ATP and Sulfonylurea Sensitivity of Mutant ATP-Sensitive K+ Channels in Neonatal Diabetes

Koster, Joseph C.; Remedi, Marı́a S.; Dao, Crystal; Nichols, Colin G.

doi:10.2337/diabetes.54.9.2645

Cited by 91 publications

(131 citation statements)

References 32 publications

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“…These data are in keeping with experimental data showing that mutation V59M is at least as sensitive to glibenclamide as the transient neonatal diabetes-related KCNJ11 mutation I182V [10]. In summary, we believe that sulfonylurea therapy is feasible in most patients with KCNJ11-related permanent neonatal diabetes mellitus.…”

supporting

confidence: 88%

Sulfonylurea treatment outweighs insulin therapy in short-term metabolic control of patients with permanent neonatal diabetes mellitus due to activating mutations of the KCNJ11 (KIR6.2) gene

et al. 2006

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supporting

confidence: 88%

Sulfonylurea treatment outweighs insulin therapy in short-term metabolic control of patients with permanent neonatal diabetes mellitus due to activating mutations of the KCNJ11 (KIR6.2) gene

et al. 2006

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“…It also predicted that an increase of K ATP density, or loss of sensitivity to inhibitory glucose, would lead to reduced islet excitability and secretory response. Transgenic mice expressing mutant beta cell K ATP channels (Kir6.2[ΔN30]) with reduced ATP sensitivity (and presumably reduced glucose sensitivity) do have a severely undersecreting phenotype [31], and this appears to be the mechanism of PNDM in humans [22,23,43]. We can thus add an extension of the 'ascending' limb into the region of subnormal excitability (Fig.…”

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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“…The model also predicts that in the converse situation, an increase of K ATP channel density or loss of sensitivity to inhibitory glucose would lead to reduced islet excitability and a diminished secretory response. Indeed, transgenic mice expressing mutant b-cell K ATP channels (Kir6.2[nN30]) with reduced ATP sensitivity (and presumably reduced glucose sensitivity) do have a severely undersecreting phenotype [43], and this appears to be the mechanism of neonatal diabetes in humans [49][50][51]. We can thus add an extension of the ascending limb into the region of subnormal excitability (figure 1).…”

Section: 'Inverse U' Model For B-cell Response To Hyperexcitabilitymentioning

confidence: 99%

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.

show abstract

ATP and Sulfonylurea Sensitivity of Mutant ATP-Sensitive K+ Channels in Neonatal Diabetes

Cited by 91 publications

References 32 publications

Sulfonylurea treatment outweighs insulin therapy in short-term metabolic control of patients with permanent neonatal diabetes mellitus due to activating mutations of the KCNJ11 (KIR6.2) gene

Sulfonylurea treatment outweighs insulin therapy in short-term metabolic control of patients with permanent neonatal diabetes mellitus due to activating mutations of the KCNJ11 (KIR6.2) gene

Hyperinsulinism in mice with heterozygous loss of KATP channels

β‐cell hyperexcitability: from hyperinsulinism to diabetes

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