Disruption of
            <i>Sur2</i>
            -containing K
            <sub>ATP</sub>
            channels enhances insulin-stimulated glucose uptake in skeletal muscle

Chutkow, William A.; Samuel, Varman T.; Hansen, Polly A.; Pu, Jielin; Valdivia, Carmen R.; Makielski, Jonathan C.; Burant, Charles F.

doi:10.1073/pnas.201390398

Cited by 109 publications

(105 citation statements)

References 48 publications

(38 reference statements)

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“…Quantitatively, the phenotypes within each of these groups are not identical: in our hands, SUR À/À mice are even more glucose intolerant than Kir6.2 À/À mice [34], and enhanced glucose tolerance is more pronounced in Kir6.2 þ/À mice than in SUR þ/À mice [35]. In part, these differences may be the result of strain differences, but in addition, K ATP channels in skeletal muscles are formed from Kir6.2 plus SUR2A [29,37], which will mean that Kir6.2 KO mice (but not Sur1 KO mice) will have increased peripheral glucose sensitivity, which in turn may contribute to maintenance of glucose tolerance. [AAA]), when fed a normal diet (ND).…”

Section: Hyperexcitability and Hyperinsulinism In Animal Models: Key mentioning

confidence: 54%

β‐cell hyperexcitability: from hyperinsulinism to diabetes

Nichols

Koster

Remedi

2007

Diabetes Obesity Metabolism

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Nutrient oxidation in b cells generates a rise in [ATP]: [ADP] ratio. This reduces K ATP channel activity, leading to depolarization, activation of voltage-dependent Ca 2þ channels, Ca 2þ entry and insulin secretion. Consistent with this paradigm, loss-of-function mutations in the genes (KCNJ11 and ABCC8) that encode the two subunits (Kir6.2 and SUR1, respectively) of the ATP-sensitive K þ (K ATP ) channel underlie hyperinsulinism in humans, a genetic disorder characterized by dysregulated insulin secretion. In mice with genetic suppression of K ATP channel subunit expression, partial loss of K ATP channel conductance also causes hypersecretion, but unexpectedly, complete loss results in an undersecreting, mildly glucose-intolerant phenotype. When challenged by a high-fat diet, normal mice and mice with reduced K ATP channel density respond with hypersecretion, but mice with more significant or complete loss of K ATP channels cross over, or progress further, to an undersecreting, diabetic phenotype. It is our contention that in mice, and perhaps in humans, there is an inverse U-shaped response to hyperexcitabilty, leading first to hypersecretion but with further exacerbation to undersecretion and diabetes. The causes of the overcompensation and diabetic susceptibility are poorly understood but may have broader implications for the progression of hyperinsulinism and type 2 diabetes in humans.

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Section: Hyperexcitability and Hyperinsulinism In Animal Models: Key mentioning

confidence: 54%

β‐cell hyperexcitability: from hyperinsulinism to diabetes

Nichols

Koster

Remedi

2007

Diabetes Obesity Metabolism

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“…The glibenclamide effect is expected to be altered in the mutant. Earlier characterizations at the nucleic acid level suggest that the disruption cassette is present in SUR2, which is confirmed by the loss of the conventional glibenclamide-sensitive K ATP currents (I KATP ) in isolated cardiomyocytes [14] and vascular smooth muscle cells [15]. This mouse was thought to be a SUR2 null mouse based on lines of functional data.…”

Section: Introductionmentioning

confidence: 81%

“…Mutating either component abolishes the drug effect. A previously generated SUR2 mutant mouse has a disruption cassette inserted between exons 10−16 to disrupt NBD1 of SUR2 [14]. The glibenclamide effect is expected to be altered in the mutant.…”

Section: Introductionmentioning

confidence: 99%

“…In the present work, however, a non-conventional glibenclamideinsensitive, ATP-sensitive current (I KATPn ) was found in the mutant. Using a panel of newly developed SUR2 isoform-or variant-specific antibodies that were unavailable in earlier study [14], novel SUR2 short forms in the sizes of 28−68 kDa were discovered in the mutant. Evidence at both mRNA and protein levels indicated that the short forms lacked NBD1 but had NBD2, and they could interact with Kir6.1 or Kir6.2, which may account for I KATPn .…”

Section: Introductionmentioning

confidence: 99%

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Cardiac sulfonylurea receptor short form-based channels confer a glibenclamide-insensitive KATP activity

Pu¹,

Ye²,

Kroboth³

et al. 2008

Journal of Molecular and Cellular Cardiology

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The cardiac sarcolemmal ATP-sensitive potassium channel (K ATP ) consists of a Kir6.2 pore and a SUR2 regulatory subunit, which is an ATP-binding cassette (ABC) transporter. K ATP channels have been proposed to play protective roles during ischemic preconditioning. A SUR2 mutant mouse was previously generated by disrupting the first nucleotide-binding domain (NBD1), where a glibenclamide action site was located. In the mutant ventricular myocytes, a non-conventional glibenclamide-insensitive (10 μM), ATP-sensitive current (I KATPn ) was detected in 33% of singlechannel recordings with an average amplitude of 12.3±5.4 pA per patch, an IC 50 to ATP inhibition at 10 μM, and a mean burst duration at 20.6±1.8 ms. Newly designed SUR2-isoform or variantspecific antibodies identified novel SUR2 short forms in the sizes of 28 and 68 kDa in addition to a 150-kDa long form in the sarcolemmal membrane of wild-type (WT) heart. We hypothesized that channels constituted by these short forms that lack NBD1, confer I KATPn . The absence of the long form in the mutant corresponded to loss of the conventional glibenclamide-sensitive K ATP currents (I KATP ) in isolated cardiomyocytes and vascular smooth muscle cells but the SUR2 short forms remained intact. Nested exonic RT-PCR in the mutant indicated that the short forms lacked NBD1 but contained NBD2. The SUR2 short forms co-immunoprecipitated with Kir6.1 or Kir6.2 suggesting that the short forms may function as hemi-transporters reported in other eukaryotic ABC transporter subgroups. Our results indicate that different K ATP compositions may co-exist in cardiac sarcolemmal membrane.

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“…In part these differences may be the result of strain differences: we did not perform the multiple backcrosses of the SUR1 −/− mice necessary to reach isogenicity. In addition, K ATP channels in skeletal muscle are formed from Kir6.2 plus SUR2A [32,39], which will mean that Kir6.2 KO mice (but not SUR1 KO mice) will have increased peripheral glucose sensitivity, which may contribute to maintenance of glucose tolerance.…”

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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Disruption of Sur2 -containing K _ATP channels enhances insulin-stimulated glucose uptake in skeletal muscle

Cited by 109 publications

References 48 publications

β‐cell hyperexcitability: from hyperinsulinism to diabetes

β‐cell hyperexcitability: from hyperinsulinism to diabetes

Cardiac sulfonylurea receptor short form-based channels confer a glibenclamide-insensitive KATP activity

Hyperinsulinism in mice with heterozygous loss of KATP channels

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Disruption of Sur2 -containing K ATP channels enhances insulin-stimulated glucose uptake in skeletal muscle

Cited by 109 publications

References 48 publications

β‐cell hyperexcitability: from hyperinsulinism to diabetes

β‐cell hyperexcitability: from hyperinsulinism to diabetes

Cardiac sulfonylurea receptor short form-based channels confer a glibenclamide-insensitive KATP activity

Hyperinsulinism in mice with heterozygous loss of KATP channels

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Disruption of Sur2 -containing K _ATP channels enhances insulin-stimulated glucose uptake in skeletal muscle