CIDeRplusGeneral Information:
| Id: | 8,640 |
| Diseases: |
Diabetes mellitus, type II
- [OMIM]
Insulin resistance |
| Mammalia | |
| review | |
| Reference: | Newsholme P and Krause M(2012) Nutritional regulation of insulin secretion: implications for diabetes Clin Biochem Rev 33: 35-47 [PMID: 22896743] |
Interaction Information:
| Comment | A rise in the ATP/ADP ratio serves to suppress ATP-sensitive potassium (K ATP) channels and activate voltage-gated Ca2+ channels, leading to stimulation of insulin granule exocytosis. |
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Formal Description Interaction-ID: 89360 |
phenotype increased ATP/ADP ratio decreases_activity of complex/PPI ATP-sensitive potassium channel complex |
| Comment | A rise in the ATP/ADP ratio serves to suppress ATP-sensitive potassium (K ATP) channels and activate voltage-gated Ca2+ channels, leading to stimulation of insulin granule exocytosis. |
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Formal Description Interaction-ID: 90756 |
phenotype increased ATP/ADP ratio increases_activity of complex/PPI Voltage-gated calcium channel |
| Comment | A rise in the ATP/ADP ratio serves to suppress ATP-sensitive potassium (K ATP) channels and activate voltage-gated Ca2+ channels, leading to stimulation of insulin granule exocytosis. |
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Formal Description Interaction-ID: 90757 |
phenotype increased ATP/ADP ratio increases_activity of process insulin granule exocytosis |
| Comment | The positively charged amino acid L-arginine is recognised as not only a powerful secretagogue, but also an essential synergic compound for nutrient-dependent insulin secretion. |
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Formal Description Interaction-ID: 90758 |
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| Comment | Insulin secretion from the pancreatic islet beta-cell is regulated by a number of factors, but the predominant stimulatory signal is the rise in blood glucose that occurs with the ingestion of carbohydrate containing meals. |
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Formal Description Interaction-ID: 90759 |
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| Comment | Glucose not only directly stimulates insulin secretion from beta-cells via its metabolism but also modulates the action of several other effectors, including free fatty acids, amino acids and incretin hormones (group of hormones secreted in response to nutrients from a meal, e.g. glucagon-like peptide-1 (GLP-1)). |
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Formal Description Interaction-ID: 90760 |
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| Comment | Glucose not only directly stimulates insulin secretion from beta-cells via its metabolism but also modulates the action of several other effectors, including free fatty acids, amino acids and incretin hormones (group of hormones secreted in response to nutrients from a meal, e.g. glucagon-like peptide-1 (GLP-1)). |
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Formal Description Interaction-ID: 90761 |
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| Comment | Glucose not only directly stimulates insulin secretion from beta-cells via its metabolism but also modulates the action of several other effectors, including free fatty acids, amino acids and incretin hormones (group of hormones secreted in response to nutrients from a meal, e.g. glucagon-like peptide-1 (GLP-1)). |
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Formal Description Interaction-ID: 90762 |
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| Comment | The triggering signal for insulin exocytosis is ATP produced in glycolysis and mitochondrial glucose oxidation. |
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Formal Description Interaction-ID: 90763 |
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| Comment | Glucose is transported into the pancreatic beta-cell by the non-insulin-dependent glucose transporter GLUT2 in rodents and by both GLUT1 and GLUT2 in humans. |
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Formal Description Interaction-ID: 90764 |
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| Comment | Glucose is transported into the pancreatic beta-cell by the non-insulin-dependent glucose transporter GLUT2 in rodents and by both GLUT1 and GLUT2 in humans. |
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Formal Description Interaction-ID: 90765 |
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| Drugbank entries | Show/Hide entries for SLC2A2 |
| Comment | For most mammalian cells, fatty acid metabolism is mainly controlled by substrate supply. In the fasted state, fatty acids are converted into long-chain acyl-CoA by acyl-CoA synthetase (ACS) and enter the mitochondria via carnitine palmitoyl transferase 1 (CPT-1), where they are oxidised via the beta-oxidation pathway for energy production, maintaining the basal levels of insulin secretion. After a carbohydrate-containing meal, fatty acid oxidation is inhibited, since the regulatory molecule malonyl-CoA is synthesised by acetyl-CoA carboxylase (ACC) from an acetate group derived from citrate which is elevated following synthesis from glucose and/or amino acids. Malonyl-CoA inhibits CPT-1, thus blocking transport of long chain acyl-CoA into the mitochondria. |
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Formal Description Interaction-ID: 90766 |
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| Comment | Accumulation of long chain acyl-CoA in the cytosol leads to an increase of intracellular Ca2+ levels and to changes in acylation state of proteins involved both in regulation of ion channel activity and exocytosis. In addition, long-chain acyl-CoA can also enhance the fusion of insulin-secretory vesicles with the plasma membrane and insulin release. |
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Formal Description Interaction-ID: 90767 |
drug/chemical compound increases_activity of phenotype increased intracellular calcium level |
| Comment | Accumulation of long chain acyl-CoA in the cytosol leads to an increase of intracellular Ca2+ levels and to changes in acylation state of proteins involved both in regulation of ion channel activity and exocytosis. In addition, long-chain acyl-CoA can also enhance the fusion of insulin-secretory vesicles with the plasma membrane and insulin release. |
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Formal Description Interaction-ID: 90768 |
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| Comment | Effects of fatty acids on glucose-induced insulin secretion are directly correlated with chain length and the degree of unsaturation, where long-chain fatty acids (such as palmitate or linoleate) acutely increase but chronically reduce insulin release in response to glucose stimulation. Chronic incubation (24 hours) of beta-cells with a polyunsaturated fatty acid (arachidonic acid) increased insulin secretion while, on the other hand, exposure of a clonal pancreatic beta-cell line (BRIN-BD11) for 24 hours to a saturated fatty acid (palmitic acid) resulted in inhibition of insulin secretion. |
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Formal Description Interaction-ID: 90769 |
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| Comment | Amino acids such as glutamine, alanine, arginine and others are known to cause increments in GSIS, indicating that beta-cell amino acid and glucose metabolism share common pathways. Specifically, mitochondrial metabolism is crucial for the coupling of amino acid and glucose recognition to exocytosis of insulin granules. |
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Formal Description Interaction-ID: 90770 |
drug/chemical compound increases_activity of |
| Comment | Amino acids such as glutamine, alanine, arginine and others are known to cause increments in GSIS, indicating that beta-cell amino acid and glucose metabolism share common pathways. Specifically, mitochondrial metabolism is crucial for the coupling of amino acid and glucose recognition to exocytosis of insulin granules. |
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Formal Description Interaction-ID: 90771 |
drug/chemical compound increases_activity of |
| Comment | Amino acids such as glutamine, alanine, arginine and others are known to cause increments in GSIS, indicating that beta-cell amino acid and glucose metabolism share common pathways. Specifically, mitochondrial metabolism is crucial for the coupling of amino acid and glucose recognition to exocytosis of insulin granules. |
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Formal Description Interaction-ID: 90772 |
drug/chemical compound increases_activity of |
| Comment | Arginine is known for stimulating insulin release through electrogenic transport into the beta-cell via the mCAT2A amino acid transporter, resulting in membrane depolarisation, a rise in intracellular Ca2+ through opening of voltage-gated Ca2+ channels, and then insulin secretion. |
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Formal Description Interaction-ID: 90773 |
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| Comment | Arginine is known for stimulating insulin release through electrogenic transport into the beta-cell via the mCAT2A amino acid transporter, resulting in membrane depolarisation, a rise in intracellular Ca2+ through opening of voltage-gated Ca2+ channels, and then insulin secretion. |
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Formal Description Interaction-ID: 90783 |
drug/chemical compound increases_activity of phenotype increased intracellular calcium level |
| Comment | Arginine may also be converted to L-glutamate and thus influence insulin secretion by the generation of further metabolic coupling factors. |
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Formal Description Interaction-ID: 90784 |
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| Comment | L-arginine exerts many positive influences on beta-cell metabolism: i) stimulation of beta-cell insulin secretion; ii) provision of anti-oxidant and protective responses (glutathione synthesis); iii) increasing glucose consumption; and iv) inducing basal glutamate synthesis. |
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Formal Description Interaction-ID: 90786 |
drug/chemical compound increases_activity of process |
| Comment | L-arginine exerts many positive influences on beta-cell metabolism: i) stimulation of beta-cell insulin secretion; ii) provision of anti-oxidant and protective responses (glutathione synthesis); iii) increasing glucose consumption; and iv) inducing basal glutamate synthesis. |
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Formal Description Interaction-ID: 90789 |
drug/chemical compound increases_activity of process |
| Comment | L-glutamine is rapidly taken up and metabolised by islets, however, alone it does not stimulate insulin secretion or enhance glucose-induced insulin secretion. Activation of glutamate dehydrogenase (GDH) by addition of leucine enhances insulin secretion by increasing the entry of glutamine carbon into the tricarboxylic acid cycle. The production of gamma-aminobutyric acid (GABA) from glutamine has been proposed as an explanation for the paradox that glutamine alone does not stimulate insulin release. Under this scheme, glutamine is preferentially metabolised to GABA and L-aspartate. There is no oxidation of glutamine in the process and thus stimulus-secretion coupling via ATP would be minimal. |
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Formal Description Interaction-ID: 90790 |
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| Comment | L-glutamine is rapidly taken up and metabolised by islets, however, alone it does not stimulate insulin secretion or enhance glucose-induced insulin secretion. Activation of glutamate dehydrogenase (GDH) by addition of leucine enhances insulin secretion by increasing the entry of glutamine carbon into the tricarboxylic acid cycle. The production of gamma-aminobutyric acid (GABA) from glutamine has been proposed as an explanation for the paradox that glutamine alone does not stimulate insulin release. Under this scheme, glutamine is preferentially metabolised to GABA and L-aspartate. There is no oxidation of glutamine in the process and thus stimulus-secretion coupling via ATP would be minimal. L-aspartate is formed after entry of L-glutamate into the tricarboxylic acid cycle. |
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Formal Description Interaction-ID: 90794 |
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| Comment | L-glutamate produced from glutamine entered the gamma-glutamyl cycle and resulted in an increased production of glutathione. |
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Formal Description Interaction-ID: 90796 |
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| Comment | L-glutamate produced from glutamine entered the gamma-glutamyl cycle and resulted in an increased production of glutathione. |
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Formal Description Interaction-ID: 90800 |
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| Comment | L-glutamate produced from glutamine entered the gamma-glutamyl cycle and resulted in an increased production of glutathione. |
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Formal Description Interaction-ID: 90801 |
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| Drugbank entries | Show/Hide entries for |
| Comment | As glutamate is known to inhibit glucagon secretion from the pancreatic alpha-cell, glutamate release from the beta-cell may additionally represent a novel paracrine mechanism for pancreatic islet hormone release. |
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Formal Description Interaction-ID: 90803 |
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| Comment | In RINm5F cells, the insulinotropic action of L-alanine has been reported to be a result of co-transport with Na+, which resulted in membrane depolarisation leading to an increase in intracellular Ca2+. Additionally, by use of the respiratory poison oligomycin, the metabolism and oxidation of alanine were shown to be important for its ability to stimulate insulin secretion. |
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Formal Description Interaction-ID: 90804 |
drug/chemical compound increases_activity of phenotype increased intracellular calcium level |
| Comment | In RINm5F cells, the insulinotropic action of L-alanine has been reported to be a result of co-transport with Na+, which resulted in membrane depolarisation leading to an increase in intracellular Ca2+. Additionally, by use of the respiratory poison oligomycin, the metabolism and oxidation of alanine were shown to be important for its ability to stimulate insulin secretion. |
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Formal Description Interaction-ID: 90805 |
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| Comment | Homocysteine can inhibit insulin section. Homocysteine is a sulfhydryl-containing amino acid formed during the metabolism of methionine and which can be taken up by cells mainly via cysteine transporters. The effects of homocysteine were not limited to glucose but also impaired amino acid-stimulated insulin secretion. |
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Formal Description Interaction-ID: 90807 |
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| Comment | Homocysteine can inhibit insulin section. Homocysteine is a sulfhydryl-containing amino acid formed during the metabolism of methionine and which can be taken up by cells mainly via cysteine transporters. |
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Formal Description Interaction-ID: 90809 |
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| Comment | A novel mechanism by which homocysteine blunts insulin secretion is by its effect on NO production. Homocysteine is a known precursor of asymmetric dimethylarginine (ADMA), which is an endogenous methylated amino acid that inhibits the constitutive endothelial and neuronal isoforms of nitric oxide synthase (NOS) but a less potent inhibitor of the iNOS isoform. Homocysteine is also an inhibitor of the enzyme dimethylarginine dimethylhydrolase (DDAH), a key regulatory enzyme which metabolises ADMA. Thus homocysteine is capable of inducing a further increment in ADMA and therefore decreasing the availability of NO. Since a constant low production of NO is essential for insulin secretion and beta-cell function, homocysteine may cause further damage. |
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Formal Description Interaction-ID: 90810 |
drug/chemical compound increases_quantity of drug/chemical compound |
| Comment | A novel mechanism by which homocysteine blunts insulin secretion is by its effect on NO production. Homocysteine is a known precursor of asymmetric dimethylarginine (ADMA), which is an endogenous methylated amino acid that inhibits the constitutive endothelial and neuronal isoforms of nitric oxide synthase (NOS) but a less potent inhibitor of the iNOS isoform. Homocysteine is also an inhibitor of the enzyme dimethylarginine dimethylhydrolase (DDAH), a key regulatory enzyme which metabolises ADMA. Thus homocysteine is capable of inducing a further increment in ADMA and therefore decreasing the availability of NO. Since a constant low production of NO is essential for insulin secretion and beta-cell function, homocysteine may cause further damage. |
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Formal Description Interaction-ID: 90813 |
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| Drugbank entries | Show/Hide entries for NOS1 |
| Comment | A novel mechanism by which homocysteine blunts insulin secretion is by its effect on NO production. Homocysteine is a known precursor of asymmetric dimethylarginine (ADMA), which is an endogenous methylated amino acid that inhibits the constitutive endothelial and neuronal isoforms of nitric oxide synthase (NOS) but a less potent inhibitor of the iNOS isoform. Homocysteine is also an inhibitor of the enzyme dimethylarginine dimethylhydrolase (DDAH), a key regulatory enzyme which metabolises ADMA. Thus homocysteine is capable of inducing a further increment in ADMA and therefore decreasing the availability of NO. Since a constant low production of NO is essential for insulin secretion and beta-cell function, homocysteine may cause further damage. |
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Formal Description Interaction-ID: 90814 |
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| Drugbank entries | Show/Hide entries for NOS3 |
| Comment | A novel mechanism by which homocysteine blunts insulin secretion is by its effect on NO production. Homocysteine is a known precursor of asymmetric dimethylarginine (ADMA), which is an endogenous methylated amino acid that inhibits the constitutive endothelial and neuronal isoforms of nitric oxide synthase (NOS) but a less potent inhibitor of the iNOS isoform. Homocysteine is also an inhibitor of the enzyme dimethylarginine dimethylhydrolase (DDAH), a key regulatory enzyme which metabolises ADMA. Thus homocysteine is capable of inducing a further increment in ADMA and therefore decreasing the availability of NO. Since a constant low production of NO is essential for insulin secretion and beta-cell function, homocysteine may cause further damage. |
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Formal Description Interaction-ID: 90815 |
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| Drugbank entries | Show/Hide entries for NOS2 |
| Comment | A novel mechanism by which homocysteine blunts insulin secretion is by its effect on NO production. Homocysteine is a known precursor of asymmetric dimethylarginine (ADMA), which is an endogenous methylated amino acid that inhibits the constitutive endothelial and neuronal isoforms of nitric oxide synthase (NOS) but a less potent inhibitor of the iNOS isoform. Homocysteine is also an inhibitor of the enzyme dimethylarginine dimethylhydrolase (DDAH), a key regulatory enzyme which metabolises ADMA. Thus homocysteine is capable of inducing a further increment in ADMA and therefore decreasing the availability of NO. Since a constant low production of NO is essential for insulin secretion and beta-cell function, homocysteine may cause further damage. |
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Formal Description Interaction-ID: 90817 |
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| Comment | A novel mechanism by which homocysteine blunts insulin secretion is by its effect on NO production. Homocysteine is a known precursor of asymmetric dimethylarginine (ADMA), which is an endogenous methylated amino acid that inhibits the constitutive endothelial and neuronal isoforms of nitric oxide synthase (NOS) but a less potent inhibitor of the iNOS isoform. Homocysteine is also an inhibitor of the enzyme dimethylarginine dimethylhydrolase (DDAH), a key regulatory enzyme which metabolises ADMA. Thus homocysteine is capable of inducing a further increment in ADMA and therefore decreasing the availability of NO. Since a constant low production of NO is essential for insulin secretion and beta-cell function, homocysteine may cause further damage. |
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Formal Description Interaction-ID: 90818 |
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| Comment | A novel mechanism by which homocysteine blunts insulin secretion is by its effect on NO production. Homocysteine is a known precursor of asymmetric dimethylarginine (ADMA), which is an endogenous methylated amino acid that inhibits the constitutive endothelial and neuronal isoforms of nitric oxide synthase (NOS) but a less potent inhibitor of the iNOS isoform. Homocysteine is also an inhibitor of the enzyme dimethylarginine dimethylhydrolase (DDAH), a key regulatory enzyme which metabolises ADMA. Thus homocysteine is capable of inducing a further increment in ADMA and therefore decreasing the availability of NO. Since a constant low production of NO is essential for insulin secretion and beta-cell function, homocysteine may cause further damage. |
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Formal Description Interaction-ID: 90819 |
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