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PubMed2005

Common variants in the ATP-sensitive K+ channel genes KCNJ11 (Kir6.2) and ABCC8 (SUR1) in relation to glucose intolerance: population-based studies and meta-analyses.

AIMS: To evaluate the relation between common variants in the ATP-sensitive K+ channel genes and glucose intolerance. METHODS: We conducted a meta-analysis of reported association studies in Caucasian populations for common variants in the ABCC8 (exons 16 and 18) and the KCNJ11 (E23K) gene and examined sources of heterogeneity in the results. The meta-analysis was based on 7768-10216 subjects (depending on the gene variant), and included two new population-based studies in the Netherlands with 725 cases and 742 controls. RESULTS: For the KCNJ11 variant, the summary odds ratio (OR) for glucose intolerance was 1.12 (1.01-1.23, P=0.03) for the EK genotype and 1.44 (1.17-1.78, P=0.0007) for the KK genotype, as compared with the EE genotype. For the ABCC8 exon 16 variant, the OR was 1.06 (0.94-1.19, P=0.34) for ct and 0.93 (0.71-1.20, P=0.56) for tt, as compared with the cc genotype. For ABCC8 exon 18, the OR was 1.20 (0.97-1.49, P=0.10) for CT/TT, as compared with the CC genotype. Studies of the ABCC8 variants that were published first or had smaller sample sizes (for the exon 18 variant) showed stronger associations, which may indicate publication bias. For the ABCC8 exon 18 and the KCNJ11 variant, associations were stronger for studies of clinical diabetes than newly detected glucose intolerance. The population attributable risk for clinical Type 2 diabetes was 6.2% for the KCNJ11 KK genotype and 10.1% for the KCNJ11 EK and KK genotype combined. CONCLUSIONS: The common KCNJ11 E23K gene variant, but not the ABCC8 exon 16 or exon 18 variant, was consistently associated with Type 2 diabetes.

ATP-Binding Cassette Transporters↗

PubMed2001

Unbalanced expression of 11p15 imprinted genes in focal forms of congenital hyperinsulinism: association with a reduction to homozygosity of a mutation in ABCC8 or KCNJ11.

Congenital hyperinsulinism (CHI), previously named persistent hyperinsulinemic hypoglycemia of infancy, is characterized by profound hypoglycemia because of excessive insulin secretion. CHI presents as two different morphological forms: a diffuse form with functional abnormality of islets throughout the pancreas and a focal form with focal islet cell adenomatous hyperplasia, which can be cured by partial pancreatectomy. Recently, we have shown that focal adenomatous hyperplasia involves the specific loss of the maternal 11p15 region and a constitutional mutation of a paternally inherited allele of the gene encoding the regulating subunit of the K(+)(ATP) channel, the sulfonylurea receptor (ABCC8 or SUR1). In the present study on a large series of 31 patients, describing both morphological features and molecular data, we report that 61% of cases (19 out of 31) carried a paternally inherited mutation not only in the ABCC8 gene as previously described but also in the second gene encoding the K(+)(ATP) channel, the inward rectifying potassium channel (KCNJ11 or KIR6.2), in 15 cases and 4 cases, respectively. Moreover our results are consistent with the presence of a duplicated paternal 11p15 allele probably because of mitotic recombination or reduplication of the paternal chromosome after somatic loss of the maternal chromosome. In agreement with the loss of the maternal chromosome, the level of expression of a maternally expressed tumor suppressor gene, H19, was greatly reduced compared to the level of expression of the paternally expressed growth promoter gene, IGF2. The expression of IGF2 was on average only moderately increased. Thus, focal forms of CHI can be considered to be a recessive somatic disease, associating an imbalance in the expression of imprinted genes in the 11p15.5 region to a somatic reduction to homozygosity of an ABCC8- or KCNJ11-recessive mutation. The former is responsible for the abnormal growth rate, as in embryonic tumors, whereas the latter leads to unregulated secretion of insulin.

ATP-Binding Cassette Transporters↗

PubMed2004

Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.

BACKGROUND: Patients with permanent neonatal diabetes usually present within the first three months of life and require insulin treatment. In most, the cause is unknown. Because ATP-sensitive potassium (K(ATP)) channels mediate glucose-stimulated insulin secretion from the pancreatic beta cells, we hypothesized that activating mutations in the gene encoding the Kir6.2 subunit of this channel (KCNJ11) cause neonatal diabetes. METHODS: We sequenced the KCNJ11 gene in 29 patients with permanent neonatal diabetes. The insulin secretory response to intravenous glucagon, glucose, and the sulfonylurea tolbutamide was assessed in patients who had mutations in the gene. RESULTS: Six novel, heterozygous missense mutations were identified in 10 of the 29 patients. In two patients the diabetes was familial, and in eight it arose from a spontaneous mutation. Their neonatal diabetes was characterized by ketoacidosis or marked hyperglycemia and was treated with insulin. Patients did not secrete insulin in response to glucose or glucagon but did secrete insulin in response to tolbutamide. Four of the patients also had severe developmental delay and muscle weakness; three of them also had epilepsy and mild dysmorphic features. When the most common mutation in Kir6.2 was coexpressed with sulfonylurea receptor 1 in Xenopus laevis oocytes, the ability of ATP to block mutant K(ATP) channels was greatly reduced. CONCLUSIONS: Heterozygous activating mutations in the gene encoding Kir6.2 cause permanent neonatal diabetes and may also be associated with developmental delay, muscle weakness, and epilepsy. Identification of the genetic cause of permanent neonatal diabetes may facilitate the treatment of this disease with sulfonylureas.

DNA Mutational Analysis↗

PubMed2006

Mutations in the genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) in diabetes mellitus and hyperinsulinism.

The beta-cell ATP-sensitive potassium channel is a key component of stimulus-secretion coupling in the pancreatic beta-cell. The channel couples metabolism to membrane electrical events, bringing about insulin secretion. Given the critical role of this channel in glucose homeostasis, it is not surprising that mutations in the genes encoding for the two essential subunits of the channel can result in both hypo- and hyperglycemia. The channel consists of four subunits of the inwardly rectifying potassium channel Kir6.2 and four subunits of the sulfonylurea receptor 1. It has been known for some time that loss of function mutations in KCNJ11, which encodes for Kir6.2, and ABCC8, which encodes for SUR1, can cause oversecretion of insulin and result in hyperinsulinemia (HI) of infancy; however, heterozygous activating mutations in KCNJ11 that result in the opposite phenotype of diabetes have recently been described. This review focuses on reported mutations in both genes, the spectrum of phenotypes, and the implications for treatment when patients are diagnosed with mutations in these genes.

ATP-Binding Cassette Transporters↗

PubMed2003

Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes.

The genes ABCC8 and KCNJ11, which encode the subunits sulfonylurea receptor 1 (SUR1) and inwardly rectifying potassium channel (Kir6.2) of the beta-cell ATP-sensitive potassium (K(ATP)) channel, control insulin secretion. Common polymorphisms in these genes (ABCC8 exon 16-3t/c, exon 18 T/C, KCNJ11 E23K) have been variably associated with type 2 diabetes, but no large ( approximately 2,000 subjects) case-control studies have been performed. We evaluated the role of these three variants by studying 2,486 U.K. subjects: 854 with type 2 diabetes, 1,182 population control subjects, and 150 parent-offspring type 2 diabetic trios. The E23K allele was associated with diabetes in the case-control study (odds ratio [OR] 1.18 [95% CI 1.04-1.34], P = 0.01) but did not show familial association with diabetes. Neither the exon 16 nor the exon 18 ABCC8 variants were associated with diabetes (1.04 [0.91-1.18], P = 0.57; 0.93 [0.71-1.23], P = 0.63, respectively). Meta-analysis of all case-control data showed that the E23K allele was associated with type 2 diabetes (K allele OR 1.23 [1.12-1.36], P = 0.000015; KK genotype 1.65 [1.34-2.02], P = 0.000002); but the ABCC8 variants were not associated. Our results confirm that E23K increases risk of type 2 diabetes and show that large-scale association studies are important for the identification of diabetes susceptibility alleles.

ATP-Binding Cassette Transporters↗

PubMed2004

Current status of the E23K Kir6.2 polymorphism: implications for type-2 diabetes.

The ATP-sensitive potassium (KATP) channel couples membrane excitability to cellular metabolism and is a critical mediator in the process of glucose-stimulated insulin secretion. Increasing numbers of KATP channel polymorphisms are being described and linked to altered insulin secretion indicating that genes encoding this ion channel could be susceptibility markers for type-2 diabetes. Genetic variation of KATP channels may result in altered beta-cell electrical activity, glucose homeostasis, and increased susceptibility to type-2 diabetes. Of particular interest is the Kir6.2 E23K polymorphism, which is linked to increased susceptibility to type-2 diabetes in Caucasian populations and may also be associated with weight gain and obesity, both of which are major diabetes risk factors. This association highlights the potential contribution of both genetic and environmental factors to the development and progression of type-2 diabetes. In addition, the common occurrence of the E23K polymorphism in Caucasian populations may have conferred an evolutionary advantage to our ancestors. This review will summarize the current status of the association of KATP channel polymorphisms with type-2 diabetes, focusing on the possible mechanisms by which these polymorphisms alter glucose homeostasis and offering insights into possible evolutionary pressures that may have contributed to the high prevalence of KATP channel polymorphisms in the Caucasian population.

Biological Evolution↗

PubMed2005

Proteasomal degradation of Kir6.2 channel protein and its inhibition by a Na+ channel blocker aprindine.

ATP-sensitive K+ channels (K(ATP):SUR2A+Kir6.2) play a pivotal role in cardiac protection against ischemia and reperfusion injury. When expressed in COS cells, Kir6.2 was short-lived with a half-life time of 1.9 h. The half-life time of Kir6.2 was prolonged by proteasome inhibitors MG132, ALLN, proteasome inhibitor 1, and lactacystine, but not at all by a lysosomal inhibitor chloroquine. MG132 also increased the level of ubiquitinated Kir6.2 without affecting its localization in the endoplasmic reticulum and Golgi apparatus. In electrophysiological recordings, MG132 augmented nicorandil-activated K(ATP) currents in COS cells expressing SUR2A and Kir6.2 as well as the same currents in neonatal rat cardiomyocytes. Like MG132, a Na+ channel blocker aprindine prolonged the half-life time of Kir6.2 and augmented K(ATP). Finally, both aprindine and MG132 inhibited the 20S proteasome activity in vitro. These results suggest a novel activity of aprindine to enhance K(ATP) currents by inhibiting proteasomal degradation of Kir 6.2 channels, which may be beneficial in the setting of cardiac ischemia.

Animals↗

PubMed2006

The E23K polymorphism in Kir6.2 gene and coronary heart disease.

BACKGROUND: The G to A mutation in the Kir 6.2, the ATP-sensitive potassium channel subunit, resulted a glutamate (E) to lysine (K) substitution at codon 23, and the A allele was shown to have a relationship with high risk to type 2 diabetes in previous study. Their role in coronary heart disease (CHD) has not been evaluated. We hypothesized that the polymorphism would be associated with increased susceptibility to CHD. METHODS: The E23K gene polymorphism of Kir6.2 gene was analyzed by PCR-restriction site polymorphism (PCR-RSP) methods in 101 controls and 119 CHD patients. Serum lipids and C reactive protein concentrations were measured in all subjects. RESULTS: Among the CHD patients, the frequency of the G allele was higher (63.4% vs. 56.9%, P>0.05) and the frequency of the A allele was lower (36.6% vs. 43.1%, P>0.05) than among controls. No significant differences were found in allele frequencies between CHD and controls (P>0.05), but there were significant differences in GG and combined (GA+AA) genotypes frequencies (42.0% vs. 28.7%, and 58.0% vs. 71.3%, P<0.050). CONCLUSIONS: The E23K gene polymorphism in Kir6.2 gene appeared to be related to high susceptibility to CHD.

Base Sequence↗

PubMed2006

Evidence for functional ATP-sensitive (K(ATP)) potassium channels in human and equine articular chondrocytes.

OBJECTIVE: Chondrocytes are highly sensitive to variations in extracellular glucose and oxygen levels in the extracellular matrix. As such, they must possess a number of mechanisms to detect and respond to alterations in the metabolic state of cartilage. In other organs such as the pancreas, heart and brain, such detection is partly mediated by a family of potassium channels known as K(ATP) (adenosine 5'-triphosphate-sensitive potassium) channels. Here we investigate whether chondrocytes too express functional K(ATP) channels, which might, potentially, serve to couple metabolic state with cell activity. METHODS: Immunohistochemistry was used to explore K(ATP) channel expression in equine and human chondrocytes. Biophysical properties of equine chondrocyte K(ATP) channels were investigated with patch-clamp electrophysiology. RESULTS: Polyclonal antibodies directed against the K(ATP) Kir6.1 subunit revealed high levels of expression in human and equine chondrocytes mainly in superficial and middle zones of normal cartilage. Kir6.1 was also detected in superficial chondrocytes in osteoarthritic (OA) cartilage. In single-channel electrophysiological studies of equine chondrocytes, we found K(ATP) channels to have a maximum unitary conductance of 47 +/- 9 pS (n=5) and a density of expression comparable to that seen in excitable cells. CONCLUSION: We have shown, for the first time, functional K(ATP) channels in chondrocytes. This suggests that K(ATP) channels are involved in coupling metabolic and electrical activities in chondrocytes through sensing of extracellular glucose and intracellular adenosine triphosphate (ATP) levels. Altered K(ATP) channel expression in OA chondrocytes may result in impaired intracellular ATP sensing and optimal metabolic regulation.

Adenosine Triphosphate↗

PubMed2006

Kir6.2-containing ATP-sensitive potassium channels protect cortical neurons from ischemic/anoxic injury in vitro and in vivo.

ATP-sensitive potassium (K(ATP)) channels are weak inward rectifiers that appear to play an important role in protecting neurons against ischemic damage. Cerebral stroke is a major health issue, and vulnerability to stroke damage is regional within the brain. Thus, we set out to determine whether K(ATP) channels protect cortical neurons against ischemic insults. Experiments were performed using Kir6.2(-/-) K(ATP) channel knockout and Kir6.2(+/+) wildtype mice. We compared results obtained in Kir6.2(-/-) and wildtype mice to evaluate the protective role of K(ATP) channels against focal ischemia in vivo, and, using cortical slices, against anoxic stress in vitro. Immunohistochemistry confirmed the presence of K(ATP) channels in the cortex of wildtype, but not Kir6.2(-/-), mice. Results from in vivo and in vitro experimental models indicate that Kir6.2-containing K(ATP) channels in the cortex provide protection from neuronal death. Briefly, in vivo focal ischemia (15 min) induced severe neurological deficits and large cortical infarcts in Kir6.2(-/-) mice, but not in wildtype mice. Imaging analyses of cortical slices exposed briefly to oxygen and glucose deprivation (OGD) revealed a substantial number of damaged cells (propidium iodide-labeled) in the Kir6.2(-/-) OGD group, but few degenerating neurons in the wildtype OGD group, or in the wildtype and Kir6.2(-/-) control groups. Slices from the three control groups had far more surviving cells (anti-NeuN antibody-labeled) than slices from the Kir6.2(-/-) OGD group. These findings suggest that stimulation of endogenous cortical K(ATP) channels may provide a useful strategy for limiting the damage that results from cerebral ischemic stroke.

Animals↗

PubMed2005

Regulation of the ATP-sensitive K channel Kir6.2 by ATP and PIP(2).

ATP-sensitive K (K(ATP)) channels are blocked by ATP and activated by PIP(2). Both negatively-charged ligands are presumed to bind to positively-charged residues on the N-and C-termini of the channel's cytoplasmic domain. Evidence summarized here suggests that the channel's interaction with ATP and PIP(2) is regulated by separate groups of residues, involving both direct charge-charge interactions and allosteric effects. ATP interaction is regulated by R50 in the N-terminus and by K185, R192 and R201 in the C-terminus. R192 and R201 mutations decrease channel sensitivity to ATP, ADP and AMP to a similar extent, implying that they regulate interaction with either the alpha phosphate group, common to all three adenine nucleotides, or the adenosine moiety. K185 mutations, and to a lesser extent R50 mutations, decrease ATP and ADP sensitivity without markedly affecting AMP sensitivity, implying that they regulate interaction with the beta phosphate of ATP and ADP. In addition, when open probability decreases due to rundown, ATP sensitivity increases in R50, K185 and R192, but not in R201 mutants. Combining these observations with recent structural data, we hypothesize the following scenario: 1) the ATP binding site is located at the outside of the channel's cytoplasmic domain away from the pore. 2) When the channel is open, R50 and K185 interact directly with the beta phosphate of ATP, whereas R192, which appears to be removed from the ATP binding site, modulates the initial interaction with ATP allosterically. 3) When the channel closes, R201 is in position to interact with the alpha phosphate of ATP to stabilize the closed state. 4) PIP(2) also interacts with the channel's cytoplasmic domain, but at distinct positively-charged residues located above the ATP binding site and near to the plasma membrane. These residues include R54 in the N-terminus and R176, R177 and R206 in the C-terminus. Thus, the binding domains of ATP and PIP(2) in the N- and C-termini do not appear to overlap.

Adenosine Triphosphate↗

PubMed2005

Neonatal diabetes mellitus: from understudy to center stage.

PURPOSE OF REVIEW: Although neonatal diabetes mellitus is rare, its molecular basis has far-reaching implications for understanding the regulation of beta cell function, a prerequisite for understanding and treating type1 and type 2 diabetes mellitus especially by the manipulation of stem cells. The purpose of this review is to highlight the recent exciting discoveries concerning the genetic and molecular basis of the spectrum of disorders constituting neonatal diabetes mellitus. RECENT FINDINGS: Recent reports in the literature, all in the past year, have identified activating mutations in the KATP channel that prevent its closure and hence insulin secretion as the major cause of permanent neonatal diabetes mellitus. Concurrently, a transgenic mouse model of transient neonatal diabetes mellitus due to mutations in ZAC/HYMAI provides an exquisite tool to study its human counterpart. Already, mutations in KATP and ZAC/HYMAI have been shown to be associated with type 1 and type 2 diabetes mellitus in later life; some mutations in KATP are amenable to treatment with sulfonylureas. SUMMARY: The discoveries of the genes responsible for rarely occurring transient and permanent neonatal diabetes mellitus, and transgenic animal models to study them, are exciting milestones on the road to understanding and treating the common forms of type 1 and type 2 diabetes mellitus in children and adolescents.

Animals↗

PubMed2006

Targeted expression of Kir6.2 in mitochondria confers protection against hypoxic stress.

Selective K(+) transport in the inner mitochondrial membrane has been attributed to at least three different channel types: ATP-sensitive, Ca(2+)-regulated and voltage-dependent K(+) channels. Studies utilizing their selective modulators have suggested that an increased activity of these channels plays an important role in the cellular protection from metabolic stress. However, direct evidence for this effect is largely absent, and recent findings on the lack of specificity for several channel openers and blockers have questioned the actual contribution of the mitochondrial K(+) channels in the preservation of cellular viability. In order to directly investigate the role of enhanced mitochondrial K(+) uptake in cellular protection, we selectively expressed the inward rectifying K(+) channel Kir6.2 in the mitochondria of HEK293 and HL-1 cells. Targeted Kir6.2 expression was achieved by cloning the Kir6.2 gene in pCMV/mito/GFP vector and the proper trafficking to mitochondria was confirmed by colocalization studies and Western blot. An increased K(+) influx to mitochondria overexpressing Kir6.2, as evidenced by using the K(+)-sensitive PBFI AM fluorescent dye, substantially improved the cellular viability after hypoxic stress, which was assessed by lactate dehydrogenase (LDH) release. In parallel, monitoring of mitochondrial Ca(2+) during stress, via the specific indicator rhod-2, revealed a significant attenuation of Ca(2+) accumulation in mitochondria overexpressing K(+) channels. This effect was abolished in mitochondria expressing an inactive mutant of Kir6.2. Mitochondria expressing Kir6.2 K(+) channel also exhibited a significant degree of depolarization that became even more pronounced during the stress. In conclusion, this study provides the first non-pharmacological evidence that an increased K(+) influx to mitochondria protects against hypoxic stress by preventing detrimental effects of Ca(2+) overload.

Animals↗

PubMed2006

Minireview: pharmacogenetics and beyond: the interaction of therapeutic response, beta-cell physiology, and genetics in diabetes.

Defining the molecular genetics of diabetes gives new insight into the underlying etiology and so should help improve treatment. The genetic etiology is now known for most patients with beta-cell monogenic diabetes, allowing genetic classification. We review how this genetic knowledge alters treatment. Patients with a glucose-sensing beta-cell defect due to glucokinase mutations have regulated, mild, fasting hyperglycemia. Oral hypoglycemic agents or low-dose insulin rarely improve glycemic control. Patients with hepatic nuclear factor-1alpha (HNF1alpha) mutations have progressive beta-cell deterioration and require treatment. HNF1alpha patients are 4 times more sensitive to sulfonylureas than matched type 2 diabetic patients. This is partly due to greater insulin secretion, reflecting the fact that the defect in HNF1alpha deficiency precedes the K(ATP) channel where sulfonylureas act. HNF1beta is expressed in pancreatic stem cells before differentiation into endocrine or exocrine cells, so patients with HNF1beta mutations have reduced pancreatic development, resulting in early-onset diabetes and exocrine dysfunction. These patients usually rapidly require insulin and are not sensitive to sulfonylureas. Thirty-five to 50% of patients diagnosed with diabetes before 6 months have a mutation in Kir6.2. The mutated KATP channel in these patients does not close in response to increased ATP concentrations, but can be closed when sulfonylureas bind to the sulfonylurea receptor 1 subunit of the channel by an ATP-independent route. These patients are usually insulin dependent, but have excellent glycemic control on high-dose sulfonylureas tablets. In conclusion, the defining of molecular genetic etiology in monogenic diabetes has identified several specific beta-cell defects, and these are critical in determining the response to treatment.

Animals↗

PubMed2004

Glibenclamide treatment in permanent neonatal diabetes mellitus due to an activating mutation in Kir6.2.

Permanent neonatal diabetes mellitus (PNDM) is a rare form of diabetes characterized by insulin-requiring hyperglycemia that is diagnosed within the first months of life. Recently, activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 were identified in 10 PNDM patients. Tolbutamide-stimulated insulin secretion, demonstrated in 3 of these patients suggested that some PNDM patients may respond to oral sulfonylurea treatment. In this report, we describe an infant with PNDM due to an arginine-to-histidine substitution at position 201 (R201H) of the gene encoding Kir6.2. After insulin pump therapy for six months, he was shifted to oral glybenclamide therapy at a daily dose of 0.8 mg/kg. Basal c-peptide level increased by two fold during glybenclamide treatment, but no further elevation was observed following intravenous glucose administration. Outpatient, continuous glucose monitoring while on a normal infant diet demonstrated a marked improvement in glycemic control. This study demonstrates the feasibility of oral sulfonylurea treatment in PNDM patients with Kir6.2 mutations even during infancy, and the superiority of this approach over insulin administration.

Blood Glucose↗

PubMed2006

Expression of ATP-insensitive KATP channels in pancreatic beta-cells underlies a spectrum of diabetic phenotypes.

Glucose metabolism in pancreatic beta-cells elevates cytoplasmic [ATP]/[ADP], causing closure of ATP-sensitive K(+) channels (K(ATP) channels), Ca(2+) entry through voltage-dependent Ca(2+) channels, and insulin release. Decreased responsiveness of K(ATP) channels to the [ATP]/[ADP] ratio should lead to decreased insulin secretion and diabetes. We generated mice expressing K(ATP) channels with reduced ATP sensitivity in their beta-cells. Previously, we described a severe diabetes, with nearly complete neonatal lethality, in four lines (A-C and E) of these mice. We have now analyzed an additional three lines (D, F, and G) in which the transgene is expressed at relatively low levels. These animals survive past weaning but are glucose intolerant and can develop severe diabetes. Despite normal islet morphology and insulin content, islets from glucose-intolerant animals exhibit reduced glucose-stimulated insulin secretion. The data demonstrate that a range of phenotypes can be expected for a reduction in ATP sensitivity of beta-cell K(ATP) channels and provide models for the corollary neonatal diabetes in humans.

Animals↗

PubMed2004

Diet-induced glucose intolerance in mice with decreased beta-cell ATP-sensitive K+ channels.

ATP-sensitive K+ channels (K(ATP) channels) control electrical activity in beta-cells and therefore are key players in excitation-secretion coupling. Partial suppression of beta-cell K(ATP) channels in transgenic (AAA) mice causes hypersecretion of insulin and enhanced glucose tolerance, whereas complete suppression of these channels in Kir6.2 knockout (KO) mice leads to hyperexcitability, but mild glucose intolerance. To test the interplay of hyperexcitability and dietary stress, we subjected AAA and KO mice to a high-fat diet. After 3 months on the diet, both AAA and KO mice converted to an undersecreting and markedly glucose-intolerant phenotype. Although Kir6.2 is expressed in multiple tissues, its primary functional consequence in both AAA and KO mice is enhanced beta-cell electrical activity. The results of our study provide evidence that, when combined with dietary stress, this hyperexcitability is a causal diabetic factor. We propose an "inverse U" model for the response to enhanced beta-cell excitability: the expected initial hypersecretion can progress to undersecretion and glucose-intolerance, either spontaneously or in response to dietary stress.

Animals↗

PubMed2004

Metabolic regulation of the pancreatic beta-cell ATP-sensitive K+ channel: a pas de deux.

Closure of ATP-sensitive K+ channels (KATP channels) is a key step in glucose-stimulated insulin secretion. The precise mechanism(s) by which glucose metabolism regulates KATP channel activity, however, remains controversial. It is widely believed that the principal determinants are the intracellular concentrations of the metabolic ligands, ATP and ADP, which have opposing actions on KATP channels, with ATP closing and MgADP opening the channel. However, the sensitivity of the channel to these nucleotides in the intact cell, and their relative contribution to the regulation of channel activity, remains unclear. The precise role of phosphoinositides and long-chain acyl-CoA esters, which are capable of modulating the channel ATP sensitivity, is also uncertain. Furthermore, it is still a matter of debate whether it is changes in the concentration of ATP, of MgADP, or of other agents, which couples glucose metabolism to KATP channel activity. In this article, we review current knowledge of the metabolic regulation of the KATP channel and provide evidence that MgADP (or MgATP hydrolysis), acting at the regulatory subunit of the channel, shifts the ATP concentration-response curve into a range in which the channel pore can respond to dynamic changes in cytosolic ATP. This metabolic pas de deux orchestrates the pivotal role of ATP in metabolic regulation of the KATP channel.

Acyl Coenzyme A↗