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Chronic β-Cell Depolarization Impairs β-Cell Identity by Disrupting a Network of Ca-Regulated Genes.
Stancill JS, Cartailler JP, Clayton HW, O'Connor JT, Dickerson MT, Dadi PK, Osipovich AB, Jacobson DA, Magnuson MA
(2017) Diabetes 66: 2175-2187
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Calcium, Calcium Signaling, Cell Adhesion, Cell Cycle Proteins, Cell Lineage, Cell Polarity, Gene Expression, Gene Expression Regulation, Insulin-Secreting Cells, KATP Channels, Mice, Pancreatic Polypeptide-Secreting Cells, S100 Calcium Binding Protein A6, S100 Calcium-Binding Protein A4, S100 Proteins, Sulfonylurea Receptors
Show Abstract · Added June 2, 2017
We used mice lacking , a key component of the β-cell K-channel, to analyze the effects of a sustained elevation in the intracellular Ca concentration ([Ca]) on β-cell identity and gene expression. Lineage tracing analysis revealed the conversion of β-cells lacking into pancreatic polypeptide cells but not to α- or δ-cells. RNA-sequencing analysis of FACS-purified β-cells confirmed an increase in gene expression and revealed altered expression of more than 4,200 genes, many of which are involved in Ca signaling, the maintenance of β-cell identity, and cell adhesion. The expression of and , two highly upregulated genes, is closely correlated with membrane depolarization, suggesting their use as markers for an increase in [Ca] Moreover, a bioinformatics analysis predicts that many of the dysregulated genes are regulated by common transcription factors, one of which, , was confirmed to be directly controlled by Ca influx in β-cells. Interestingly, among the upregulated genes is , a putative marker of β-cell dedifferentiation, and other genes associated with β-cell failure. Taken together, our results suggest that chronically elevated β-cell [Ca] in islets contributes to the alteration of β-cell identity, islet cell numbers and morphology, and gene expression by disrupting a network of Ca-regulated genes.
© 2017 by the American Diabetes Association.
4 Communities
4 Members
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18 MeSH Terms
Direct activation of β-cell KATP channels with a novel xanthine derivative.
Raphemot R, Swale DR, Dadi PK, Jacobson DA, Cooper P, Wojtovich AP, Banerjee S, Nichols CG, Denton JS
(2014) Mol Pharmacol 85: 858-65
MeSH Terms: Glucose, HEK293 Cells, Humans, Ion Channel Gating, Islets of Langerhans, KATP Channels, Patch-Clamp Techniques, Structure-Activity Relationship, Sulfonylurea Receptors, Xanthine, Xanthines
Show Abstract · Added February 12, 2015
ATP-regulated potassium (KATP) channel complexes of inward rectifier potassium channel (Kir) 6.2 and sulfonylurea receptor (SUR) 1 critically regulate pancreatic islet β-cell membrane potential, calcium influx, and insulin secretion, and consequently, represent important drug targets for metabolic disorders of glucose homeostasis. The KATP channel opener diazoxide is used clinically to treat intractable hypoglycemia caused by excessive insulin secretion, but its use is limited by off-target effects due to lack of potency and selectivity. Some progress has been made in developing improved Kir6.2/SUR1 agonists from existing chemical scaffolds and compound screening, but there are surprisingly few distinct chemotypes that are specific for SUR1-containing KATP channels. Here we report the serendipitous discovery in a high-throughput screen of a novel activator of Kir6.2/SUR1: VU0071063 [7-(4-(tert-butyl)benzyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione]. The xanthine derivative rapidly and dose-dependently activates Kir6.2/SUR1 with a half-effective concentration (EC50) of approximately 7 μM, is more efficacious than diazoxide at low micromolar concentrations, directly activates the channel in excised membrane patches, and is selective for SUR1- over SUR2A-containing Kir6.1 or Kir6.2 channels, as well as Kir2.1, Kir2.2, Kir2.3, Kir3.1/3.2, and voltage-gated potassium channel 2.1. Finally, we show that VU0071063 activates native Kir6.2/SUR1 channels, thereby inhibiting glucose-stimulated calcium entry in isolated mouse pancreatic β cells. VU0071063 represents a novel tool/compound for investigating β-cell physiology, KATP channel gating, and a new chemical scaffold for developing improved activators with medicinal chemistry.
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11 MeSH Terms
Use of biological knowledge to inform the analysis of gene-gene interactions involved in modulating virologic failure with efavirenz-containing treatment regimens in ART-naïve ACTG clinical trials participants.
Grady BJ, Torstenson ES, McLaren PJ, DE Bakker PI, Haas DW, Robbins GK, Gulick RM, Haubrich R, Ribaudo H, Ritchie MD
(2011) Pac Symp Biocomput : 253-64
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, Member 2, ATP-Binding Cassette Transporters, Anti-HIV Agents, Benzoxazines, Computational Biology, Double-Blind Method, Drug Resistance, Viral, Epistasis, Genetic, Genome-Wide Association Study, HIV Infections, HIV-1, Humans, Polymorphism, Single Nucleotide, Potassium Channels, Inwardly Rectifying, Receptors, Drug, Risk Factors, Software, Sulfonylurea Receptors, Treatment Failure
Show Abstract · Added March 13, 2015
Personalized medicine is a high priority for the future of health care. The idea of tailoring an individual's wellness plan to their unique genetic code is one which we hope to realize through the use of pharmacogenomics. There have been examples of tremendous success in pharmacogenomic associations however there are many such examples in which only a small proportion of trait variance has been explained by the genetic variation. Although the increased use of GWAS could help explain more of this variation, it is likely that a significant proportion of the genetic architecture of these pharmacogenomic traits are due to complex genetic effects such as epistasis, also known as gene-gene interactions, as well as gene-drug interactions. In this study, we utilize the Biofilter software package to look for candidate epistasis contributing to risk for virologic failure with efavirenz-containing antiretroviral therapy (ART) regimens in treatment-naïve participants of AIDS Clinical Trials Group (ACTG) randomized clinical trials. A total of 904 individuals from three ACTG trials with data on efavirenz treatment are analyzed after race-stratification into white, black, and Hispanic ethnic groups. Biofilter was run considering 245 candidate ADME (absorption, distribution, metabolism, and excretion) genes and using database knowledge of gene and protein interaction networks to produce approximately 2 million SNP-SNP interaction models within each ethnic group. These models were evaluated within the PLATO software package using pair wise logistic regression models. Although no interaction model remained significant after correction for multiple comparisons, an interaction between SNPs in the TAP1 and ABCC9 genes was one of the top models before correction. The TAP1 protein is responsible for intracellular transport of antigen to MHC class I molecules, while ABCC9 codes for a transporter which is part of the subfamily of ABC transporters associated with multi-drug resistance. This study demonstrates the utility of the Biofilter method to prioritize the search for gene-gene interactions in large-scale genomic datasets, although replication in a larger cohort is required to confirm the validity of this particular TAP1-ABCC9 finding.
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19 MeSH Terms
Differential structure of atrial and ventricular KATP: atrial KATP channels require SUR1.
Flagg TP, Kurata HT, Masia R, Caputa G, Magnuson MA, Lefer DJ, Coetzee WA, Nichols CG
(2008) Circ Res 103: 1458-65
MeSH Terms: ATP-Binding Cassette Transporters, Animals, COS Cells, Cercopithecus aethiops, Heart Atria, Heart Ventricles, KATP Channels, Mice, Mice, Knockout, Mice, Transgenic, Potassium Channels, Inwardly Rectifying, Receptors, Drug, Sulfonylurea Receptors
Show Abstract · Added February 23, 2011
The isoform-specific structure of the ATP-sensitive potassium (K(ATP)) channel endows it with differential fundamental properties, including physiological activation and pharmacology. Numerous studies have convincingly demonstrated that the pore-forming Kir6.2 (KCNJ11) and regulatory SUR2A (ABCC9) subunits are essential elements of the sarcolemmal K(ATP) channel in cardiac ventricular myocytes. Using a novel antibody directed against the COOH terminus of SUR1 (ABCC8), we show that this K(ATP) subunit is also expressed in mouse myocardium and is the dominant SUR isoform in the atrium. This suggests differential sarcolemmal K(ATP) composition in atria and ventricles, and, to test this, K(ATP) currents were measured in isolated atrial and ventricular myocytes from wild-type and SUR1(-/-) animals. K(ATP) conductance is essentially abolished in SUR1(-/-) atrial myocytes but is normal in SUR1(-/-) ventricular myocytes. Furthermore, pharmacological properties of wild-type atrial K(ATP) match closely the properties of heterologously expressed SUR1/Kir6.2 channels, whereas ventricular K(ATP) properties match those of heterologously expressed SUR2A/Kir6.2 channels. Collectively, the data demonstrate a previously unappreciated K(ATP) channel heterogeneity: SUR1 is an essential component of atrial, but not ventricular, K(ATP) channels. Differential molecular make-up of the 2 channels underlies differential pharmacology, with important implications when considering sulfonylurea therapy or dissecting the role of cardiac K(ATP) pharmacologically, as well as for understanding of the role of diazoxide in preconditioning.
1 Communities
1 Members
1 Resources
13 MeSH Terms
Exendin-(9-39) corrects fasting hypoglycemia in SUR-1-/- mice by lowering cAMP in pancreatic beta-cells and inhibiting insulin secretion.
De León DD, Li C, Delson MI, Matschinsky FM, Stanley CA, Stoffers DA
(2008) J Biol Chem 283: 25786-93
MeSH Terms: ATP-Binding Cassette Transporters, Animals, Cyclic AMP, Gene Expression Regulation, Glucagon-Like Peptide-1 Receptor, Glucose, Hypoglycemia, Insulin, Insulin Secretion, Insulin-Secreting Cells, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Models, Biological, Peptide Fragments, Potassium Channels, Inwardly Rectifying, Receptors, Drug, Receptors, Glucagon, Sulfonylurea Receptors
Show Abstract · Added December 21, 2016
Congenital hyperinsulinism is a disorder of pancreatic beta-cell function characterized by failure to suppress insulin secretion in the setting of hypoglycemia, resulting in brain damage or death if untreated. Loss-of-function mutations in the K(ATP) channel (composed of two subunits: Kir6.2 and SUR-1) are responsible for the most common and severe form of congenital hyperinsulinism. Most patients are unresponsive to available medical therapy and require palliative pancreatectomy. Similar to the human condition, the SUR-1(-/-) mouse is hypoglycemic when fasted and hyperglycemic when glucose-loaded. We have previously reported that the glucagon-like peptide-1 receptor antagonist exendin-(9-39) raises fasting blood glucose in normal mice. Here we examine the effect of exendin-(9-39) on fasting blood glucose in SUR-1(-/-) mice. Mice were randomized to receive exendin-(9-39) or vehicle. Fasting blood glucose levels in SUR-1(-/-) mice treated with exendin-(9-39) were significantly higher than in vehicle-treated mice and not different from wild-type littermates. Exendin-(9-39) did not further worsen glucose tolerance and had no effect on body weight and insulin sensitivity. Isolated islet perifusion studies demonstrated that exendin-(9-39) blocked amino acid-stimulated insulin secretion, which is abnormally increased in SUR-1(-/-) islets. Furthermore, cAMP content in SUR-1(-/-) islets was reduced by exendin-(9-39) both basally and when stimulated by amino acids, whereas cytosolic calcium levels were not affected. These findings suggest that cAMP plays a key role in K(ATP)-independent insulin secretion and that the GLP-1 receptor is constitutively active in SUR-1(-/-) beta-cells. Our findings indicate that exendin-(9-39) normalizes fasting hypoglycemia in SUR-1(-/-) mice via a direct effect on insulin secretion, thereby raising exendin-(9-39) as a potential therapeutic agent for K(ATP) hyperinsulinism.
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20 MeSH Terms
Role of sulfonylurea receptor type 1 subunits of ATP-sensitive potassium channels in myocardial ischemia/reperfusion injury.
Elrod JW, Harrell M, Flagg TP, Gundewar S, Magnuson MA, Nichols CG, Coetzee WA, Lefer DJ
(2008) Circulation 117: 1405-13
MeSH Terms: ATP-Binding Cassette Transporters, Animals, Diabetes Complications, Fibrosis, Hypoglycemic Agents, KATP Channels, Mice, Mice, Knockout, Multidrug Resistance-Associated Proteins, Myocardial Infarction, Myocardial Reperfusion Injury, Myocarditis, Myocytes, Cardiac, Patch-Clamp Techniques, Potassium Channels, Potassium Channels, Inwardly Rectifying, Receptors, Drug, Sulfonylurea Compounds, Sulfonylurea Receptors, Ventricular Dysfunction, Left
Show Abstract · Added February 23, 2011
BACKGROUND - Opening of cardiac ATP-sensitive potassium channels (K(ATP) channels) is a well-characterized protective mechanism against ischemia and reperfusion injury. Evidence exists for an involvement of both sarcolemmal and mitochondrial K(ATP) channels in such protection. Classically, cardiac sarcolemmal K(ATP) channels are thought to be composed of Kir6.2 (inward-rectifier potassium channel 6.2) and SUR2A (sulfonylurea receptor type 2A) subunits; however, the evidence is strong that SUR1 (sulfonylurea receptor type 1) subunits are also expressed in the heart and that they may have a functional role. The aim of this study, therefore, was to examine the role of SUR1 in myocardial infarction.
METHODS AND RESULTS - We subjected mice lacking SUR1 subunits to in vivo myocardial ischemia/reperfusion injury. Interestingly, the SUR1-null mice were markedly protected against the ischemic insult, displaying a reduced infarct size and preservation of left ventricular function, which suggests a role for this K(ATP) channel subunit in cardiovascular function during conditions of stress.
CONCLUSIONS - SUR1 subunits have a high sensitivity toward many sulfonylureas and certain K(ATP) channel-opening drugs. Their potential role during ischemic events should therefore be considered both in the interpretation of experimental data with pharmacological agents and in the clinical arena when the cardiovascular outcome of patients treated with antidiabetic sulfonylureas is being considered.
1 Communities
1 Members
1 Resources
20 MeSH Terms
Insulin gene mutations as a cause of permanent neonatal diabetes.
Støy J, Edghill EL, Flanagan SE, Ye H, Paz VP, Pluzhnikov A, Below JE, Hayes MG, Cox NJ, Lipkind GM, Lipton RB, Greeley SA, Patch AM, Ellard S, Steiner DF, Hattersley AT, Philipson LH, Bell GI, Neonatal Diabetes International Collaborative Group
(2007) Proc Natl Acad Sci U S A 104: 15040-4
MeSH Terms: ATP-Binding Cassette Transporters, Amino Acid Sequence, Diabetes Mellitus, Female, Genetic Linkage, Heterozygote, Humans, Infant, Infant, Newborn, Insulin, Male, Models, Biological, Molecular Sequence Data, Mutation, Missense, Pedigree, Potassium Channels, Potassium Channels, Inwardly Rectifying, Proinsulin, Protein Folding, Protein Precursors, Receptors, Drug, Sulfonylurea Receptors
Show Abstract · Added February 22, 2016
We report 10 heterozygous mutations in the human insulin gene in 16 probands with neonatal diabetes. A combination of linkage and a candidate gene approach in a family with four diabetic members led to the identification of the initial INS gene mutation. The mutations are inherited in an autosomal dominant manner in this and two other small families whereas the mutations in the other 13 patients are de novo. Diabetes presented in probands at a median age of 9 weeks, usually with diabetic ketoacidosis or marked hyperglycemia, was not associated with beta cell autoantibodies, and was treated from diagnosis with insulin. The mutations are in critical regions of the preproinsulin molecule, and we predict that they prevent normal folding and progression of proinsulin in the insulin secretory pathway. The abnormally folded proinsulin molecule may induce the unfolded protein response and undergo degradation in the endoplasmic reticulum, leading to severe endoplasmic reticulum stress and potentially beta cell death by apoptosis. This process has been described in both the Akita and Munich mouse models that have dominant-acting missense mutations in the Ins2 gene, leading to loss of beta cell function and mass. One of the human mutations we report here is identical to that in the Akita mouse. The identification of insulin mutations as a cause of neonatal diabetes will facilitate the diagnosis and possibly, in time, treatment of this disorder.
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22 MeSH Terms
Hyperinsulinism in mice with heterozygous loss of K(ATP) channels.
Remedi MS, Rocheleau JV, Tong A, Patton BL, McDaniel ML, Piston DW, Koster JC, Nichols CG
(2006) Diabetologia 49: 2368-78
MeSH Terms: ATP-Binding Cassette Transporters, Animals, Blood Glucose, Hyperinsulinism, Insulin, Insulin Secretion, Kinetics, Loss of Heterozygosity, Mice, Mice, Knockout, Multidrug Resistance-Associated Proteins, Potassium Channels, Potassium Channels, Inwardly Rectifying, Receptors, Drug, Sulfonylurea Receptors
Show Abstract · Added December 21, 2016
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 approximately 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.
0 Communities
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15 MeSH Terms
Association studies of variants in the genes involved in pancreatic beta-cell function in type 2 diabetes in Japanese subjects.
Yokoi N, Kanamori M, Horikawa Y, Takeda J, Sanke T, Furuta H, Nanjo K, Mori H, Kasuga M, Hara K, Kadowaki T, Tanizawa Y, Oka Y, Iwami Y, Ohgawara H, Yamada Y, Seino Y, Yano H, Cox NJ, Seino S
(2006) Diabetes 55: 2379-86
MeSH Terms: ATP-Binding Cassette Transporters, Alleles, Diabetes Mellitus, Type 2, Gene Frequency, Genetic Variation, Genotype, Humans, Islets of Langerhans, Japan, Microarray Analysis, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Potassium Channels, Potassium Channels, Inwardly Rectifying, Receptors, Drug, Sequence Analysis, DNA, Sulfonylurea Receptors, Transcription Factors
Show Abstract · Added February 22, 2016
Because impaired insulin secretion is characteristic of type 2 diabetes in Asians, including Japanese, the genes involved in pancreatic beta-cell function are candidate susceptibility genes for type 2 diabetes. We examined the association of variants in genes encoding several transcription factors (TCF1, TCF2, HNF4A, ISL1, IPF1, NEUROG3, PAX6, NKX2-2, NKX6-1, and NEUROD1) and genes encoding the ATP-sensitive K(+) channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) with type 2 diabetes in a Japanese cohort of 2,834 subjects. The exon 16 -3c/t variant rs1799854 in ABCC8 showed a significant association (P = 0.0073), and variants in several genes showed nominally significant associations (P < 0.05) with type 2 diabetes. Although the E23K variant rs5219 in KCNJ11 showed no association with diabetes in Japanese (for the K allele, odds ratio [OR] 1.08 [95% CI 0.97-1.21], P = 0.15), 95% CI around the OR overlaps in meta-analysis of European populations, suggesting that our results are not inconsistent with the previous studies. This is the largest association study so far conducted on these genes in Japanese and provides valuable information for comparison with other ethnic groups.
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18 MeSH Terms
Cholinergic regulation of fuel-induced hormone secretion and respiration of SUR1-/- mouse islets.
Doliba NM, Qin W, Vatamaniuk MZ, Buettger CW, Collins HW, Magnuson MA, Kaestner KH, Wilson DF, Carr RD, Matschinsky FM
(2006) Am J Physiol Endocrinol Metab 291: E525-35
MeSH Terms: ATP-Binding Cassette Transporters, Acetylcholine, Acetylcholinesterase, Amino Acids, Animals, Calcium, Cell Respiration, Cholinergic Fibers, Gene Expression, Glucagon, Glucose, Glucose Transporter Type 2, Glyburide, Hormones, Insulin, Insulin Secretion, Islets of Langerhans, Large-Conductance Calcium-Activated Potassium Channel beta Subunits, Mice, Mice, Inbred C57BL, Mice, Knockout, Multidrug Resistance-Associated Proteins, Oxygen Consumption, Potassium Channels, Inwardly Rectifying, RNA, Messenger, Receptors, Drug, Sulfonylurea Receptors
Show Abstract · Added February 23, 2011
Neural and endocrine factors (i.e., Ach and GLP-1) restore defective glucose-stimulated insulin release in pancreatic islets lacking sulfonylurea type 1 receptors (SUR1(-/-)) (Doliba NM, Qin W, Vatamaniuk MZ, Li C, Zelent D, Najafi H, Buettger CW, Collins HW, Carr RD, Magnuson MA, and Matschinsky FM. Am J Physiol Endocrinol Metab 286: E834-E843, 2004). The goal of the present study was to assess fuel-induced respiration in SUR1(-/-) islets and to correlate it with changes in intracellular Ca(2+), insulin, and glucagon secretion. By use of a method based on O(2) quenching of phosphorescence, the O(2) consumption rate (OCR) of isolated islets was measured online in a perifusion system. Basal insulin release (IR) was 7-10 times higher in SUR1(-/-) compared with control (CON) islets, but the OCR was comparable. The effect of high glucose (16.7 mM) on IR and OCR was markedly reduced in SUR1(-/-) islets compared with CON. Ach (0.5 microM) in the presence of 16.7 mM glucose caused a large burst of IR in CON and SUR1(-/-) islets with minor changes in OCR in both groups of islets. In SUR1(-/-) islets, high glucose failed to inhibit glucagon secretion during stimulation with amino acids or Ach. We conclude that 1) reduced glucose responsiveness of SUR1(-/-) islets may be in part due to impaired energetics, as evidenced by significant decrease in glucose-stimulated OCR; 2) elevated intracellular Ca(2+) levels may contribute to altered insulin and glucagon secretion in SUR1(-/-) islets; and 3) The amplitudes of the changes in OCR during glucose and Ach stimulation do not correlate with IR in normal and SUR1(-/-) islets suggesting that the energy requirements for exocytosis are minor compared with other ATP-consuming reactions.
1 Communities
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27 MeSH Terms