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General Information:

Id:	4,140
Diseases:	Diabetes mellitus, type II - [OMIM] Insulin resistance
Organism:	Mus musculus
Publication type:	article
Reference:	Cheng K et al.(2010) Hypoxia-inducible factor-1alpha regulates beta cell function in mouse and human islets J. Clin. Invest. 120: 2171-2183 [PMID: 20440072]

Interaction Information:

Comment	To confirm that ARNT was bound to HIF-1alpha, coimmunoprecipitation studies were performed in Min6 cells. Immunoprecipitation with ARNT antibodies revealed low levels of associated HIF-1alpha in the cytoplasm and nucleus, under normoxic conditions.
Formal Description Interaction-ID: 42685	gene/protein HIF1A interacts (colocalizes) with gene/protein ARNT
Drugbank entries	Show/Hide entries for HIF1A
Drugbank DB08687	N-[(1-CHLORO-4-HYDROXYISOQUINOLIN-3-YL)C ... not specified HIF1A

Comment	C57BL/6 mice with beta cell-specific Hif1a disruption (beta-Hif1a-null mice) exhibited glucose intolerance, beta cell dysfunction, and developed severe glucose intolerance on a high-fat diet.
Formal Description Interaction-ID: 42689	gene/protein HIF1A affects_activity of phenotype impaired glucose tolerance
Drugbank entries	Show/Hide entries for HIF1A
Drugbank DB08687	N-[(1-CHLORO-4-HYDROXYISOQUINOLIN-3-YL)C ... not specified HIF1A

Comment	C57BL/6 mice with beta cell-specific Hif1a disruption (beta-Hif1a-null mice) exhibited glucose intolerance, beta cell dysfunction, and developed severe glucose intolerance on a high-fat diet.
Formal Description Interaction-ID: 42690	gene/protein HIF1A affects_activity of phenotype reduced pancreatic beta cell function
Drugbank entries	Show/Hide entries for HIF1A
Drugbank DB08687	N-[(1-CHLORO-4-HYDROXYISOQUINOLIN-3-YL)C ... not specified HIF1A

Comment	In beta-Hif1a-null islets, there was a more than 40% decrease in Glut2, glucokinase (Gck), glucose-6-phosphoisomerase (G6pi), phosphofructokinase (Pfk), hepatocyte nuclear factor 4alpha (Hnf4a), phosphoglycerate mutase 2 (Pgam2), and Akt2.
Formal Description Interaction-ID: 42691	gene/protein HIF1A affects_expression of gene/protein SLC2A2 in pancreas, in pancreatic beta cells
Drugbank entries	Show/Hide entries for HIF1A or SLC2A2
Drugbank DB08687	N-[(1-CHLORO-4-HYDROXYISOQUINOLIN-3-YL)C ... not specified HIF1A
Drugbank DB00428	Streptozocin ligand SLC2A2

Comment	In beta-Hif1a-null islets, there was a more than 40% decrease in Glut2, glucokinase (Gck), glucose-6-phosphoisomerase (G6pi), phosphofructokinase (Pfk), hepatocyte nuclear factor 4alpha (Hnf4a), phosphoglycerate mutase 2 (Pgam2), and Akt2.
Formal Description Interaction-ID: 42692	gene/protein HIF1A affects_expression of gene/protein GCK in pancreas, in pancreatic beta cells
Drugbank entries	Show/Hide entries for HIF1A or GCK
Drugbank DB08687	N-[(1-CHLORO-4-HYDROXYISOQUINOLIN-3-YL)C ... not specified HIF1A
Drugbank DB02379	Beta-D-Glucose not specified GCK
Drugbank DB07358	2-amino-N-(4-methyl-1,3-thiazol-2-yl)-5- ... not specified GCK
Drugbank DB07359	3-[(4-fluorophenyl)sulfanyl]-N-(4-methyl ... not specified GCK
Drugbank DB08118	2-(methylamino)-N-(4-methyl-1,3-thiazol- ... not specified GCK
Drugbank DB08210	2-AMINO-4-FLUORO-5-[(1-METHYL-1H-IMIDAZO ... not specified GCK
Drugbank DB02379	Beta-D-Glucose not specified GCK

Comment	In beta-Hif1a-null islets, there was a more than 40% decrease in Glut2, glucokinase (Gck), glucose-6-phosphoisomerase (G6pi), phosphofructokinase (Pfk), hepatocyte nuclear factor 4alpha (Hnf4a), phosphoglycerate mutase 2 (Pgam2), and Akt2.
Formal Description Interaction-ID: 42693	gene/protein HIF1A affects_expression of gene/protein GPI in pancreas, in pancreatic beta cells
Drugbank entries	Show/Hide entries for HIF1A or GPI
Drugbank DB08687	N-[(1-CHLORO-4-HYDROXYISOQUINOLIN-3-YL)C ... not specified HIF1A
Drugbank DB02007	Alpha-D-Glucose-6-Phosphate not specified GPI
Drugbank DB02076	6-Phosphogluconic Acid not specified GPI
Drugbank DB02093	5-Phospho-D-Arabinohydroxamic Acid not specified GPI
Drugbank DB02548	Sorbitol 6-phosphate not specified GPI
Drugbank DB03042	5-Phosphoarabinonic Acid not specified GPI
Drugbank DB03581	Glucose-6-Phosphate not specified GPI
Drugbank DB03937	Erythose-4-Phosphate not specified GPI
Drugbank DB04493	Fructose-6-Phosphate not specified GPI
Drugbank DB02007	Alpha-D-Glucose-6-Phosphate not specified GPI
Drugbank DB02076	6-Phosphogluconic Acid not specified GPI
Drugbank DB02093	5-Phospho-D-Arabinohydroxamic Acid not specified GPI
Drugbank DB02548	Sorbitol 6-phosphate not specified GPI
Drugbank DB03042	5-Phosphoarabinonic Acid not specified GPI
Drugbank DB03581	Glucose-6-Phosphate not specified GPI
Drugbank DB03937	Erythose-4-Phosphate not specified GPI
Drugbank DB04493	Fructose-6-Phosphate not specified GPI

Comment	In beta-Hif1a-null islets, there was a more than 40% decrease in Glut2, glucokinase (Gck), glucose-6-phosphoisomerase (G6pi), phosphofructokinase (Pfk), hepatocyte nuclear factor 4alpha (Hnf4a), phosphoglycerate mutase 2 (Pgam2), and Akt2.
Formal Description Interaction-ID: 42694	gene/protein HIF1A affects_expression of gene/protein PFK in pancreas, in pancreatic beta cells
Drugbank entries	Show/Hide entries for HIF1A
Drugbank DB08687	N-[(1-CHLORO-4-HYDROXYISOQUINOLIN-3-YL)C ... not specified HIF1A

Comment	In beta-Hif1a-null islets, there was a more than 40% decrease in Glut2, glucokinase (Gck), glucose-6-phosphoisomerase (G6pi), phosphofructokinase (Pfk), hepatocyte nuclear factor 4alpha (Hnf4a), phosphoglycerate mutase 2 (Pgam2), and Akt2.
Formal Description Interaction-ID: 42695	gene/protein HIF1A affects_expression of gene/protein HNF4A in pancreas, in pancreatic beta cells
Drugbank entries	Show/Hide entries for HIF1A or HNF4A
Drugbank DB08687	N-[(1-CHLORO-4-HYDROXYISOQUINOLIN-3-YL)C ... not specified HIF1A
Drugbank DB08231	MYRISTIC ACID not specified HNF4A

Comment	In beta-Hif1a-null islets, there was a more than 40% decrease in Glut2, glucokinase (Gck), glucose-6-phosphoisomerase (G6pi), phosphofructokinase (Pfk), hepatocyte nuclear factor 4alpha (Hnf4a), phosphoglycerate mutase 2 (Pgam2), and Akt2.
Formal Description Interaction-ID: 42696	gene/protein HIF1A affects_expression of gene/protein PGAM2 in pancreas, in pancreatic beta cells
Drugbank entries	Show/Hide entries for HIF1A or PGAM2
Drugbank DB08687	N-[(1-CHLORO-4-HYDROXYISOQUINOLIN-3-YL)C ... not specified HIF1A
Drugbank DB01681	Benzene Hexacarboxylic Acid not specified PGAM2
Drugbank DB04510	3-Phosphoglyceric Acid not specified PGAM2
Drugbank DB01681	Benzene Hexacarboxylic Acid not specified PGAM2
Drugbank DB04510	3-Phosphoglyceric Acid not specified PGAM2

Comment	In beta-Hif1a-null islets, there was a more than 40% decrease in Glut2, glucokinase (Gck), glucose-6-phosphoisomerase (G6pi), phosphofructokinase (Pfk), hepatocyte nuclear factor 4alpha (Hnf4a), phosphoglycerate mutase 2 (Pgam2), and Akt2.
Formal Description Interaction-ID: 42697	gene/protein HIF1A affects_expression of gene/protein AKT2 in pancreas, in pancreatic beta cells
Drugbank entries	Show/Hide entries for HIF1A or AKT2
Drugbank DB08687	N-[(1-CHLORO-4-HYDROXYISOQUINOLIN-3-YL)C ... not specified HIF1A
Drugbank DB07812	N-[(1S)-2-amino-1-phenylethyl]-5-(1H-pyr ... not specified AKT2
Drugbank DB07859	4-(4-CHLOROPHENYL)-4-[4-(1H-PYRAZOL-4-YL ... not specified AKT2
Drugbank DB07947	ISOQUINOLINE-5-SULFONIC ACID (2-(2-(4-CH ... not specified AKT2
Drugbank DB08073	(2S)-1-(1H-INDOL-3-YL)-3-{[5-(3-METHYL-1 ... not specified AKT2

Comment	Control islets had higher ATP content after exposure to high glucose. Islets from beta-Hif1a-null mice had significantly lower basal ATP levels (60% decrease) and the increase in ATP levels with 25 mmol/l glucose was severely blunted. This was despite similar islet insulin content and nonsignificant, higher beta cell content in beta-Hif1a-null mice.
Formal Description Interaction-ID: 42698	gene/protein HIF1A affects_activity of phenotype decreased intracellular ATP level in pancreas, in pancreatic beta cells
Drugbank entries	Show/Hide entries for HIF1A
Drugbank DB08687	N-[(1-CHLORO-4-HYDROXYISOQUINOLIN-3-YL)C ... not specified HIF1A

Comment	RNAi-mediated knockdown of Hif1a in Min6 cells caused a more than 80% decrease in Arnt expression, and islets from beta-Hif1a-null mice had a 50% decrease in Arnt expression, which was similar to the reduction in Hif1a itself. This was paralleled by a decrease in ARNT protein in immunostained pancreas of beta-Hif1a-null versus floxed control mice. Together these experiments show that decreasing HIF-1alpha in islets and beta cells led to decreased ARNT.
Formal Description Interaction-ID: 42708	gene/protein HIF1A increases_expression of gene/protein ARNT in pancreas, in pancreatic beta cells
Drugbank entries	Show/Hide entries for HIF1A
Drugbank DB08687	N-[(1-CHLORO-4-HYDROXYISOQUINOLIN-3-YL)C ... not specified HIF1A

Comment	Removing iron by chelation improved HIF-1alpha activity and beta cell function.
Formal Description Interaction-ID: 42717	drug/chemical compound Iron chelator increases_activity of gene/protein HIF1A in pancreas, in pancreatic beta cells
Drugbank entries	Show/Hide entries for HIF1A
Drugbank DB08687	N-[(1-CHLORO-4-HYDROXYISOQUINOLIN-3-YL)C ... not specified HIF1A

Comment	Removing iron by chelation improved HIF-1alpha activity and beta cell function.
Formal Description Interaction-ID: 42723	drug/chemical compound Iron chelator decreases_activity of phenotype reduced pancreatic beta cell function in pancreas, in pancreatic beta cells

Comment	The effect of adding iron in the form of ferric citrate was studied. At high doses, there was obvious cell death. At lower doses, there were significant decreases in Hif1a, Hnf4a, Glut1, and Glut2 expression. There was also significantly impaired glucose-stimulated insulin secretion (GSIS), with only a nonsignificant 13% increase, following high glucose in iron-treated cells.
Formal Description Interaction-ID: 42724	drug/chemical compound Iron decreases_expression of gene/protein HIF1A in pancreas, in pancreatic beta cells
Drugbank entries	Show/Hide entries for HIF1A
Drugbank DB08687	N-[(1-CHLORO-4-HYDROXYISOQUINOLIN-3-YL)C ... not specified HIF1A

Comment	The effect of adding iron in the form of ferric citrate was studied. At high doses, there was obvious cell death. At lower doses, there were significant decreases in Hif1a, Hnf4a, Glut1, and Glut2 expression. There was also significantly impaired glucose-stimulated insulin secretion (GSIS), with only a nonsignificant 13% increase, following high glucose in iron-treated cells.
Formal Description Interaction-ID: 42725	drug/chemical compound Iron decreases_expression of gene/protein HNF4A in pancreas, in pancreatic beta cells
Drugbank entries	Show/Hide entries for HNF4A
Drugbank DB08231	MYRISTIC ACID not specified HNF4A

Comment	The effect of adding iron in the form of ferric citrate was studied. At high doses, there was obvious cell death. At lower doses, there were significant decreases in Hif1a, Hnf4a, Glut1, and Glut2 expression. There was also significantly impaired glucose-stimulated insulin secretion (GSIS), with only a nonsignificant 13% increase, following high glucose in iron-treated cells.
Formal Description Interaction-ID: 42726	drug/chemical compound Iron decreases_expression of gene/protein SLC2A1 in pancreas, in pancreatic beta cells

Comment	The effect of adding iron in the form of ferric citrate was studied. At high doses, there was obvious cell death. At lower doses, there were significant decreases in Hif1a, Hnf4a, Glut1, and Glut2 expression. There was also significantly impaired glucose-stimulated insulin secretion (GSIS), with only a nonsignificant 13% increase, following high glucose in iron-treated cells.
Formal Description Interaction-ID: 42727	drug/chemical compound Iron decreases_expression of gene/protein SLC2A2 in pancreas, in pancreatic beta cells
Drugbank entries	Show/Hide entries for SLC2A2
Drugbank DB00428	Streptozocin ligand SLC2A2

Comment	The effect of adding iron in the form of ferric citrate was studied. At high doses, there was obvious cell death. At lower doses, there were significant decreases in Hif1a, Hnf4a, Glut1, and Glut2 expression. There was also significantly impaired glucose-stimulated insulin secretion (GSIS), with only a nonsignificant 13% increase, following high glucose in iron-treated cells.
Formal Description Interaction-ID: 42728	drug/chemical compound Iron decreases_activity of process insulin secretion involved in cellular response to glucose stimulus in pancreas, in pancreatic beta cells

Comment	Increasing HIF-1alpha levels by inhibiting its degradation through iron chelation markedly improved insulin secretion and glucose tolerance in control mice fed a high-fat diet but not in beta-Hif1a-null mice.
Formal Description Interaction-ID: 42729	drug/chemical compound Iron chelator increases_activity of process insulin secretion involved in cellular response to glucose stimulus in pancreas, in pancreatic beta cells

Comment	Increasing HIF-1alpha levels by inhibiting its degradation through iron chelation markedly improved insulin secretion and glucose tolerance in control mice fed a high-fat diet but not in beta-Hif1a-null mice.
Formal Description Interaction-ID: 42730	drug/chemical compound Iron chelator increases_activity of phenotype improved glucose tolerance in pancreas, in pancreatic beta cells