Nature's KATP-Channel Knockout

Dunne, M. J.; Aynsley-Green, A; Lindley, K. J.

doi:10.1152/physiologyonline.1997.12.5.197

Cited by 8 publications

(12 citation statements)

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“…One model to account for a correlation between K AT P c h a nnel defects and impaired -cell function is that the loss of K AT P channels facilitates inappropriate Ca 2 + i n flux and accelerated rates of exocytosis (33). This model is supported by recent studies using transgenic animals expressing a dominant-negative form of Kir6.2 in -cells (34), and by in vivo data indicating that in some patients blockers of voltage-gated Ca 2 + channels assist in the maintenance of normoglycemia (35).…”

Section: T Otonkoski and Associatesmentioning

confidence: 99%

A point mutation inactivating the sulfonylurea receptor causes the severe form of persistent hyperinsulinemic hypoglycemia of infancy in Finland.

et al. 1999

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Mutations in genes encoding the ATP-regulated potassium (K(ATP)) channels of the pancreatic beta-cell (SUR1 and Kir6.2) are the major known cause of persistent hyperinsulinemic hypoglycemia of infancy (PHHI). We collected all cases of PHHI diagnosed in Finland between 1983 and 1997 (n = 24). The overall incidence was 1:40,400, but in one area of Central Finland it was as high as 1:3,200. Haplotype analysis using polymorphic markers spanning the SUR1/Kir6.2 gene cluster confirmed linkage to the 11p region. Sequence analysis revealed a novel point mutation in exon 4 of SUR1, predicting a valine to aspartic acid change at amino acid 187 (V187D). Of the total cases, 15 affected individuals harbored this mutation in heterozygous or homozygous form, and all of these had severe hyperinsulinemia that responded poorly to medical treatment and required subtotal pancreatectomy. No K(ATP) channel activity was observed in beta-cells isolated from a homozygous patient or after coexpression of recombinant Kir6.2 and SUR1 carrying the V187D mutation. Thus, the mutation produces a nonfunctional channel and, thereby, continuous insulin secretion. This unique SUR1 mutation explains the majority of PHHI cases in Finland and is strongly associated with a severe form of the disease. These findings provide diagnostic and prognostic utility for suspected PHHI patients.

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Section: T Otonkoski and Associatesmentioning

confidence: 99%

A point mutation inactivating the sulfonylurea receptor causes the severe form of persistent hyperinsulinemic hypoglycemia of infancy in Finland.

et al. 1999

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“…The significance of this loss of channel function is that beta cells can no longer adequately control the regulated entry of Ca 2ϩ ions. Since elevated [Ca 2ϩ ] i concentrations have been reported in isolated PHHI beta cells, this unregulated Ca 2ϩ influx has been suggested to stimulate Ca 2ϩ -dependent exocytosis, which underpins insulin hypersecretion (11). Recently, two related but clinically distinct disorders of familial hyperinsulinemia-induced hypoglycemia have also been linked to defects in beta cell stimulus-response coupling mechanisms.…”

Section: Persistent Hyperinsulinemic Hypoglycemia Of Infancy (Phhi)mentioning

confidence: 99%

Engineering a Glucose-responsive Human Insulin-secreting Cell Line from Islets of Langerhans Isolated from a Patient with Persistent Hyperinsulinemic Hypoglycemia of Infancy

Macfarlane¹,

Chapman²,

Shepherd³

et al. 1999

Journal of Biological Chemistry

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Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is a neonatal disease characterized by dysregulation of insulin secretion accompanied by profound hypoglycemia. We have discovered that islet cells, isolated from the pancreas of a PHHI patient, proliferate in culture while maintaining a beta celllike phenotype. The PHHI-derived cell line (NES2Y) exhibits insulin secretory characteristics typical of islet cells derived from these patients, i.e. they have no K ATP channel activity and as a consequence secrete insulin at constitutively high levels in the absence of glucose. In addition, they exhibit impaired expression of the homeodomain transcription factor PDX1, which is a key component of the signaling pathway linking nutrient metabolism to the regulation of insulin gene expression. To repair these defects NES2Y cells were triple-transfected with cDNAs encoding the two components of the K ATP channel (SUR1 and Kir6.2) and PDX1. One selected clonal cell line (NISK9) had normal K ATP channel activity, and as a result of changes in intracellular Ca 2؉ homeostasis ([Ca 2؉ ] i ) secreted insulin within the physiological range of glucose concentrations. This approach to engineering PHHI-derived islet cells may be of use in gene therapy for PHHI and in cell engineering techniques for administering insulin for the treatment of diabetes mellitus. Persistent hyperinsulinemic hypoglycemia of infancy (PHHI)1 is a potentially lethal disease of the newborn. It is characterized by inappropriate insulin release in relation to the corresponding levels of glycemia (1, 2). Affected children run the risk of severe neurological damage unless immediate and adequate steps are taken to avoid profound hypoglycemia. Treatment involves administration of glucose along with drugs such as diazoxide and somatostatin that inhibit insulin secretion. However, in many cases this is not effective, and within the first few weeks of birth a near total (ϳ95%) pancreatectomy is required to control blood glucose levels.Recently, it has been shown that PHHI arises from defects in the regulation of insulin secretion. This is due principally to the loss of function of ATP-regulated potassium (K ATP ) channels. Genetic linkage has identified a susceptibility locus for PHHI within a region of chromosome 11 that encodes subunits of these channels (3, 4), while direct recordings of beta cells isolated from PHHI patients (following pancreatectomy) have documented the absence of K ATP channels (5). In beta cells these channels are composed of at least two subunits as follows: a K ϩ channel pore, Kir6.2, and an ATP-binding cassette protein, SUR1 (6, 7). Open K ATP channels set the resting membrane potential for the beta cell and a change in the intracellular ATP/ADP ratio following glucose metabolism results in their closure and the initiation of a depolarization of the cell membrane. This in turn activates voltage-dependent calcium channels and the ensuing influx of calcium stimulates membrane docking and fusion of preformed insulin granules resulting ...

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“…Pharmacological manipulation of K ATP channels is of obvious therapeutic value, clearly demonstrated in the treatment of hypo‐ and hyperglycaemia ( Ashford, 1990 ). Sulphonylureas such as tolbutamide and glibenclamide are routinely used to treat non‐insulin dependent diabetes mellitus (NIDDM) by stimulating insulin secretion, whereas the inhibition of insulin release by K ATP openers such as diazoxide is sometimes used in the treatment of persistent hyperinsulinaemic hypoglycaemia of infancy ( Dunne et al ., 1997 ).…”

Section: Introductionmentioning

confidence: 99%

Sensitivity of Kir6.2‐SUR1 currents, in the absence and presence of sodium azide, to the K_ATP channel inhibitors, ciclazindol and englitazone

McKay

Kinsella

Campbell

et al. 2000

British J Pharmacology

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1 Two electrode voltage clamp and single channel recordings were used to investigate the actions of various ATP-sensitive K + (K ATP ) channel inhibitors on cloned K ATP channels, expressed in Xenopus oocytes and HEK 293 cells. 2 Oocytes expressing Kir6.2 and SUR1 gave rise to inwardly rectifying K + currents following bath application of 3 mM sodium azide. Inside-out recordings from non-azide treated oocytes demonstrated the presence of K ATP channels which were activated by direct application of 3 mM azide and 0.1 mM Mg-ATP. 3 Tolbutamide inhibited azide-induced macroscopic Kir6.2-SUR1 currents, recorded from Xenopus oocytes, with an IC 50 value similar to native K ATP channels. Ciclazindol and englitazone also inhibited these currents in a concentration-dependent manner, but with relative potencies substantially less than for native K ATP channels. 4 Single channel currents recorded from inside-out patches excised from oocytes expressing Kir6.2-SUR1 currents were inhibited by tolbutamide, Mg-ATP, englitazone and ciclazindol, in the absence of azide, with potencies similar to native K ATP channels. In the presence of azide, Kir6.2-SUR1 currents were inhibited by englitazone and tolbutamide but not ciclazindol. 5 Single channel currents derived from Kir6.2D26, expressed in HEK 293 cells, were inhibited by ciclazindol and englitazone irrespective of the absence or presence of SUR1. 6 In conclusion, heterologously expressed Kir6.2 and SUR1 recapitulate the pharmacological pro®le of native pancreatic b-cell K ATP channels. However, currents induced by azide exhibit a substantially reduced sensitivity to ciclazindol. It is likely that ciclazindol and englitazone inhibit K ATP currents by interaction with the Kir6.2 subunit.

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Nature's KATP-Channel Knockout

Cited by 8 publications

References 0 publications

A point mutation inactivating the sulfonylurea receptor causes the severe form of persistent hyperinsulinemic hypoglycemia of infancy in Finland.

A point mutation inactivating the sulfonylurea receptor causes the severe form of persistent hyperinsulinemic hypoglycemia of infancy in Finland.

Engineering a Glucose-responsive Human Insulin-secreting Cell Line from Islets of Langerhans Isolated from a Patient with Persistent Hyperinsulinemic Hypoglycemia of Infancy

Sensitivity of Kir6.2‐SUR1 currents, in the absence and presence of sodium azide, to the K_ATP channel inhibitors, ciclazindol and englitazone

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Nature's KATP-Channel Knockout

Cited by 8 publications

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A point mutation inactivating the sulfonylurea receptor causes the severe form of persistent hyperinsulinemic hypoglycemia of infancy in Finland.

A point mutation inactivating the sulfonylurea receptor causes the severe form of persistent hyperinsulinemic hypoglycemia of infancy in Finland.

Engineering a Glucose-responsive Human Insulin-secreting Cell Line from Islets of Langerhans Isolated from a Patient with Persistent Hyperinsulinemic Hypoglycemia of Infancy

Sensitivity of Kir6.2‐SUR1 currents, in the absence and presence of sodium azide, to the KATP channel inhibitors, ciclazindol and englitazone

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Sensitivity of Kir6.2‐SUR1 currents, in the absence and presence of sodium azide, to the K_ATP channel inhibitors, ciclazindol and englitazone