BPDZ 154 Activates Adenosine 5′-Triphosphate-Sensitive Potassium Channels:<i>In Vitro</i>Studies Using Rodent Insulin-Secreting Cells and Islets Isolated from Patients with Hyperinsulinism

Cosgrove, Karen E.; Antoine, Marie; Lee, Anne T.; Barnes, Philippa D.; Tullio, Pascale De; Clayton, Peter E.; McCloy, R F; Lonlay, P. De; Nihoul‐Feketé, Claire; Robert, Jean Jacques; Saudubray, Jean Marie; Rahier, Jacques; Lindley, Keith; Hussain, Khalid; Aynsley-Green, A.; Pirotte, Bernard; Lebrun, Philippe; Dunne, Mark J.

doi:10.1210/jc.2002-020439

Cited by 30 publications

(39 citation statements)

References 42 publications

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“…A newer more potent synthetic diazoxide analog, 6,7-dichloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (BPDZ 154), has been evaluated [65]. In patients with CHI associated with severe loss of K ATP channel function, neither diazoxide nor BPDZ 154 was effective in suppressing insulin release in vivo.…”

Section: Medical Managementmentioning

confidence: 99%

Diagnosis and Management of Hyperinsulinaemic Hypoglycaemia of Infancy

Hussain¹

2007

Horm Res Paediatr

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Hyperinsulinaemic hypoglycaemia is a cause of persistent hypoglycaemia in the neonatal and infancy periods. Prompt recognition and management of patients with hyperinsulinaemic hypoglycaemia are essential, if brain damage and long-term neurological sequelae are to be avoided. Hyperinsulinaemic hypoglycaemia can be transient, prolonged, or persistent (congenital). Advances in the fields of molecular biology, genetics, and pancreatic β-cell physiology are beginning to provide novel insights into the mechanisms causing congenital forms of hyperinsulinism. So far mutations in six different genes have been described that lead to unregulated insulin secretion. The histological differentiation of focal and diffuse congenital hyperinsulinism has radically changed the surgical approach to this disease. Until recently, highly invasive investigations were performed to localize the focal lesion, but recent experience with ¹⁸F-L-dopa positron emission tomography scanning suggests that this technique is highly sensitive for differentiating diffuse from focal disease as well as for accurately locating the focal lesion. Despite recent advances, the genetic basis of congenital hyperinsulinism is still unknown in about 50% of the patients, and the management of medically unresponsive diffuse disease remains a real challenge.

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Section: Medical Managementmentioning

confidence: 99%

Diagnosis and Management of Hyperinsulinaemic Hypoglycaemia of Infancy

Hussain¹

2007

Horm Res Paediatr

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150

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“…These mutations can lead to type 1 channelopathy without channel activity, or to type 2 channelopathy with a decreased channel activity due either to defective function, or to decreased number of channels. Heterogeneous outcome is observed for the same mutation as some cells manifest a type 1 channelopathy, others a type 2 channelopathy, and other mutated cells have a normal activity of the potassium channel [29, 30]. This observation could be explained by interactions with modulator genes, exogenous factors, or variable degree of penetrance of the mutation.…”

Section: Molecular Basismentioning

confidence: 99%

Molecular Mechanisms of Neonatal Hyperinsulinism

et al. 2006

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Congenital hyperinsulinism (CHI), characterized by profound hypoglycaemia related to inappropriate insulin secretion, may be associated histologically with either diffuse insulin hypersecretion or focal adenomatous hyperplasia, which share a similar clinical presentation, but result from different molecular mechanisms. Whereas diffuse CHI is of autosomal recessive, or less frequently of autosomal dominant, inheritance, focal CHI is sporadic. The most common mechanism underlying CHI is dysfunction of the pancreatic ATP-sensitive potassium channel (K⁺_ATP). The two subunits of the K⁺_ATP channel are encoded by the sulfonylurea receptor gene (SUR1 or ABCC8) and the inward-rectifying potassium channel gene (KIR6.2 or KCNJ11), both located in the 11p15.1 region. Germ-line, paternally inherited, mutations of the SUR1 or KIR6.2 genes, together with somatic maternal haplo-insufficiency for 11p15.5, were shown to result in focal CHI. Diffuse CHI results from germ-line mutations in the SUR1 or KIR6.2 genes, but also from mutations in several other genes, namely glutamate dehydrogenase (with associated hyperammonaemia), glucokinase, short-chain L-3-hydroxyacyl-CoA dehydrogenase, and insulin receptor gene. Hyperinsulinaemic hypoglycaemia may be observed in several overlapping syndromes, such as Beckwith-Wiedemann syndrome (BWS), Perlman syndrome, and, more rarely, Sotos syndrome. Mosaic genome-wide paternal isodisomy has recently been reported in patients with clinical signs of BWS and CHI. The primary causes of CHI are genetically heterogeneous and have not yet been completely unveiled. However, secondary causes of hyperinsulinism have to be considered such as fatty acid oxidation deficiency, congenital disorders of glycosylation and factitious hypoglycaemia secondary to Munchausen by proxy syndrome.

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“…Distinction between these 2 forms has major therapeutic implications: whereas medically unresponsive DiCHI usually requires near total pancreatectomy, FoCHI can be cured by a selective localized resection of the lesion (18,19 (20,21). Studies of 3 FoCHI cases showed that functional K ATP channels are absent from β cells within the focal lesion and present and normally regulated in the adjacent pancreas (22). In vitro data on insulin secretion by CHI pancreas are scanty and sometimes controversial.…”

Section: Introductionmentioning

confidence: 99%

In vitro insulin secretion by pancreatic tissue from infants with diazoxide-resistant congenital hyperinsulinism deviates from model predictions

Henquin¹,

Nenquin²,

Sempoux³

et al. 2011

J. Clin. Invest.

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Congenital hyperinsulinism (CHI) is the major cause of persistent neonatal hypoglycemia. CHI most often occurs due to mutations in the ABCC8 (which encodes sulfonylurea receptor 1) or KCNJ11 (which encodes the potassium channel Kir6.2) gene, which result in a lack of functional KATP channels in pancreatic β cells. Diffuse forms of CHI (DiCHI), in which all β cells are abnormal, often require subtotal pancreatectomy, whereas focal forms (FoCHI), which are characterized by localized hyperplasia of abnormal β cells, can be cured by resection of the lesion. Here, we characterized the in vitro kinetics of insulin secretion by pancreatic fragments from 6 DiCHI patients and by focal lesion and normal adjacent pancreas from 18 FoCHI patients. Responses of normal pancreas were similar to those reported for islets from adult organ donors. Compared with normal pancreas, basal insulin secretion was elevated in both FoCHI and DiCHI tissue. Affected tissues were heterogeneous in their secretory responses, with increased glucose levels often producing a rapid increase in insulin secretion that could be followed by a paradoxical decrease below prestimulatory levels. The KATP channel blocker tolbutamide was consistently ineffective in stimulating insulin secretion; conversely, the KATP channel activator diazoxide often caused an unanticipated increase in insulin secretion. These observed alterations in secretory behavior were similar in focal lesion and DiCHI tissue, and independent of the specific mutation in ABCC8 or KCNJ11. They cannot be explained by classic models of β cell function. Our results provide insight into the excessive and sometimes paradoxical changes in insulin secretion observed in CHI patients with inactivating mutations of KATP channels. IntroductionCongenital hyperinsulinism (CHI) is the major cause of persistent hypoglycemia in newborns and infants (1, 2). The underlying genetic etiology and biochemical mechanisms are multiple, resulting in heterogeneous clinical presentation from relatively mild, medically responsive forms to severe forms requiring near total pancreatectomy. The most common and severe cases of CHI are caused by inactivating mutations in ABCC8 (90%) and KCNJ11 (10%) genes, which are both located on chromosome 11p15 and respectively encode sulfonylurea receptor 1 (SUR1) and Kir6.2, the regulatory and pore-forming subunits of ATP-sensitive K (K ATP ) channels in pancreatic β cells (2-6). More than 150 mutations in ABCC8 and about 25 mutations in KCNJ11 have been reported (6, 7), which cause defective channel trafficking to the plasma membrane or impairment of channel regulation by nucleotides.Glucose control of insulin secretion is normally achieved through the interaction of triggering and amplifying pathways in β cells (reviewed in ref. 8). K ATP channels play an essential role in the triggering pathway. When β cells sense a rise in blood glucose, their metabolism accelerates, causing an increase in ATP and

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BPDZ 154 Activates Adenosine 5′-Triphosphate-Sensitive Potassium Channels:In VitroStudies Using Rodent Insulin-Secreting Cells and Islets Isolated from Patients with Hyperinsulinism

Cited by 30 publications

References 42 publications

Diagnosis and Management of Hyperinsulinaemic Hypoglycaemia of Infancy

Diagnosis and Management of Hyperinsulinaemic Hypoglycaemia of Infancy

Molecular Mechanisms of Neonatal Hyperinsulinism

In vitro insulin secretion by pancreatic tissue from infants with diazoxide-resistant congenital hyperinsulinism deviates from model predictions

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