonay{at}nck.ap-hop-paris.fr.

Collaborative interactions were funded by a European Community–funded Concerted Action Grant (QLG1-2000-00513). I.G. is a grant recipient from AJP-Laboratories Gallia.

Abbreviations: AIR, Acute insulin response; CaAIR, acute insulin response to peripheral iv calcium gluconate stimulation; CHI, congenital hyperinsulinism; IVGTT, iv glucose tolerance test; KATP, ATP-sensitive potassium; PACS, pancreatic arterial calcium stimulation; PVS, pancreatic venous sampling.

Received June 2, 2003.

Accepted August 21, 2003.


   References
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Aynsley-Green A, Polak JM, Bloom SR, Gough MH, Keeling J, Ashcroft SJ, Turner RC, Baum JD 1981 Nesidioblastosis of the pancreas: definition of the syndrome and the management of the severe neonatal hyperinsulinaemic hypoglycaemia. Arch Dis Child 56:496–508[Abstract]
  2. Landau H, Perlman M, Meyer S, Isacsohn M, Krausz M, Mayan H, Lijovetzky G, Schiller M 1982 Persistent neonatal hypoglycemia due to hyperinsulinism: medical aspects. Pediatrics 70:440–446[Abstract/Free Full Text]
  3. Cornblath M, Schwartz R, Aynsley-Green A, Lloyd JK 1990 Hypoglycemia in infancy: the need for a rational definition. A Ciba Foundation discussion meeting. Pediatrics 85:834–837[Abstract/Free Full Text]
  4. Goossens A, Gepts W, Saudubray JM, Bonnefont JP, Nihoul F, Heitz PU, Kloppel G 1989 Diffuse and focal nesidioblastosis. A clinicopathological study of 24 patients with persistent neonatal hyperinsulinemic hypoglycemia. Am J Surg Pathol 13:766–775[Medline]
  5. Rahier J, Sempoux C, Fournet JC, Poggi F, Brunelle F, Nihoul-Fekete C, Saudubray JM, Jaubert F 1998 Partial or near-total pancreatectomy for persistent neonatal hyperinsulinaemic hypoglycaemia: the pathologist’s role. Histopathology 32:15–19[CrossRef][Medline]
  6. Sempoux C, Guiot Y, Dubois D, Nollevaux MC, Saudubray JM, Nihoul-Fekete C, Rahier J 1998 Pancreatic B-cell proliferation in persistent hyperinsulinemic hypoglycemia of infancy: an immunohistochemical study of 18 cases. Mod Pathol 11:444–449[Medline]
  7. De Lonlay P, Fournet JC, Rahier J, Gross-Morand MS, Poggi-Travert F, Foussier V, Bonnefont JP, Brusset MC, Brunelle F, Robert JJ, Nihoul-Fekete C, Saudubray JM, Junien C 1997 Somatic deletion of the imprinted 11p15 region in sporadic persistent hyperinsulinemic hypoglycemia of infancy is specific of focal adenomatous hyperplasia and endorses partial pancreatectomy. J Clin Invest 100:802–807[Medline]
  8. Fournet JC, Mayaud C, de Lonlay P, Gross-Morand MS, Verkarre V, Castanet M, Devillers M, Rahier J, Brunelle F, Robert JJ, Nihoul-Fekete C, Saudubray JM, Junien C 2001 Unbalanced expression of 11p15 imprinted genes in focal forms of congenital hyperinsulinism: association with a reduction to homozygosity of a mutation in ABCC8 or KCNJ11. Am J Pathol 158:2177–2184[Abstract/Free Full Text]
  9. Nestorowicz A, Wilson BA, Schoor KP, Inoue H, Glaser B, Landau H, Stanley CA, Thornton PS, Clement JPT, Bryan J, Aguilar-Bryan L, Permutt MA 1996 Mutations in the sulfonylurea receptor gene are associated with familial hyperinsulinism in Ashkenazi Jews. Hum Mol Genet 5:1813–1822[Abstract/Free Full Text]
  10. Thomas PM, Cote GJ, Wohllk N, Mathew PM, Gagel RF 1996 The molecular basis for familial persistent hyperinsulinemic hypoglycemia of infancy. Proc Assoc Am Physicians 108:14–19[Medline]
  11. Huopio H, Reimann F, Ashfield R, Komulainen J, Lenko HL, Rahier J, Vauhkonen I, Kere J, Laakso M, Ashcroft F, Otonkoski T 2000 Dominantly inherited hyperinsulinism caused by a mutation in the sulfonylurea receptor type 1. J Clin Invest 106:897–906[Medline]
  12. Glaser B, Kesavan P, Heyman M, Davis E, Cuesta A, Buchs A, Stanley CA, Thornton PS, Permutt MA, Matschinsky FM, Herold KC 1998 Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J Med 338:226–230[Free Full Text]
  13. Stanley CA, Lieu YK, Hsu BY, Burlina AB, Greenberg CR, Hopwood NJ, Perlman K, Rich BH, Zammarchi E, Poncz M 1998 Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J Med 338:1352–1357[Abstract/Free Full Text]
  14. Clayton PT, Eaton S, Aynsley-Green A, Edginton M, Hussain K, Krywawych S, Datta V, Malingre HE, Berger R, van den Berg IE 2001 Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of beta-oxidation in insulin secretion. J Clin Invest 108:457–465[CrossRef][Medline]
  15. Filler RM, Weinberg MJ, Cutz E, Wesson DE, Ehrlich RM 1991 Current status of pancreatectomy for persistent idiopathic neonatal hypoglycemia due to islet cell dysplasia. Prog Pediatr Surg 26:60–75[Medline]
  16. Menni F, de Lonlay P, Sevin C, Touati G, Peigne C, Barbier V, Nihoul-Fekete C, Saudubray JM, Robert JJ 2001 Neurologic outcomes of 90 neonates and infants with persistent hyperinsulinemic hypoglycemia. Pediatrics 107:476–479[Abstract/Free Full Text]
  17. Cretolle C, Fekete CN, Jan D, Nassogne MC, Saudubray JM, Brunelle F, Rahier J 2002 Partial elective pancreatectomy is curative in focal form of permanent hyperinsulinemic hypoglycaemia in infancy: a report of 45 cases from 1983 to 2000. J Pediatr Surg 37:155–158[CrossRef][Medline]
  18. Brunelle F, Negre V, Barth MO, Fekete CN, Czernichow P, Saudubray JM, Kuntz F, Tach T, Lallemand D 1989 Pancreatic venous samplings in infants and children with primary hyperinsulinism. Pediatr Radiol 19:100–103[CrossRef][Medline]
  19. Dubois J, Brunelle F, Touati G, Sebag G, Nuttin C, Thach T, Nikoul-Fekete C, Rahier J, Saudubray JM 1995 Hyperinsulinism in children: diagnostic value of pancreatic venous sampling correlated with clinical, pathological and surgical outcome in 25 cases. Pediatr Radiol 25:512–516[CrossRef][Medline]
  20. Ferry Jr RJ, Kelly A, Grimberg A, Koo-McCoy S, Shapiro MJ, Fellows KE, Glaser B, Aguilar-Bryan L, Stafford DE, Stanley CA 2000 Calcium-stimulated insulin secretion in diffuse and focal forms of congenital hyperinsulinism. J Pediatr 137:239–246[CrossRef][Medline]
  21. Grimberg A, Ferry Jr RJ, Kelly A, Koo-McCoy S, Polonsky K, Glaser B, Permutt MA, Aguilar-Bryan L, Stafford D, Thornton PS, Baker L, Stanley CA 2001 Dysregulation of insulin secretion in children with congenital hyperinsulinism due to sulfonylurea receptor mutations. Diabetes 50:322–328[Abstract/Free Full Text]
  22. Lyonnet S, Bonnefont JP, Saudubray JM, Nihoule-Fekete C, Brunelle F 1989 Localisation of focal lesion permitting partial pancreatectomy in infants. Lancet 2:671
  23. Abernethy LJ, Davidson DC, Lamont GL, Shepherd RM, Dunne MJ 1998 Intra-arterial calcium stimulation test in the investigation of hyperinsulinaemic hypoglycaemia. Arch Dis Child 78:359–363[Abstract/Free Full Text]
  24. Chigot V, De Lonlay P, Nassogne MC, Laborde K, Delagne V, Fournet JC, Nihoul-Fekete C, Saudubray JM, Brunelle F 2001 Pancreatic arterial calcium stimulation in the diagnosis and localisation of persistent hyperinsulinemic hypoglycaemia of infancy. Pediatr Radiol 31:650–655[CrossRef][Medline]
  25. De Lonlay-Debeney P, Poggi-Travert F, Fournet JC, Sempoux C, Vici CD, Brunelle F, Touati G, Rahier J, Junien C, Nihoul-Fekete C, Robert JJ, Saudubray JM 1999 Clinical features of 52 neonates with hyperinsulinism. N Engl J Med 340:1169–1175[Abstract/Free Full Text]
  26. Straub SG, Cosgrove KE, Ammala C, Shepherd RM, O’Brien RE, Barnes PD, Kuchinski N, Chapman JC, Schaeppi M, Glaser B, Lindley KJ, Sharp GW, Aynsley-Green A, Dunne MJ 2001 Hyperinsulinism of infancy: the regulated release of insulin by KATP channel-independent pathways. Diabetes 50:329–339[Abstract/Free Full Text]
  27. Huopio H, Jaaskelainen J, Komulainen J, Miettinen R, Karkkainen P, Laakso M, Tapanainen P, Voutilainen R, Otonkoski T 2002 Acute insulin response tests for the differential diagnosis of congenital hyperinsulinism. J Clin Endocrinol Metab 87:4502–4507[Abstract/Free Full Text]
  28. Cosgrove KE, Antoine MH, Lee AT, Barnes PD, de Tullio P, Clayton P, McCloy R, De Lonlay P, Nihoul-Fekete C, Robert JJ, Saudubray JM, Rahier J, Lindley KJ, Hussain K, Aynsley-Green A, Pirotte B, Lebrun P, Dunne MJ 2002 BPDZ 154 activates adenosine 5'-triphosphate-sensitive potassium channels: in vitro studies using rodent insulin-secreting cells and islets isolated from patients with hyperinsulinism. J Clin Endocrinol Metab 87:4860–4868[Abstract/Free Full Text]
  29. Robert JJ, Deschamps I, Chevenne D, Roger M, MoGenet A, Boitard C 1991 Relationship between first-phase insulin secretion and age, HLA, islet cell antibody status, and development of type I diabetes in 220 juvenile first-degree relatives of diabetic patients. Diabetes Care 14:718–723[Abstract]



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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals