Dysregulation of Insulin Secretion in Children With Congenital Hyperinsulinism due to Sulfonylurea Receptor Mutations

Grimberg, Adda; Ferry, Robert J.; Kelly, Andrea; Koo-McCoy, Samantha; Polonsky, Kenneth S.; Gläser, Benjamin; Permutt, M. A.; Aguilar‐Bryan, Lydia; Stafford, Diane; Thornton, Paul; Baker, Lester; Stanley, Charles A.

doi:10.2337/diabetes.50.2.322

Cited by 127 publications

(111 citation statements)

References 53 publications

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“…Although only limited data are available, there are reports that some CHI patients, even those non-surgically treated, can spontaneously progress to diabetes [7,48,49]. In addition, we have shown that normally hypersecreting Kir6.2[AAA] transgenic mice on a Kir6.2 +/− background (which, although untested, presumably have a greater reduction in K ATP channel activity than each genotype alone), but not Kir6.2 +/− mice, can progress from a hypersecreting phenotype to an undersecreting diabetic phenotype, when challenged by a highfat diet [18].…”

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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Section: Discussionmentioning

confidence: 99%

Hyperinsulinism in mice with heterozygous loss of KATP channels

et al. 2006

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“…A few PHHI cases have been examined in which there was no surgical treatment. In patients aged 11-13 years old, acute and prolonged insulin secretion were both suppressed, indicating that this progression can occur in untreated cases (18,27). In each of the previous genetic models of K ATP deficiency [in which beta cell K ATP currents are either completely absent (6, 7) or significantly reduced (5)], neonatal hyperinsulinemia and hypoglycemia very rapidly progressed to hyperglycemia with reduced glucoseinduced insulin secretion.…”

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

confidence: 99%

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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“…A second implication is that in humans with severe loss of K ATP channels, a progression from HI to glucose intolerance, as seen in K ATP channel KO mice [26][27][28]36], might be expected, either spontaneously or in response to dietary stress. Although only limited data are available, there are reports that some non-surgically treated patients with HI spontaneously progress to type 2 diabetes [11,20,56], that is onto the descending limb of the inverse U progression. The demonstration of reversibility of the process by removal of glibenclamide in mouse islets suggests the possibility that suppression of excitability with diazoxide, or dietary restriction, may prove beneficial in such patients.…”

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.

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Dysregulation of Insulin Secretion in Children With Congenital Hyperinsulinism due to Sulfonylurea Receptor Mutations

Cited by 127 publications

References 53 publications

Hyperinsulinism in mice with heterozygous loss of KATP channels

Hyperinsulinism in mice with heterozygous loss of KATP channels

Hyperinsulinism induced by targeted suppression of beta cell K _ATP channels

β‐cell hyperexcitability: from hyperinsulinism to diabetes

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Dysregulation of Insulin Secretion in Children With Congenital Hyperinsulinism due to Sulfonylurea Receptor Mutations

Cited by 127 publications

References 53 publications

Hyperinsulinism in mice with heterozygous loss of KATP channels

Hyperinsulinism in mice with heterozygous loss of KATP channels

Hyperinsulinism induced by targeted suppression of beta cell K ATP channels

β‐cell hyperexcitability: from hyperinsulinism to diabetes

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Product

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Hyperinsulinism induced by targeted suppression of beta cell K _ATP channels