Loss of functional KATP channels in pancreatic β–cells causes persistent hyperinsulinemic hypoglycemia of infancy

Kane, Cheikhou; Shepherd, Ruth M.; Squires, Paul E.; Johnson, Paul; James, R. F. L.; Milla, Peter J.; Aynsley-Green, A; Lindley, Keith; Dunne, Mark J.

doi:10.1038/nm1296-1344

Cited by 231 publications

(158 citation statements)

References 21 publications

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“…In the least severe forms of the disease, there may be a slower onset of hyperinsulinemia, and it may be chronically treatable without progression to beta cell failure. Importantly, although a complete lack of K ATP activity has been reported in human PHHI beta cells (34)(35)(36), active K ATP channels have been observed in other patient samples (36,37), consistent with the reduced channel activity that is the result of many disease mutations when they are expressed in recombinant systems (3, 38, 39 ‡). ‡Cosgrove, K. E., Gonzalez, A. M., Lee, A. T., Barnes, P. J., Hussaim, K., Aynsley-Green, A., Lindley, K. J., Pirotte, B., Lebrun We are very grateful to Dr. Stan Misler for use of his Ca 2ϩ imaging facility and for valuable discussions during the course of this work.…”

Section: Normal Islet Morphology Is Maintained In Kir62[aaa]mentioning

confidence: 73%

Hyperinsulinism induced by targeted suppression of beta cell K _ATP channels

Koster

Remedi

Flagg

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

112

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ATP-sensitive K ؉ (KATP) channels couple cell metabolism to electrical activity. To probe the role of KATP in glucose-induced insulin secretion, we have generated transgenic mice expressing a dominant-negative, GFP-tagged KATP channel subunit in which residues 132-134 (Gly-Tyr-Gly) in the selectivity filter were replaced by Ala-Ala-Ala, under control of the insulin promoter. Transgene expression was confirmed by both beta cell-specific green fluorescence and complete suppression of channel activity in those cells (Ϸ70%) that did fluoresce. Transgenic mice developed normally with no increased mortality and displayed normal body weight, blood glucose levels, and islet architecture. However, hyperinsulinism was evident in adult mice as (i) a disproportionately high level of circulating serum insulin for a given glucose concentration (Ϸ2-fold increase in blood insulin), (ii) enhanced glucose-induced insulin release from isolated islets, and (iii) mild yet significant enhancement in glucose tolerance. Enhanced glucose-induced insulin secretion results from both increased glucose sensitivity and increased release at saturating glucose concentration. The results suggest that incomplete suppression of KATP channel activity can give rise to a maintained hyperinsulinism.T he ATP-sensitive K ϩ channel (K ATP ) has long been proposed as a critical link in glucose-induced insulin release from pancreatic beta cells ( Fig. 1A; refs. 1 and 2). According to this paradigm, a high intracellular [ATP]͞[ADP] ratio in the fed state inhibits K ATP channels, causing membrane depolarization, leading to Ca 2ϩ entry through voltage-dependent Ca 2ϩ channels and insulin exocytosis. A rise in circulating insulin, in turn, leads to an increased peripheral glucose uptake and compensatory drop in blood glucose. Conversely, a falling intracellular [ATP]͞ [ADP] ratio during the fasting state is presumed to relieve inhibition of K ATP channels, resulting in membrane hyperpolarization and cessation of Ca 2ϩ -induced insulin release (3).Direct evidence for this paradigm is provided by the stimulatory and inhibitory effects of the K ATP -specific drugs, sulfonylureas and diazoxide, respectively, on insulin secretion in vivo (4) and the generation of transgenic and knockout mouse models with expression of altered or deficient pancreatic K ATP (5-7) that exhibit beta cell dysfunction. Profound neonatal diabetes due to permanent suppression of insulin release is observed in transgenic mice expressing overactive beta cell K ATP channels, dramatically illustrating the ability of K ATP channels to inhibit secretion (8). Conversely, the recent discovery of numerous mutations in pancreatic K ATP channel subunits (both the poreforming Kir6.2 and SUR1) in human patients with persistent hyperinsulinemic hypoglycemia of infancy (PHHI) (3) establishes a causative link between suppressed K ATP activity, and the corollary metabolic disorder of hyperinsulinism (3). PHHIassociated K ATP mutations can be classified into two major categories: those that suppress channe...

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Section: Normal Islet Morphology Is Maintained In Kir62[aaa]mentioning

confidence: 73%

Hyperinsulinism induced by targeted suppression of beta cell K _ATP channels

Koster

Remedi

Flagg

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

112

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“…Decreased K ATP channel activity and insulin secretion in vivo: predictions vs findings It is now clear that K ATP channels are a critical link between glucose metabolism and insulin secretion, underlined by the finding that gain of K ATP activity can cause permanent neonatal diabetes mellitus (PNDM) [22][23][24][25] whereas CHI results from lossof-function K ATP mutations [5,[26][27][28][29][30]. We previously described a mouse model of beta cell K ATP gain-of-function that reiterates the PNDM phenotype [31].…”

Section: Discussionmentioning

confidence: 99%

Hyperinsulinism in mice with heterozygous loss of KATP channels

et al. 2006

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Aims/hypothesis ATP-sensitive K + (K ATP ) channels couple glucose metabolism to insulin secretion in pancreatic beta cells. In humans, loss-of-function mutations of beta cell K ATP subunits (SUR1, encoded by the gene ABCC8, or Kir6.2, encoded by the gene KCNJ11) cause congenital hyperinsulinaemia. Mice with dominant-negative reduction of beta cell K ATP (Kir6.2[AAA]) exhibit hyperinsulinism, whereas mice with zero K ATP (Kir6.2 −/− ) show transient hyperinsulinaemia as neonates, but are glucose-intolerant as adults. Thus, we propose that partial loss of beta cell K ATP in vivo causes insulin hypersecretion, but complete absence may cause insulin secretory failure. Materials and methods Heterozygous Kir6.2 +/− and SUR1 +/− animals were generated by backcrossing from knockout animals. Glucose tolerance in intact animals was determined following i.p. loading. Glucose-stimulated insulin secretion (GSIS), islet K ATP conductance and glucose dependence of intracellular Ca 2+ were assessed in isolated islets. Results In both of the mechanistically distinct models of reduced K ATP (Kir6.2 +/− and SUR1 +/− ), K ATP density is reduced by ∼60%. While both Kir6.2 −/− and SUR1 −/− mice are glucose-intolerant and have reduced glucose-stimulated insulin secretion, heterozygous Kir6.2 +/− and SUR1 +/− mice show enhanced glucose tolerance and increased GSIS, paralleled by a left-shift in glucose dependence of intracellular Ca 2+ oscillations. Conclusions/interpretation The results confirm that incomplete loss of beta cell K ATP in vivo underlies a hyperinsulinaemic phenotype, whereas complete loss of K ATP underlies eventual secretory failure.

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“…Loss of function of the pancreatic islet K ATP channel, because of mutation of either the SUR1 or Kir6.2 subunit (11)(12)(13)(14), has been demonstrated to lead to persistent hyperinsulinemic hypoglycemia of infancy, an autosomal recessive disorder characterized by unregulated insulin secretion and severe hypoglycemia (15). Disease phenotypes have not yet been assigned to the other K ATP channels.…”

Section: Atp-sensitive Potassium (K Atp )mentioning

confidence: 99%

A Novel Sulfonylurea Receptor Family Member Expressed in the Embryonic Drosophila Dorsal Vessel and Tracheal System

Nasonkin¹,

Alikaşifoğlu²,

Ambrose³

et al. 1999

Journal of Biological Chemistry

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Sulfonylurea receptors (SURx) are required subunits of the ATP-sensitive potassium channel. SURx alone is electrophysiologically inert. However, when SURx is combined with an inward rectifier Kir6.2 subunit, ATPsensitive potassium channel activity is generated. We report the identification, characterization, and localization of Dsur, a novel Drosophila gene that is highly related to the vertebrate SUR family. The Dsur coding sequence contains structural features characteristic of the ABC transporter family and, in addition, harbors 1.7 kilobases of a distinctive sequence that does not share homology with any known gene. When Dsur alone is expressed in Xenopus oocytes glibenclamide-sensitive potassium channel activity occurs. During Drosophila embryogenesis, the Dsur gene is specifically expressed in the developing tracheal system and dorsal vessel. Studies of the Drosophila genome support that only a single Dsur gene is present. Our data reveal conservation of glibenclamide-sensitive potassium channels in Drosophila and suggest that Dsur may play an important role during Drosophila embryogenesis. The lack of gene duplication in the Drosophila system provides a unique opportunity for functional studies of SUR using a genetic approach.

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Loss of functional KATP channels in pancreatic β–cells causes persistent hyperinsulinemic hypoglycemia of infancy

Cited by 231 publications

References 21 publications

Hyperinsulinism induced by targeted suppression of beta cell K _ATP channels

Hyperinsulinism induced by targeted suppression of beta cell K _ATP channels

Hyperinsulinism in mice with heterozygous loss of KATP channels

A Novel Sulfonylurea Receptor Family Member Expressed in the Embryonic Drosophila Dorsal Vessel and Tracheal System

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Loss of functional KATP channels in pancreatic β–cells causes persistent hyperinsulinemic hypoglycemia of infancy

Cited by 231 publications

References 21 publications

Hyperinsulinism induced by targeted suppression of beta cell K ATP channels

Hyperinsulinism induced by targeted suppression of beta cell K ATP channels

Hyperinsulinism in mice with heterozygous loss of KATP channels

A Novel Sulfonylurea Receptor Family Member Expressed in the Embryonic Drosophila Dorsal Vessel and Tracheal System

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Hyperinsulinism induced by targeted suppression of beta cell K _ATP channels

Hyperinsulinism induced by targeted suppression of beta cell K _ATP channels