Oscillations of membrane potential and cytosolic Ca2+ concentration in SUR1−/− beta cells

Düfer, Martina; Haspel, D.; Koehler, Peter; Aguilar‐Bryan, Lydia; Bryan, Joseph; Drews, Gisela

doi:10.1007/s00125-004-1348-0

Cited by 68 publications

(70 citation statements)

References 53 publications

(63 reference statements)

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“…7). Conversely, Kir6.2 −/− or SUR1 −/− mice, which have maximal hyperexcitability, and high [Ca 2+ ] i even at low glucose concentration [14,42], would be positioned on the 'descending' limb (Fig. 7).…”

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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“…Comparison of Sur1KO and Control Islets-After four days of culture in 10 mM glucose, acute stimulation with glucose induced smaller mitochondrial hyperpolarization and oxygen consumption in single islet cells and intact islets from Sur1KO than control mice (30,31). Although this could suggest that glucose metabolism is impaired in islets lacking K ATP channels, the activity of glucokinase and the expression of genes of major metabolic enzymes were normal, leading the authors to conclude that a defect in glucose catabolism is not likely the cause of the defect in glucose-stimulated insulin secretion (31).…”

Section: Discussionmentioning

confidence: 99%

Overnight Culture Unmasks Glucose-induced Insulin Secretion in Mouse Islets Lacking ATP-sensitive K+ Channels by Improving the Triggering Ca2+ Signal

Szöllősi¹,

Nenquin²,

Henquin³

2007

Journal of Biological Chemistry

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“…3. In contrast to wild-type β cells, the application of sodium azide did not result in hyperpolarization of Sur1KO β cells but did reduce the amplitude of Ca 2+ -dependent action potentials by directly inhibiting Ca 2+ channels [44,45]. Neither tolbutamide nor diazoxide had any effect on V m oscillations in K ATP null islets.…”

Section: Transgenic Mouse Modelsmentioning

confidence: 65%

“…The early electrophysiological studies done on isolated β cells from HI neonates using the patch clamp technique demonstrated a loss of K ATP channel activity and persistent Ca 2+ -dependent action potentials consistent with their excessive insulin release [47,73]. Similar analyses on isolated Sur1KO β cells identified a similar electrophysiological phenotype with loss of K ATP channels, persistent Ca 2+ -dependent action potentials, and elevated and slowly oscillating [Ca 2+ ] c , although in contrast to HI neonates, the knockout animals have normal blood sugar and insulin levels [44,133,137]. Later membrane potential measurements on Sur1KO β cells with intracellular microelectrodes revealed an oscillatory pattern ( Fig.…”

Section: Transgenic Mouse Modelsmentioning

confidence: 67%

“…Several mechanisms proposed to account for the generation of these oscillations involve the response of K ATP channels to changes in ATP/ADP (see, for example, 40, 81). Using intracellular microelectrode recording techniques, Düfer et al [44] showed that Sur1KO islets exhibit V m and [Ca 2+ ] c oscillations in 15 mM glucose, which, in contrast to wildtype islets, persist in 0.5 mM glucose, implying K ATP channels are not essential for oscillation. The microelectrode experiments showed that the electrical activity of Sur1KO β cells in islets was modulated by glucose as illustrated in Fig.…”

Section: Transgenic Mouse Modelsmentioning

confidence: 99%

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ABCC8 and ABCC9: ABC transporters that regulate K+ channels

Bryan

Muñoz

Zhang

et al. 2006

Pflugers Arch - Eur J Physiol

145

117

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The sulfonylurea receptors (SURs) ABCC8/ SUR1 and ABCC9/SUR2 are members of the C-branch of the transport adenosine triphosphatase superfamily. Unlike their brethren, the SURs have no identified transport function; instead, evolution has matched these molecules with K + selective pores, either K IR 6.1/KCNJ8 or K IR 6.2/ KCNJ11, to assemble adenosine triphosphate (ATP)-sensitive K + channels found in endocrine cells, neurons, and both smooth and striated muscle. Adenine nucleotides, the major regulators of ATP-sensitive K + (K ATP ) channel activity, exert a dual action. Nucleotide binding to the pore reduces the activity or channel open probability, whereas Mg-nucleotide binding and/or hydrolysis in the nucleotidebinding domains of SUR antagonize this inhibitory action to stimulate channel openings. Mutations in either subunit can alter this balance and, in the case of the SUR1/KIR6.2 channels found in neurons and insulin-secreting pancreatic β cells, are the cause of monogenic forms of hyperinsulinemic hypoglycemia and neonatal diabetes. Additionally, the subtle dysregulation of K ATP channel activity by a K IR 6.2 polymorphism has been suggested as a predisposing factor in type 2 diabetes mellitus. Studies on K ATP channel null mice are clarifying the roles of these metabolically sensitive channels in a variety of tissues.

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Oscillations of membrane potential and cytosolic Ca2+ concentration in SUR1−/− beta cells

Cited by 68 publications

References 53 publications

Hyperinsulinism in mice with heterozygous loss of KATP channels

Hyperinsulinism in mice with heterozygous loss of KATP channels

Overnight Culture Unmasks Glucose-induced Insulin Secretion in Mouse Islets Lacking ATP-sensitive K+ Channels by Improving the Triggering Ca2+ Signal

ABCC8 and ABCC9: ABC transporters that regulate K+ channels

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