CIDeRplusGeneral Information:
| Id: | 7,531 |
| Diseases: |
Diabetes mellitus, type II
- [OMIM]
Insulin resistance |
| Homo sapiens | |
| review | |
| Reference: | Muller TD et al.(2017) The New Biology and Pharmacology of Glucagon Physiol. Rev. 97: 721-766 [PMID: 28275047] |
Interaction Information:
| Comment | Postprandial levels of glucagon are elevated in patients with type 2 diabetes, suggesting that failure of glucose to suppress glucagon action plays a causal role in the pathology of type 2 diabetes. |
|
Formal Description Interaction-ID: 74316 |
|
| Comment | Somatostatin was identified as a suppressor of glucagon and insulin secretion. |
|
Formal Description Interaction-ID: 74917 |
|
| Comment | Somatostatin was identified as a suppressor of glucagon and insulin secretion. |
|
Formal Description Interaction-ID: 74918 |
|
| Comment | Glucagon is a multifaceted hormone with biological action beyond glucose metabolism. These activities include central regulation of energy intake, stimulation of brown fat thermogenesis, inhibition of gastric motility, modulation of lipid metabolism through activation of lipolysis and inhibition of lipid synthesis, improvement of cardiac output, and stimulation of autophagy and of renal glomerular filtration with water reabsorption. |
|
Formal Description Interaction-ID: 74919 |
|
| Comment | Glucagon is a multifaceted hormone with biological action beyond glucose metabolism. These activities include central regulation of energy intake, stimulation of brown fat thermogenesis, inhibition of gastric motility, modulation of lipid metabolism through activation of lipolysis and inhibition of lipid synthesis, improvement of cardiac output, and stimulation of autophagy and of renal glomerular filtration with water reabsorption. |
|
Formal Description Interaction-ID: 74920 |
|
| Comment | Glucagon is a multifaceted hormone with biological action beyond glucose metabolism. These activities include central regulation of energy intake, stimulation of brown fat thermogenesis, inhibition of gastric motility, modulation of lipid metabolism through activation of lipolysis and inhibition of lipid synthesis, improvement of cardiac output, and stimulation of autophagy and of renal glomerular filtration with water reabsorption. |
|
Formal Description Interaction-ID: 74921 |
|
| Comment | Glucagon is a multifaceted hormone with biological action beyond glucose metabolism. These activities include central regulation of energy intake, stimulation of brown fat thermogenesis, inhibition of gastric motility, modulation of lipid metabolism through activation of lipolysis and inhibition of lipid synthesis, improvement of cardiac output, and stimulation of autophagy and of renal glomerular filtration with water reabsorption. |
|
Formal Description Interaction-ID: 74923 |
|
| Comment | Glucagon is a multifaceted hormone with biological action beyond glucose metabolism. These activities include central regulation of energy intake, stimulation of brown fat thermogenesis, inhibition of gastric motility, modulation of lipid metabolism through activation of lipolysis and inhibition of lipid synthesis, improvement of cardiac output, and stimulation of autophagy and of renal glomerular filtration with water reabsorption. |
|
Formal Description Interaction-ID: 74924 |
|
| Comment | Glucagon is a multifaceted hormone with biological action beyond glucose metabolism. These activities include central regulation of energy intake, stimulation of brown fat thermogenesis, inhibition of gastric motility, modulation of lipid metabolism through activation of lipolysis and inhibition of lipid synthesis, improvement of cardiac output, and stimulation of autophagy and of renal glomerular filtration with water reabsorption. |
|
Formal Description Interaction-ID: 74925 |
|
| Comment | Glucagon is a multifaceted hormone with biological action beyond glucose metabolism. These activities include central regulation of energy intake, stimulation of brown fat thermogenesis, inhibition of gastric motility, modulation of lipid metabolism through activation of lipolysis and inhibition of lipid synthesis, improvement of cardiac output, and stimulation of autophagy and of renal glomerular filtration with water reabsorption. |
|
Formal Description Interaction-ID: 74926 |
|
| Comment | Glucagon is a multifaceted hormone with biological action beyond glucose metabolism. These activities include central regulation of energy intake, stimulation of brown fat thermogenesis, inhibition of gastric motility, modulation of lipid metabolism through activation of lipolysis and inhibition of lipid synthesis, improvement of cardiac output, and stimulation of autophagy and of renal glomerular filtration with water reabsorption. |
|
Formal Description Interaction-ID: 74927 |
|
| Comment | Glucagon is a multifaceted hormone with biological action beyond glucose metabolism. These activities include central regulation of energy intake, stimulation of brown fat thermogenesis, inhibition of gastric motility, modulation of lipid metabolism through activation of lipolysis and inhibition of lipid synthesis, improvement of cardiac output, and stimulation of autophagy and of renal glomerular filtration with water reabsorption. |
|
Formal Description Interaction-ID: 74928 |
|
| Comment | Glucagon is a multifaceted hormone with biological action beyond glucose metabolism. These activities include central regulation of energy intake, stimulation of brown fat thermogenesis, inhibition of gastric motility, modulation of lipid metabolism through activation of lipolysis and inhibition of lipid synthesis, improvement of cardiac output, and stimulation of autophagy and of renal glomerular filtration with water reabsorption. |
|
Formal Description Interaction-ID: 74929 |
|
| Comment | Glucagon is a multifaceted hormone with biological action beyond glucose metabolism. These activities include central regulation of energy intake, stimulation of brown fat thermogenesis, inhibition of gastric motility, modulation of lipid metabolism through activation of lipolysis and inhibition of lipid synthesis, improvement of cardiac output, and stimulation of autophagy and of renal glomerular filtration with water reabsorption. |
|
Formal Description Interaction-ID: 74930 |
|
| Comment | Proglucagon is tissue-specifically processed by the prohormone convertase enzymes. In the pancreas, proglucagon gets cleaved by the prohormone convertase 2 (PC2) into glucagon, glicentin-related pancreatic polypeptide (GRPP), the intervening peptide 1 (IP-1), and a major proglucagon fragment (MPGG). In the intestine and the brain, proglucagon gets cleaved by the prohormone convertase 1 (PC1) into glicentin, oxyntomodulin (OXM), the intervening peptide 2 (IP-2), or the glucagon-like peptides 1 and 2 (GLP-1 and GLP-2). |
|
Formal Description Interaction-ID: 74931 |
|
| Drugbank entries | Show/Hide entries for PCSK2 |
| Comment | Proglucagon is tissue-specifically processed by the prohormone convertase enzymes. In the pancreas, proglucagon gets cleaved by the prohormone convertase 2 (PC2) into glucagon, glicentin-related pancreatic polypeptide (GRPP), the intervening peptide 1 (IP-1), and a major proglucagon fragment (MPGG). In the intestine and the brain, proglucagon gets cleaved by the prohormone convertase 1 (PC1) into glicentin, oxyntomodulin (OXM), the intervening peptide 2 (IP-2), or the glucagon-like peptides 1 and 2 (GLP-1 and GLP-2). |
|
Formal Description Interaction-ID: 74934 |
|
| Drugbank entries | Show/Hide entries for PCSK1 |
| Comment | Proglucagon is tissue-specifically processed by the prohormone convertase enzymes. In the pancreas, proglucagon gets cleaved by the prohormone convertase 2 (PC2) into glucagon, glicentin-related pancreatic polypeptide (GRPP), the intervening peptide 1 (IP-1), and a major proglucagon fragment (MPGG). In the intestine and the brain, proglucagon gets cleaved by the prohormone convertase 1 (PC1) into glicentin, oxyntomodulin (OXM), the intervening peptide 2 (IP-2), or the glucagon-like peptides 1 and 2 (GLP-1 and GLP-2). |
|
Formal Description Interaction-ID: 74935 |
|
| Drugbank entries | Show/Hide entries for PCSK2 |
| Comment | Proglucagon is tissue-specifically processed by the prohormone convertase enzymes. In the pancreas, proglucagon gets cleaved by the prohormone convertase 2 (PC2) into glucagon, glicentin-related pancreatic polypeptide (GRPP), the intervening peptide 1 (IP-1), and a major proglucagon fragment (MPGG). In the intestine and the brain, proglucagon gets cleaved by the prohormone convertase 1 (PC1) into glicentin, oxyntomodulin (OXM), the intervening peptide 2 (IP-2), or the glucagon-like peptides 1 and 2 (GLP-1 and GLP-2). |
|
Formal Description Interaction-ID: 74936 |
gene/protein increases_quantity of gene/protein |
| Drugbank entries | Show/Hide entries for PCSK2 |
| Comment | Proglucagon is tissue-specifically processed by the prohormone convertase enzymes. In the pancreas, proglucagon gets cleaved by the prohormone convertase 2 (PC2) into glucagon, glicentin-related pancreatic polypeptide (GRPP), the intervening peptide 1 (IP-1), and a major proglucagon fragment (MPGG). In the intestine and the brain, proglucagon gets cleaved by the prohormone convertase 1 (PC1) into glicentin, oxyntomodulin (OXM), the intervening peptide 2 (IP-2), or the glucagon-like peptides 1 and 2 (GLP-1 and GLP-2). |
|
Formal Description Interaction-ID: 74937 |
|
| Drugbank entries | Show/Hide entries for PCSK2 |
| Comment | Proglucagon is tissue-specifically processed by the prohormone convertase enzymes. In the pancreas, proglucagon gets cleaved by the prohormone convertase 2 (PC2) into glucagon, glicentin-related pancreatic polypeptide (GRPP), the intervening peptide 1 (IP-1), and a major proglucagon fragment (MPGG). In the intestine and the brain, proglucagon gets cleaved by the prohormone convertase 1 (PC1) into glicentin, oxyntomodulin (OXM), the intervening peptide 2 (IP-2), or the glucagon-like peptides 1 and 2 (GLP-1 and GLP-2). |
|
Formal Description Interaction-ID: 74938 |
|
| Drugbank entries | Show/Hide entries for PCSK2 |
| Comment | Proglucagon is tissue-specifically processed by the prohormone convertase enzymes. In the pancreas, proglucagon gets cleaved by the prohormone convertase 2 (PC2) into glucagon, glicentin-related pancreatic polypeptide (GRPP), the intervening peptide 1 (IP-1), and a major proglucagon fragment (MPGG). In the intestine and the brain, proglucagon gets cleaved by the prohormone convertase 1 (PC1) into glicentin, oxyntomodulin (OXM), the intervening peptide 2 (IP-2), or the glucagon-like peptides 1 and 2 (GLP-1 and GLP-2). |
|
Formal Description Interaction-ID: 74939 |
|
| Drugbank entries | Show/Hide entries for PCSK1 |
| Comment | Proglucagon is tissue-specifically processed by the prohormone convertase enzymes. In the pancreas, proglucagon gets cleaved by the prohormone convertase 2 (PC2) into glucagon, glicentin-related pancreatic polypeptide (GRPP), the intervening peptide 1 (IP-1), and a major proglucagon fragment (MPGG). In the intestine and the brain, proglucagon gets cleaved by the prohormone convertase 1 (PC1) into glicentin, oxyntomodulin (OXM), the intervening peptide 2 (IP-2), or the glucagon-like peptides 1 and 2 (GLP-1 and GLP-2). |
|
Formal Description Interaction-ID: 74940 |
|
| Drugbank entries | Show/Hide entries for PCSK1 |
| Comment | Proglucagon is tissue-specifically processed by the prohormone convertase enzymes. In the pancreas, proglucagon gets cleaved by the prohormone convertase 2 (PC2) into glucagon, glicentin-related pancreatic polypeptide (GRPP), the intervening peptide 1 (IP-1), and a major proglucagon fragment (MPGG). In the intestine and the brain, proglucagon gets cleaved by the prohormone convertase 1 (PC1) into glicentin, oxyntomodulin (OXM), the intervening peptide 2 (IP-2), or the glucagon-like peptides 1 and 2 (GLP-1 and GLP-2). |
|
Formal Description Interaction-ID: 74941 |
|
| Drugbank entries | Show/Hide entries for PCSK1 |
| Comment | Proglucagon is tissue-specifically processed by the prohormone convertase enzymes. In the pancreas, proglucagon gets cleaved by the prohormone convertase 2 (PC2) into glucagon, glicentin-related pancreatic polypeptide (GRPP), the intervening peptide 1 (IP-1), and a major proglucagon fragment (MPGG). In the intestine and the brain, proglucagon gets cleaved by the prohormone convertase 1 (PC1) into glicentin, oxyntomodulin (OXM), the intervening peptide 2 (IP-2), or the glucagon-like peptides 1 and 2 (GLP-1 and GLP-2). |
|
Formal Description Interaction-ID: 74942 |
gene/protein increases_quantity of gene/protein |
| Drugbank entries | Show/Hide entries for PCSK1 |
| Comment | Proglucagon is tissue-specifically processed by the prohormone convertase enzymes. In the pancreas, proglucagon gets cleaved by the prohormone convertase 2 (PC2) into glucagon, glicentin-related pancreatic polypeptide (GRPP), the intervening peptide 1 (IP-1), and a major proglucagon fragment (MPGG). In the intestine and the brain, proglucagon gets cleaved by the prohormone convertase 1 (PC1) into glicentin, oxyntomodulin (OXM), the intervening peptide 2 (IP-2), or the glucagon-like peptides 1 and 2 (GLP-1 and GLP-2). |
|
Formal Description Interaction-ID: 74943 |
gene/protein increases_quantity of gene/protein |
| Drugbank entries | Show/Hide entries for PCSK1 |
| Comment | During the development of the pancreas, the differentiation of the alpha-cells is under tight control of a series of transcription factors, such as Prox1, Pax6, Arx, Nkx2.2, NeuroD1/Beta2, Isl1, Sox4, and Foxa2 (HNF-3beta). These transcription factors, especially Pax6, Arx, and Foxa2, are essential for alpha-cell development since mice lacking any of these factors do not produce functional alpha-cells. |
|
Formal Description Interaction-ID: 74945 |
|
| Comment | During the development of the pancreas, the differentiation of the alpha-cells is under tight control of a series of transcription factors, such as Prox1, Pax6, Arx, Nkx2.2, NeuroD1/Beta2, Isl1, Sox4, and Foxa2 (HNF-3beta). These transcription factors, especially Pax6, Arx, and Foxa2, are essential for alpha-cell development since mice lacking any of these factors do not produce functional alpha-cells. |
|
Formal Description Interaction-ID: 74946 |
|
| Comment | During the development of the pancreas, the differentiation of the alpha-cells is under tight control of a series of transcription factors, such as Prox1, Pax6, Arx, Nkx2.2, NeuroD1/Beta2, Isl1, Sox4, and Foxa2 (HNF-3beta). These transcription factors, especially Pax6, Arx, and Foxa2, are essential for alpha-cell development since mice lacking any of these factors do not produce functional alpha-cells. |
|
Formal Description Interaction-ID: 74948 |
|
| Comment | During the development of the pancreas, the differentiation of the alpha-cells is under tight control of a series of transcription factors, such as Prox1, Pax6, Arx, Nkx2.2, NeuroD1/Beta2, Isl1, Sox4, and Foxa2 (HNF-3beta). These transcription factors, especially Pax6, Arx, and Foxa2, are essential for alpha-cell development since mice lacking any of these factors do not produce functional alpha-cells. |
|
Formal Description Interaction-ID: 74949 |
|
| Comment | During the development of the pancreas, the differentiation of the alpha-cells is under tight control of a series of transcription factors, such as Prox1, Pax6, Arx, Nkx2.2, NeuroD1/Beta2, Isl1, Sox4, and Foxa2 (HNF-3beta). These transcription factors, especially Pax6, Arx, and Foxa2, are essential for alpha-cell development since mice lacking any of these factors do not produce functional alpha-cells. |
|
Formal Description Interaction-ID: 74950 |
|
| Comment | During the development of the pancreas, the differentiation of the alpha-cells is under tight control of a series of transcription factors, such as Prox1, Pax6, Arx, Nkx2.2, NeuroD1/Beta2, Isl1, Sox4, and Foxa2 (HNF-3beta). These transcription factors, especially Pax6, Arx, and Foxa2, are essential for alpha-cell development since mice lacking any of these factors do not produce functional alpha-cells. |
|
Formal Description Interaction-ID: 74952 |
|
| Comment | During the development of the pancreas, the differentiation of the alpha-cells is under tight control of a series of transcription factors, such as Prox1, Pax6, Arx, Nkx2.2, NeuroD1/Beta2, Isl1, Sox4, and Foxa2 (HNF-3beta). These transcription factors, especially Pax6, Arx, and Foxa2, are essential for alpha-cell development since mice lacking any of these factors do not produce functional alpha-cells. |
|
Formal Description Interaction-ID: 74953 |
|
| Comment | During the development of the pancreas, the differentiation of the alpha-cells is under tight control of a series of transcription factors, such as Prox1, Pax6, Arx, Nkx2.2, NeuroD1/Beta2, Isl1, Sox4, and Foxa2 (HNF-3beta). These transcription factors, especially Pax6, Arx, and Foxa2, are essential for alpha-cell development since mice lacking any of these factors do not produce functional alpha-cells. |
|
Formal Description Interaction-ID: 74954 |
|
| Comment | In pancreatic alpha-cells, Pax6 heterodimerizes with cMaf or MafB and stimulates Gcg expression by binding to the G1 element. |
|
Formal Description Interaction-ID: 74955 |
|
| Comment | In pancreatic alpha-cells, Pax6 heterodimerizes with cMaf or MafB and stimulates Gcg expression by binding to the G1 element. |
|
Formal Description Interaction-ID: 74958 |
|
| Drugbank entries | Show/Hide entries for MAF |
| Comment | In pancreatic alpha-cells, Pax6 heterodimerizes with cMaf or MafB and stimulates Gcg expression by binding to the G1 element. |
|
Formal Description Interaction-ID: 74959 |
complex/PPI MAF-PAX6 complex increases_expression of gene/protein |
| Comment | In pancreatic alpha-cells, Pax6 heterodimerizes with cMaf or MafB and stimulates Gcg expression by binding to the G1 element. |
|
Formal Description Interaction-ID: 74960 |
|
| Comment | In pancreatic alpha-cells, Pax6 heterodimerizes with cMaf or MafB and stimulates Gcg expression by binding to the G1 element. |
|
Formal Description Interaction-ID: 74961 |
|
| Comment | In pancreatic alpha-cells, Pax6 heterodimerizes with cMaf or MafB and stimulates Gcg expression by binding to the G1 element. |
|
Formal Description Interaction-ID: 74962 |
complex/PPI MAFB-PAX6 complex increases_expression of gene/protein |
| Comment | In pancreatic beta-cells, Pdx1, Pax4, and Nkx6.1 bind to G1 and inhibit Gcg expression by blocking the binding of the Pax6/Maf heterodimer to the G1 element. |
|
Formal Description Interaction-ID: 74963 |
|
| Comment | In pancreatic beta-cells, Pdx1, Pax4, and Nkx6.1 bind to G1 and inhibit Gcg expression by blocking the binding of the Pax6/Maf heterodimer to the G1 element. |
|
Formal Description Interaction-ID: 74964 |
|
| Comment | In pancreatic beta-cells, Pdx1, Pax4, and Nkx6.1 bind to G1 and inhibit Gcg expression by blocking the binding of the Pax6/Maf heterodimer to the G1 element. |
|
Formal Description Interaction-ID: 74965 |
|
| Comment | Transcription factors involved in regulating Gcg expression include Foxa1 (HNF-3alpha) and Foxa2 (HNF-3beta), which stimulate Gcg expression through binding to the G1 and G2 elements of the Gcg promoter. Mice lacking either Foxa1 or Foxa2 are severely hypoglycemic due to a 70 ‚Äď90% reduction in Gcg mRNA levels. Notably however, only mice lacking Foxa2 but not Foxa1 show a decrease in glucagon-positive alpha-cells. This implies that Foxa1 primarily affects Gcg expression through modulation of the Gcg promoter, whereas Foxa2 in addition to binding to the G1 and G2 elements also regulates alpha-cell differentiation. |
|
Formal Description Interaction-ID: 74971 |
|
| Comment | Transcription factors involved in regulating Gcg expression include Foxa1 (HNF-3alpha) and Foxa2 (HNF-3beta), which stimulate Gcg expression through binding to the G1 and G2 elements of the Gcg promoter. Mice lacking either Foxa1 or Foxa2 are severely hypoglycemic due to a 70 ‚Äď90% reduction in Gcg mRNA levels. Notably however, only mice lacking Foxa2 but not Foxa1 show a decrease in glucagon-positive alpha-cells. This implies that Foxa1 primarily affects Gcg expression through modulation of the Gcg promoter, whereas Foxa2 in addition to binding to the G1 and G2 elements also regulates alpha-cell differentiation. |
|
Formal Description Interaction-ID: 74972 |
|
| Comment | Expression of Gcg is additionally controlled by protein kinase A (PKA) and the exchange protein activated by cAMP signaling pathways (Epac), in response to increased levels of cAMP. |
|
Formal Description Interaction-ID: 74974 |
|
| Comment | Expression of Gcg is additionally controlled by protein kinase A (PKA) and the exchange protein activated by cAMP signaling pathways (Epac), in response to increased levels of cAMP. |
|
Formal Description Interaction-ID: 74976 |
|
| Comment | Expression of Gcg is additionally controlled by protein kinase A (PKA) and the exchange protein activated by cAMP signaling pathways (Epac), in response to increased levels of cAMP. |
|
Formal Description Interaction-ID: 74977 |
|
| Drugbank entries | Show/Hide entries for cAMP |
| Comment | Insulin inhibits Gcg expression in alpha-cells, while stimulating Gcg mRNA levels in the intestine. |
|
Formal Description Interaction-ID: 74978 |
|
| Comment | Insulin inhibits Gcg expression in alpha-cells, while stimulating Gcg mRNA levels in the intestine. |
|
Formal Description Interaction-ID: 74979 |
|
| Comment | Specific effectors of the Wnt signaling pathway promote Gcg expression in the intestine but not the pancreas. |
|
Formal Description Interaction-ID: 74980 |
|
| Comment | Glucagon is predominantly produced in the pancreatic alpha-cells, but small amounts are also synthesized in enteroendocrine L-cells of the intestinal mucosa, as well as in a subset of neurons in the nucleus tractus solitarius (NTS) of the brain stem. |
|
Formal Description Interaction-ID: 74987 |
|
| Comment | Glucagon is predominantly produced in the pancreatic alpha-cells, but small amounts are also synthesized in enteroendocrine L-cells of the intestinal mucosa, as well as in a subset of neurons in the nucleus tractus solitarius (NTS) of the brain stem. |
|
Formal Description Interaction-ID: 74994 |
|
| Comment | Glucagon is predominantly produced in the pancreatic alpha-cells, but small amounts are also synthesized in enteroendocrine L-cells of the intestinal mucosa, as well as in a subset of neurons in the nucleus tractus solitarius (NTS) of the brain stem. |
|
Formal Description Interaction-ID: 74997 |
|
| Comment | In contrast to the secretion of insulin, the release of glucagon is stimulated under conditions of hypoglycemia and subsequently decreases when blood glucose increases. |
|
Formal Description Interaction-ID: 74998 |
|
| Comment | In contrast to the secretion of insulin, the release of glucagon is stimulated under conditions of hypoglycemia and subsequently decreases when blood glucose increases. |
|
Formal Description Interaction-ID: 74999 |
|
| Comment | Glucose is taken up by the alpha-cells (and human beta-cells) through the glucose transporter 1 (GLUT1), which is encoded by the SLC2A1 gene. |
|
Formal Description Interaction-ID: 75000 |
gene/protein increases_activity of process |
| Comment | Both the alpha- and beta-cells contain ATP-sensitive potassium (K-ATP) channels, which translate variations in extracellular glucose concentrations to changes in membrane potential. The importance of K-ATP channels in regulating glucagon secretion is illustrated in mice that lack the sulfonylurea receptor (SUR1) and as such functional K-ATP channels. When fed ad libitum, SUR1 KO mice have normal glucagon levels and appropriately mobilize hepatic glycogen in response to exogenous glucagon administration. However, these mice demonstrate impaired glucagon secretion when hypoglycemic and hyperglycemia-induced inhibition of glucagon secretion is impaired in these SUR1 KO mice. |
|
Formal Description Interaction-ID: 75001 |
|
| Comment | Both the alpha- and beta-cells contain ATP-sensitive potassium (K-ATP) channels, which translate variations in extracellular glucose concentrations to changes in membrane potential. The importance of K-ATP channels in regulating glucagon secretion is illustrated in mice that lack the sulfonylurea receptor (SUR1) and as such functional K-ATP channels. When fed ad libitum, SUR1 KO mice have normal glucagon levels and appropriately mobilize hepatic glycogen in response to exogenous glucagon administration. However, these mice demonstrate impaired glucagon secretion when hypoglycemic and hyperglycemia-induced inhibition of glucagon secretion is impaired in these SUR1 KO mice. |
|
Formal Description Interaction-ID: 75005 |
|
| Comment | Both the alpha- and beta-cells contain ATP-sensitive potassium (K-ATP) channels, which translate variations in extracellular glucose concentrations to changes in membrane potential. The importance of K-ATP channels in regulating glucagon secretion is illustrated in mice that lack the sulfonylurea receptor (SUR1) and as such functional K-ATP channels. When fed ad libitum, SUR1 KO mice have normal glucagon levels and appropriately mobilize hepatic glycogen in response to exogenous glucagon administration. However, these mice demonstrate impaired glucagon secretion when hypoglycemic and hyperglycemia-induced inhibition of glucagon secretion is impaired in these SUR1 KO mice. |
|
Formal Description Interaction-ID: 75009 |
complex/PPI ATP-sensitive potassium channel complex affects_activity of process |
| Comment | Both the alpha- and beta-cells contain ATP-sensitive potassium (K-ATP) channels, which translate variations in extracellular glucose concentrations to changes in membrane potential. The importance of K-ATP channels in regulating glucagon secretion is illustrated in mice that lack the sulfonylurea receptor (SUR1) and as such functional K-ATP channels. When fed ad libitum, SUR1 KO mice have normal glucagon levels and appropriately mobilize hepatic glycogen in response to exogenous glucagon administration. However, these mice demonstrate impaired glucagon secretion when hypoglycemic and hyperglycemia-induced inhibition of glucagon secretion is impaired in these SUR1 KO mice. |
|
Formal Description Interaction-ID: 75012 |
|
| Drugbank entries | Show/Hide entries for ABCC8 |
| Comment | Both the alpha- and beta-cells contain ATP-sensitive potassium (K-ATP) channels, which translate variations in extracellular glucose concentrations to changes in membrane potential. The importance of K-ATP channels in regulating glucagon secretion is illustrated in mice that lack the sulfonylurea receptor (SUR1) and as such functional K-ATP channels. When fed ad libitum, SUR1 KO mice have normal glucagon levels and appropriately mobilize hepatic glycogen in response to exogenous glucagon administration. However, these mice demonstrate impaired glucagon secretion when hypoglycemic and hyperglycemia-induced inhibition of glucagon secretion is impaired in these SUR1 KO mice. |
|
Formal Description Interaction-ID: 75013 |
|
| Comment | Glucose is taken up by the alpha- and the beta-cells and is eventually converted by the mitochondria to ATP and water. Under conditions of high glucose concentrations, intracellular levels of ATP increase while levels of ADP decrease. In the beta-cells, this increase in ATP closes K-ATP channels with the result that positively charged potassium ions remain within the cell and depolarize the cell membrane to a point where voltage-dependent Ca2+ channels (VDCC) open. In the presence of cAMP elevating reagents (such as GLP-1 or GIP), the resulting Ca2+ influx triggers further Ca2+ release from the ER via cAMP-induced activation of Epac2. This increase in intracellular Ca2+ ultimately stimulates exocytosis of the insulin granules and release of insulin to the general circulation. Notably, the elevation in intracellular Ca2+ is correlated to an increased amount of secreted insulin. The elevated levels of Ca2+ are further an important prerequisite underlying insulin secretion by the incretin hormones GLP-1 and GIP. |
|
Formal Description Interaction-ID: 75014 |
|
| Comment | Glucose is taken up by the alpha- and the beta-cells and is eventually converted by the mitochondria to ATP and water. Under conditions of high glucose concentrations, intracellular levels of ATP increase while levels of ADP decrease. In the beta-cells, this increase in ATP closes K-ATP channels with the result that positively charged potassium ions remain within the cell and depolarize the cell membrane to a point where voltage-dependent Ca2+ channels (VDCC) open. In the presence of cAMP elevating reagents (such as GLP-1 or GIP), the resulting Ca2+ influx triggers further Ca2+ release from the ER via cAMP-induced activation of Epac2. This increase in intracellular Ca2+ ultimately stimulates exocytosis of the insulin granules and release of insulin to the general circulation. Notably, the elevation in intracellular Ca2+ is correlated to an increased amount of secreted insulin. The elevated levels of Ca2+ are further an important prerequisite underlying insulin secretion by the incretin hormones GLP-1 and GIP. |
|
Formal Description Interaction-ID: 75016 |
drug/chemical compound decreases_activity of complex/PPI ATP-sensitive potassium channel complex |
| Comment | Glucose is taken up by the alpha- and the beta-cells and is eventually converted by the mitochondria to ATP and water. Under conditions of high glucose concentrations, intracellular levels of ATP increase while levels of ADP decrease. In the beta-cells, this increase in ATP closes K-ATP channels with the result that positively charged potassium ions remain within the cell and depolarize the cell membrane to a point where voltage-dependent Ca2+ channels (VDCC) open. In the presence of cAMP elevating reagents (such as GLP-1 or GIP), the resulting Ca2+ influx triggers further Ca2+ release from the ER via cAMP-induced activation of Epac2. This increase in intracellular Ca2+ ultimately stimulates exocytosis of the insulin granules and release of insulin to the general circulation. Notably, the elevation in intracellular Ca2+ is correlated to an increased amount of secreted insulin. The elevated levels of Ca2+ are further an important prerequisite underlying insulin secretion by the incretin hormones GLP-1 and GIP. |
|
Formal Description Interaction-ID: 75017 |
drug/chemical compound increases_activity of phenotype high intracellular potassium level |
| Comment | Glucose is taken up by the alpha- and the beta-cells and is eventually converted by the mitochondria to ATP and water. Under conditions of high glucose concentrations, intracellular levels of ATP increase while levels of ADP decrease. In the beta-cells, this increase in ATP closes K-ATP channels with the result that positively charged potassium ions remain within the cell and depolarize the cell membrane to a point where voltage-dependent Ca2+ channels (VDCC) open. In the presence of cAMP elevating reagents (such as GLP-1 or GIP), the resulting Ca2+ influx triggers further Ca2+ release from the ER via cAMP-induced activation of Epac2. This increase in intracellular Ca2+ ultimately stimulates exocytosis of the insulin granules and release of insulin to the general circulation. Notably, the elevation in intracellular Ca2+ is correlated to an increased amount of secreted insulin. The elevated levels of Ca2+ are further an important prerequisite underlying insulin secretion by the incretin hormones GLP-1 and GIP. |
|
Formal Description Interaction-ID: 75106 |
phenotype high intracellular potassium level increases_activity of complex/PPI Voltage-gated calcium channel |
| Comment | Glucose is taken up by the alpha- and the beta-cells and is eventually converted by the mitochondria to ATP and water. Under conditions of high glucose concentrations, intracellular levels of ATP increase while levels of ADP decrease. In the beta-cells, this increase in ATP closes K-ATP channels with the result that positively charged potassium ions remain within the cell and depolarize the cell membrane to a point where voltage-dependent Ca2+ channels (VDCC) open. In the presence of cAMP elevating reagents (such as GLP-1 or GIP), the resulting Ca2+ influx triggers further Ca2+ release from the ER via cAMP-induced activation of Epac2. This increase in intracellular Ca2+ ultimately stimulates exocytosis of the insulin granules and release of insulin to the general circulation. Notably, the elevation in intracellular Ca2+ is correlated to an increased amount of secreted insulin. The elevated levels of Ca2+ are further an important prerequisite underlying insulin secretion by the incretin hormones GLP-1 and GIP. |
|
Formal Description Interaction-ID: 75107 |
phenotype high intracellular potassium level increases_activity of process |
| Comment | Glucose is taken up by the alpha- and the beta-cells and is eventually converted by the mitochondria to ATP and water. Under conditions of high glucose concentrations, intracellular levels of ATP increase while levels of ADP decrease. In the beta-cells, this increase in ATP closes K-ATP channels with the result that positively charged potassium ions remain within the cell and depolarize the cell membrane to a point where voltage-dependent Ca2+ channels (VDCC) open. In the presence of cAMP elevating reagents (such as GLP-1 or GIP), the resulting Ca2+ influx triggers further Ca2+ release from the ER via cAMP-induced activation of Epac2. This increase in intracellular Ca2+ ultimately stimulates exocytosis of the insulin granules and release of insulin to the general circulation. Notably, the elevation in intracellular Ca2+ is correlated to an increased amount of secreted insulin. The elevated levels of Ca2+ are further an important prerequisite underlying insulin secretion by the incretin hormones GLP-1 and GIP. |
|
Formal Description Interaction-ID: 75108 |
complex/PPI Voltage-gated calcium channel increases_activity of process |
| Comment | Glucose is taken up by the alpha- and the beta-cells and is eventually converted by the mitochondria to ATP and water. Under conditions of high glucose concentrations, intracellular levels of ATP increase while levels of ADP decrease. In the beta-cells, this increase in ATP closes K-ATP channels with the result that positively charged potassium ions remain within the cell and depolarize the cell membrane to a point where voltage-dependent Ca2+ channels (VDCC) open. In the presence of cAMP elevating reagents (such as GLP-1 or GIP), the resulting Ca2+ influx triggers further Ca2+ release from the ER via cAMP-induced activation of Epac2. This increase in intracellular Ca2+ ultimately stimulates exocytosis of the insulin granules and release of insulin to the general circulation. Notably, the elevation in intracellular Ca2+ is correlated to an increased amount of secreted insulin. The elevated levels of Ca2+ are further an important prerequisite underlying insulin secretion by the incretin hormones GLP-1 and GIP. |
|
Formal Description Interaction-ID: 75109 |
process increases_activity of |
| Comment | Glucose is taken up by the alpha- and the beta-cells and is eventually converted by the mitochondria to ATP and water. Under conditions of high glucose concentrations, intracellular levels of ATP increase while levels of ADP decrease. In the beta-cells, this increase in ATP closes K-ATP channels with the result that positively charged potassium ions remain within the cell and depolarize the cell membrane to a point where voltage-dependent Ca2+ channels (VDCC) open. In the presence of cAMP elevating reagents (such as GLP-1 or GIP), the resulting Ca2+ influx triggers further Ca2+ release from the ER via cAMP-induced activation of Epac2. This increase in intracellular Ca2+ ultimately stimulates exocytosis of the insulin granules and release of insulin to the general circulation. Notably, the elevation in intracellular Ca2+ is correlated to an increased amount of secreted insulin. The elevated levels of Ca2+ are further an important prerequisite underlying insulin secretion by the incretin hormones GLP-1 and GIP. |
|
Formal Description Interaction-ID: 75110 |
gene/protein increases_quantity of drug/chemical compound |
| Drugbank entries | Show/Hide entries for cAMP |
| Comment | Glucose is taken up by the alpha- and the beta-cells and is eventually converted by the mitochondria to ATP and water. Under conditions of high glucose concentrations, intracellular levels of ATP increase while levels of ADP decrease. In the beta-cells, this increase in ATP closes K-ATP channels with the result that positively charged potassium ions remain within the cell and depolarize the cell membrane to a point where voltage-dependent Ca2+ channels (VDCC) open. In the presence of cAMP elevating reagents (such as GLP-1 or GIP), the resulting Ca2+ influx triggers further Ca2+ release from the ER via cAMP-induced activation of Epac2. This increase in intracellular Ca2+ ultimately stimulates exocytosis of the insulin granules and release of insulin to the general circulation. Notably, the elevation in intracellular Ca2+ is correlated to an increased amount of secreted insulin. The elevated levels of Ca2+ are further an important prerequisite underlying insulin secretion by the incretin hormones GLP-1 and GIP. |
|
Formal Description Interaction-ID: 75111 |
|
| Drugbank entries | Show/Hide entries for cAMP |
| Comment | Glucose is taken up by the alpha- and the beta-cells and is eventually converted by the mitochondria to ATP and water. Under conditions of high glucose concentrations, intracellular levels of ATP increase while levels of ADP decrease. In the beta-cells, this increase in ATP closes K-ATP channels with the result that positively charged potassium ions remain within the cell and depolarize the cell membrane to a point where voltage-dependent Ca2+ channels (VDCC) open. In the presence of cAMP elevating reagents (such as GLP-1 or GIP), the resulting Ca2+ influx triggers further Ca2+ release from the ER via cAMP-induced activation of Epac2. This increase in intracellular Ca2+ ultimately stimulates exocytosis of the insulin granules and release of insulin to the general circulation. Notably, the elevation in intracellular Ca2+ is correlated to an increased amount of secreted insulin. The elevated levels of Ca2+ are further an important prerequisite underlying insulin secretion by the incretin hormones GLP-1 and GIP. |
|
Formal Description Interaction-ID: 75112 |
|
| Drugbank entries | Show/Hide entries for cAMP |
| Comment | Glucose is taken up by the alpha- and the beta-cells and is eventually converted by the mitochondria to ATP and water. Under conditions of high glucose concentrations, intracellular levels of ATP increase while levels of ADP decrease. In the beta-cells, this increase in ATP closes K-ATP channels with the result that positively charged potassium ions remain within the cell and depolarize the cell membrane to a point where voltage-dependent Ca2+ channels (VDCC) open. In the presence of cAMP elevating reagents (such as GLP-1 or GIP), the resulting Ca2+ influx triggers further Ca2+ release from the ER via cAMP-induced activation of Epac2. This increase in intracellular Ca2+ ultimately stimulates exocytosis of the insulin granules and release of insulin to the general circulation. Notably, the elevation in intracellular Ca2+ is correlated to an increased amount of secreted insulin. The elevated levels of Ca2+ are further an important prerequisite underlying insulin secretion by the incretin hormones GLP-1 and GIP. |
|
Formal Description Interaction-ID: 75113 |
gene/protein increases_activity of |
| Comment | Glucose is taken up by the alpha- and the beta-cells and is eventually converted by the mitochondria to ATP and water. Under conditions of high glucose concentrations, intracellular levels of ATP increase while levels of ADP decrease. In the beta-cells, this increase in ATP closes K-ATP channels with the result that positively charged potassium ions remain within the cell and depolarize the cell membrane to a point where voltage-dependent Ca2+ channels (VDCC) open. In the presence of cAMP elevating reagents (such as GLP-1 or GIP), the resulting Ca2+ influx triggers further Ca2+ release from the ER via cAMP-induced activation of Epac2. This increase in intracellular Ca2+ ultimately stimulates exocytosis of the insulin granules and release of insulin to the general circulation. Notably, the elevation in intracellular Ca2+ is correlated to an increased amount of secreted insulin. The elevated levels of Ca2+ are further an important prerequisite underlying insulin secretion by the incretin hormones GLP-1 and GIP. |
|
Formal Description Interaction-ID: 75114 |
process increases_activity of phenotype increased intracellular calcium level |
| Comment | Glucose is taken up by the alpha- and the beta-cells and is eventually converted by the mitochondria to ATP and water. Under conditions of high glucose concentrations, intracellular levels of ATP increase while levels of ADP decrease. In the beta-cells, this increase in ATP closes K-ATP channels with the result that positively charged potassium ions remain within the cell and depolarize the cell membrane to a point where voltage-dependent Ca2+ channels (VDCC) open. In the presence of cAMP elevating reagents (such as GLP-1 or GIP), the resulting Ca2+ influx triggers further Ca2+ release from the ER via cAMP-induced activation of Epac2. This increase in intracellular Ca2+ ultimately stimulates exocytosis of the insulin granules and release of insulin to the general circulation. Notably, the elevation in intracellular Ca2+ is correlated to an increased amount of secreted insulin. The elevated levels of Ca2+ are further an important prerequisite underlying insulin secretion by the incretin hormones GLP-1 and GIP. |
|
Formal Description Interaction-ID: 75115 |
increases_activity of phenotype increased intracellular calcium level |
| Comment | Glucose is taken up by the alpha- and the beta-cells and is eventually converted by the mitochondria to ATP and water. Under conditions of high glucose concentrations, intracellular levels of ATP increase while levels of ADP decrease. In the beta-cells, this increase in ATP closes K-ATP channels with the result that positively charged potassium ions remain within the cell and depolarize the cell membrane to a point where voltage-dependent Ca2+ channels (VDCC) open. In the presence of cAMP elevating reagents (such as GLP-1 or GIP), the resulting Ca2+ influx triggers further Ca2+ release from the ER via cAMP-induced activation of Epac2. This increase in intracellular Ca2+ ultimately stimulates exocytosis of the insulin granules and release of insulin to the general circulation. Notably, the elevation in intracellular Ca2+ is correlated to an increased amount of secreted insulin. The elevated levels of Ca2+ are further an important prerequisite underlying insulin secretion by the incretin hormones GLP-1 and GIP. |
|
Formal Description Interaction-ID: 75116 |
phenotype increased intracellular calcium level increases_activity of phenotype insulin granule exocytosis |
| Comment | Similar to the beta-cells, the alpha-cells comprise a series of ion channels that modulate the membrane potential in a glucose-dependent manner. In contrast to the beta-cells, however, the alpha-cells require a lower intracellular ATP concentration to inhibit the K-ATP channels, and thus to open the voltage-dependent Ca2+ channels. As a result, under conditions of high glucose concentration, the K-ATP channels depolarize the membrane potential to a point where Na+ and Ca2+ channels are inactive. The resulting lack of Ca2+ and Na+ influx prevents glucagon exocytosis and inhibits the release of glucagon to the general circulation. |
|
Formal Description Interaction-ID: 75117 |
phenotype decreases_activity of complex/PPI Voltage-gated sodium channel |
| Comment | Similar to the beta-cells, the alpha-cells comprise a series of ion channels that modulate the membrane potential in a glucose-dependent manner. In contrast to the beta-cells, however, the alpha-cells require a lower intracellular ATP concentration to inhibit the K-ATP channels, and thus to open the voltage-dependent Ca2+ channels. As a result, under conditions of high glucose concentration, the K-ATP channels depolarize the membrane potential to a point where Na+ and Ca2+ channels are inactive. The resulting lack of Ca2+ and Na+ influx prevents glucagon exocytosis and inhibits the release of glucagon to the general circulation. |
|
Formal Description Interaction-ID: 75118 |
phenotype decreases_activity of complex/PPI Voltage-gated calcium channel |
| Comment | Similar to the beta-cells, the alpha-cells comprise a series of ion channels that modulate the membrane potential in a glucose-dependent manner. In contrast to the beta-cells, however, the alpha-cells require a lower intracellular ATP concentration to inhibit the K-ATP channels, and thus to open the voltage-dependent Ca2+ channels. As a result, under conditions of high glucose concentration, the K-ATP channels depolarize the membrane potential to a point where Na+ and Ca2+ channels are inactive. The resulting lack of Ca2+ and Na+ influx prevents glucagon exocytosis and inhibits the release of glucagon to the general circulation. |
|
Formal Description Interaction-ID: 75119 |
complex/PPI Voltage-gated calcium channel increases_activity of process glucagon granule exocytosis |
| Comment | Similar to the beta-cells, the alpha-cells comprise a series of ion channels that modulate the membrane potential in a glucose-dependent manner. In contrast to the beta-cells, however, the alpha-cells require a lower intracellular ATP concentration to inhibit the K-ATP channels, and thus to open the voltage-dependent Ca2+ channels. As a result, under conditions of high glucose concentration, the K-ATP channels depolarize the membrane potential to a point where Na+ and Ca2+ channels are inactive. The resulting lack of Ca2+ and Na+ influx prevents glucagon exocytosis and inhibits the release of glucagon to the general circulation. |
|
Formal Description Interaction-ID: 75120 |
complex/PPI Voltage-gated sodium channel increases_activity of process glucagon granule exocytosis |
| Comment | When blood glucose concentration is low, K-ATP channels of the beta-cells are open, and this results in a membrane potential that leads to closing of the VDCC, and subsequently prevents Ca2+ influx and insulin exocytosis. In contrast, the K-ATP channels of the alpha-cells are closed under conditions of low glucose (and low ATP levels) and the K-ATP channels therefore impose a membrane potential that leads to opening of Na+ and Ca2+ channels. The subsequent Ca2+ and Na+ influx triggers the release of glucagon through exocytosis of glucagon granules. |
|
Formal Description Interaction-ID: 75121 |
phenotype increases_activity of complex/PPI ATP-sensitive potassium channel complex |
| Comment | When blood glucose concentration is low, K-ATP channels of the beta-cells are open, and this results in a membrane potential that leads to closing of the VDCC, and subsequently prevents Ca2+ influx and insulin exocytosis. In contrast, the K-ATP channels of the alpha-cells are closed under conditions of low glucose (and low ATP levels) and the K-ATP channels therefore impose a membrane potential that leads to opening of Na+ and Ca2+ channels. The subsequent Ca2+ and Na+ influx triggers the release of glucagon through exocytosis of glucagon granules. |
|
Formal Description Interaction-ID: 75122 |
phenotype decreases_activity of complex/PPI Voltage-gated calcium channel |
| Comment | When blood glucose concentration is low, K-ATP channels of the beta-cells are open, and this results in a membrane potential that leads to closing of the VDCC, and subsequently prevents Ca2+ influx and insulin exocytosis. In contrast, the K-ATP channels of the alpha-cells are closed under conditions of low glucose (and low ATP levels) and the K-ATP channels therefore impose a membrane potential that leads to opening of Na+ and Ca2+ channels. The subsequent Ca2+ and Na+ influx triggers the release of glucagon through exocytosis of glucagon granules. |
|
Formal Description Interaction-ID: 75123 |
phenotype decreases_activity of complex/PPI ATP-sensitive potassium channel complex |
| Comment | When blood glucose concentration is low, K-ATP channels of the beta-cells are open, and this results in a membrane potential that leads to closing of the VDCC, and subsequently prevents Ca2+ influx and insulin exocytosis. In contrast, the K-ATP channels of the alpha-cells are closed under conditions of low glucose (and low ATP levels) and the K-ATP channels therefore impose a membrane potential that leads to opening of Na+ and Ca2+ channels. The subsequent Ca2+ and Na+ influx triggers the release of glucagon through exocytosis of glucagon granules. |
|
Formal Description Interaction-ID: 75124 |
phenotype increases_activity of complex/PPI Voltage-gated sodium channel |
| Comment | When blood glucose concentration is low, K-ATP channels of the beta-cells are open, and this results in a membrane potential that leads to closing of the VDCC, and subsequently prevents Ca2+ influx and insulin exocytosis. In contrast, the K-ATP channels of the alpha-cells are closed under conditions of low glucose (and low ATP levels) and the K-ATP channels therefore impose a membrane potential that leads to opening of Na+ and Ca2+ channels. The subsequent Ca2+ and Na+ influx triggers the release of glucagon through exocytosis of glucagon granules. |
|
Formal Description Interaction-ID: 75125 |
phenotype increases_activity of complex/PPI Voltage-gated calcium channel |
| Comment | In the alpha-cells, the Ca2+ influx is mediated through a specific set of voltage-dependent Ca2+ channels. Depending on the species, these channels can be L-, N-, T-, or R-type Ca2+ channels, which differ from each other in the membrane potential where they open and induce Ca2+ influx. Accordingly, the L- and N-type Ca2+ channels open at a rather high voltage of around -40 to -30 mV, whereas the T-type channels open at -60 mV. |
|
Formal Description Interaction-ID: 75126 |
complex/PPI Voltage-gated calcium channel, L-type increases_activity of process |
| Comment | In the alpha-cells, the Ca2+ influx is mediated through a specific set of voltage-dependent Ca2+ channels. Depending on the species, these channels can be L-, N-, T-, or R-type Ca2+ channels, which differ from each other in the membrane potential where they open and induce Ca2+ influx. Accordingly, the L- and N-type Ca2+ channels open at a rather high voltage of around -40 to -30 mV, whereas the T-type channels open at -60 mV. |
|
Formal Description Interaction-ID: 75127 |
complex/PPI Voltage-gated calcium channel, N-type increases_activity of process |
| Comment | In the alpha-cells, the Ca2+ influx is mediated through a specific set of voltage-dependent Ca2+ channels. Depending on the species, these channels can be L-, N-, T-, or R-type Ca2+ channels, which differ from each other in the membrane potential where they open and induce Ca2+ influx. Accordingly, the L- and N-type Ca2+ channels open at a rather high voltage of around -40 to -30 mV, whereas the T-type channels open at -60 mV. |
|
Formal Description Interaction-ID: 75128 |
complex/PPI Voltage-gated calcium channel, T-type increases_activity of process |
| Comment | In the alpha-cells, the Ca2+ influx is mediated through a specific set of voltage-dependent Ca2+ channels. Depending on the species, these channels can be L-, N-, T-, or R-type Ca2+ channels, which differ from each other in the membrane potential where they open and induce Ca2+ influx. Accordingly, the L- and N-type Ca2+ channels open at a rather high voltage of around -40 to -30 mV, whereas the T-type channels open at -60 mV. |
|
Formal Description Interaction-ID: 75129 |
complex/PPI Voltage-gated calcium channel, R-type increases_activity of process |
| Comment | In 1964 several studies reported that the glucose-induced increase in plasma insulin is much greater when it is orally administered, compared with peripheral administration. This effect henceforth became known as the incretin effect. Substantial research was directed towards the identification of the intestinal factor(s) underlying the incretin effect, and it was in 1973 when John Dupré and John Brown identified the first incretin hormone as the gastric-inhibitory polypeptide, which nowadays is better known as the glucose-dependent insulinotropic polypeptide (GIP). The first evidence that GIP is an incretin hormone originates from the observation that intravenously administered GIP increases plasma insulin levels in healthy human volunteers. |
|
Formal Description Interaction-ID: 75130 |
|
| Comment | In 1964 several studies reported that the glucose-induced increase in plasma insulin is much greater when it is orally administered, compared with peripheral administration. This effect henceforth became known as the incretin effect. Substantial research was directed towards the identification of the intestinal factor(s) underlying the incretin effect, and it was in 1973 when John Dupré and John Brown identified the first incretin hormone as the gastric-inhibitory polypeptide, which nowadays is better known as the glucose-dependent insulinotropic polypeptide (GIP). The first evidence that GIP is an incretin hormone originates from the observation that intravenously administered GIP increases plasma insulin levels in healthy human volunteers. |
|
Formal Description Interaction-ID: 75131 |
|
| Comment | GIP was shown to directly act on the pancreas to enhance glucose-stimulated insulin secretion. |
|
Formal Description Interaction-ID: 75132 |
gene/protein increases_activity of |
| Comment | Identification and analysis of proglucagon led to the identification of GLP-1 and its classification as the second incretin hormone. |
|
Formal Description Interaction-ID: 75133 |
|
| Comment | Biologically active GLP-1 comprises either a 36-amino acid COOH-terminal amide or a 37-amino acid COOH-terminal acid, and promotes its biological action through activation of a specific cognate GLP-1 receptor (GLP-1R). This receptor is a seven transmembrane G protein-coupled receptor predominantly expressed in the pancreas, adipose tissue, kidney, heart, muscle, and the CNS. |
|
Formal Description Interaction-ID: 75134 |
|
| Drugbank entries | Show/Hide entries for GLP1R |
| Comment | As a classical incretin, the most prominent role of GLP-1 is to lower circulating levels of blood glucose through stimulation of insulin secretion, while simultaneously inhibiting the release of glucagon. The effect of GLP-1 to inhibit glucagon release seems to be mediated by endocrine mechanisms (e.g., via stimulation of insulin release) rather than by direct effects on the alpha-cells since GLP-1 treatment of isolated rat alpha-cells enhances rather than inhibits glucagon release. Under in vivo conditions, however, GLP-1 inhibits glucagon secretion and inhibition of GLP-1 action through infusion of the GLP-1 antagonist exendin(9 ‚Äď39)amide increases glucagon secretion in humans. |
|
Formal Description Interaction-ID: 75135 |
|
| Comment | In pancreatic beta-cells, binding of GLP-1 to its receptor leads to activation of adenylate cyclase (AC) and a subsequent increase in cAMP. The increase in cAMP leads to activation of pathways that involve PKA and cAMP-regulated guanine nucleotide exchange factors (cAMPGEFs), also known as Epac. The GLP-1-mediated increase in cAMP is crucial for both the acute and chronic insulinotropic effect of GLP-1, and enhanced cAMP hydrolysis, through overexpression of the cyclic nucleotide phosphodiesterase 3B (PDE3B), diminishes GLP-1 induced insulin secretion. |
|
Formal Description Interaction-ID: 75136 |
|
| Drugbank entries | Show/Hide entries for GLP1R |
| Comment | In pancreatic beta-cells, binding of GLP-1 to its receptor leads to activation of adenylate cyclase (AC) and a subsequent increase in cAMP. The increase in cAMP leads to activation of pathways that involve PKA and cAMP-regulated guanine nucleotide exchange factors (cAMPGEFs), also known as Epac. The GLP-1-mediated increase in cAMP is crucial for both the acute and chronic insulinotropic effect of GLP-1, and enhanced cAMP hydrolysis, through overexpression of the cyclic nucleotide phosphodiesterase 3B (PDE3B), diminishes GLP-1 induced insulin secretion. |
|
Formal Description Interaction-ID: 75137 |
|
| Drugbank entries | Show/Hide entries for cAMP |
| Comment | In pancreatic beta-cells, binding of GLP-1 to its receptor leads to activation of adenylate cyclase (AC) and a subsequent increase in cAMP. The increase in cAMP leads to activation of pathways that involve PKA and cAMP-regulated guanine nucleotide exchange factors (cAMPGEFs), also known as Epac. The GLP-1-mediated increase in cAMP is crucial for both the acute and chronic insulinotropic effect of GLP-1, and enhanced cAMP hydrolysis, through overexpression of the cyclic nucleotide phosphodiesterase 3B (PDE3B), diminishes GLP-1 induced insulin secretion. |
|
Formal Description Interaction-ID: 75138 |
gene/protein Adenylate cyclase increases_activity of complex/PPI Protein kinase A |
| Comment | In pancreatic beta-cells, binding of GLP-1 to its receptor leads to activation of adenylate cyclase (AC) and a subsequent increase in cAMP. The increase in cAMP leads to activation of pathways that involve PKA and cAMP-regulated guanine nucleotide exchange factors (cAMPGEFs), also known as Epac. The GLP-1-mediated increase in cAMP is crucial for both the acute and chronic insulinotropic effect of GLP-1, and enhanced cAMP hydrolysis, through overexpression of the cyclic nucleotide phosphodiesterase 3B (PDE3B), diminishes GLP-1 induced insulin secretion. |
|
Formal Description Interaction-ID: 75139 |
|
| Comment | An important component implicated in the chronic insulinotropic effect of GLP-1 is the pancreatic duodenal homeobox-1 protein (Pdx-1; also called islet duodenal homeobox-1, Idx-1). Pdx-1 is a transcription factor involved in pancreatic development and, when mutated, leads to MODY-type 4 diabetes. Ligand-induced activation of GLP-1R subsequently leads to activation of PKA through increased levels of cAMP, which increases Pdx-1 mRNA and translocation to the nucleus. This stimulates binding of Pdx-1 to the insulin gene promoter and its activation. |
|
Formal Description Interaction-ID: 75140 |
|
| Comment | An important component implicated in the chronic insulinotropic effect of GLP-1 is the pancreatic duodenal homeobox-1 protein (Pdx-1; also called islet duodenal homeobox-1, Idx-1). Pdx-1 is a transcription factor involved in pancreatic development and, when mutated, leads to MODY-type 4 diabetes. Ligand-induced activation of GLP-1R subsequently leads to activation of PKA through increased levels of cAMP, which increases Pdx-1 mRNA and translocation to the nucleus. This stimulates binding of Pdx-1 to the insulin gene promoter and its activation. |
|
Formal Description Interaction-ID: 75141 |
|
| Drugbank entries | Show/Hide entries for INS |
| Comment | Activated PKA phosphorylates the beta2 subunit of the L-type voltage-dependent Ca2+ channels and phosphorylates the Kir 6.2 and SUR1 subunits of K-ATP channels. |
|
Formal Description Interaction-ID: 75142 |
|
| Drugbank entries | Show/Hide entries for CACNB2 |
| Comment | Activated PKA phosphorylates the beta2 subunit of the L-type voltage-dependent Ca2+ channels and phosphorylates the Kir 6.2 and SUR1 subunits of K-ATP channels. |
|
Formal Description Interaction-ID: 75143 |
|
| Drugbank entries | Show/Hide entries for KCNJ11 |
| Comment | Activated PKA phosphorylates the beta2 subunit of the L-type voltage-dependent Ca2+ channels and phosphorylates the Kir 6.2 and SUR1 subunits of K-ATP channels. |
|
Formal Description Interaction-ID: 75144 |
|
| Drugbank entries | Show/Hide entries for ABCC8 |
| Comment | Enhanced activity of PKA leads to closure of the K-ATP channels which depolarizes beta-cells to open voltage-gated Ca2+ channels where increased Ca 2+ influx eventually results in exocytosis of insulin granules. |
|
Formal Description Interaction-ID: 75145 |
complex/PPI Protein kinase A decreases_activity of complex/PPI ATP-sensitive potassium channel complex |
| Comment | Together with phosphatidylinositol 3-kinase (PI3K), activated PKA also inhibits rectifying K+ (Kv)-channels, which leads to enhanced Ca2+ influx due to inhibition of Kv-channel induced islet cell repolarization and thus prolonged opening of VDCC. |
|
Formal Description Interaction-ID: 75146 |
complex/PPI Protein kinase A decreases_activity of complex/PPI Voltage-gated potassium channel Kv |
| Comment | Together with phosphatidylinositol 3-kinase (PI3K), activated PKA also inhibits rectifying K+ (Kv)-channels, which leads to enhanced Ca2+ influx due to inhibition of Kv-channel induced islet cell repolarization and thus prolonged opening of VDCC. |
|
Formal Description Interaction-ID: 75147 |
complex/PPI Phosphatidylinositol 3-kinase decreases_activity of complex/PPI Voltage-gated potassium channel Kv |
| Comment | Together with phosphatidylinositol 3-kinase (PI3K), activated PKA also inhibits rectifying K+ (Kv)-channels, which leads to enhanced Ca2+ influx due to inhibition of Kv-channel induced islet cell repolarization and thus prolonged opening of VDCC. |
|
Formal Description Interaction-ID: 75148 |
complex/PPI Voltage-gated potassium channel Kv increases_activity of process |
| Comment | There are two isoforms of Epac (Epac1 and Epac2), and they are both expressed in the pancreas. |
|
Formal Description Interaction-ID: 75149 |
|
| Comment | There are two isoforms of Epac (Epac1 and Epac2), and they are both expressed in the pancreas. |
|
Formal Description Interaction-ID: 75150 |
|
| Comment | GLP-1-induced increase in cAMP leads to activation of Epac2, and subsequent opening of RYR Ca2+ channels in the ER. This provides an enhanced intracellular elevation in Ca2+ and a potentiation in insulin exocytosis. |
|
Formal Description Interaction-ID: 75151 |
gene/protein increases_activity of complex/PPI Ryanodine receptor calcium channel |
| Comment | Insulin inhibits its own secretion through a negative-feedback loop that enhances cAMP hydrolysis through upregulation of PDE3B. |
|
Formal Description Interaction-ID: 75152 |
|
| Comment | Insulin inhibits its own secretion through a negative-feedback loop that enhances cAMP hydrolysis through upregulation of PDE3B. |
|
Formal Description Interaction-ID: 75153 |
|
| Drugbank entries | Show/Hide entries for cAMP |
| Comment | Insulin inhibits its own secretion through a negative-feedback loop that enhances cAMP hydrolysis through upregulation of PDE3B. |
|
Formal Description Interaction-ID: 75154 |
|
| Drugbank entries | Show/Hide entries for PDE3B |
| Comment | Insulin inhibits its own secretion through a negative-feedback loop that enhances cAMP hydrolysis through upregulation of PDE3B. |
|
Formal Description Interaction-ID: 75155 |
|
| Drugbank entries | Show/Hide entries for PDE3B or cAMP |
| Comment | GLP-1 has cardioprotective effects on the heart, increases insulin sensitivity in skeletal muscle, decreases hepatic gluconeogenesis, and promotes body weight loss through centrally regulated inhibition of food intake and a delay in gastric emptying. |
|
Formal Description Interaction-ID: 75156 |
|
| Comment | GLP-1 has cardioprotective effects on the heart, increases insulin sensitivity in skeletal muscle, decreases hepatic gluconeogenesis, and promotes body weight loss through centrally regulated inhibition of food intake and a delay in gastric emptying. |
|
Formal Description Interaction-ID: 75157 |
|
| Comment | GLP-1 has cardioprotective effects on the heart, increases insulin sensitivity in skeletal muscle, decreases hepatic gluconeogenesis, and promotes body weight loss through centrally regulated inhibition of food intake and a delay in gastric emptying. |
|
Formal Description Interaction-ID: 75158 |
|
| Comment | GLP-1 has cardioprotective effects on the heart, increases insulin sensitivity in skeletal muscle, decreases hepatic gluconeogenesis, and promotes body weight loss through centrally regulated inhibition of food intake and a delay in gastric emptying. |
|
Formal Description Interaction-ID: 75159 |
|
| Comment | The degradation of GLP-1 is achieved by the dipeptidylpeptidase 4 (DPP-IV), which cleaves native GLP-1 at the NH2-terminal alanine 2 residue, resulting in the generation of the inactive GLP-1 9-36amide or GLP-1 9 ‚Äď37. |
|
Formal Description Interaction-ID: 75160 |
|
| Drugbank entries | Show/Hide entries for DPP4 |
| Comment | The degradation of GLP-1 is achieved by the dipeptidylpeptidase 4 (DPP-IV), which cleaves native GLP-1 at the NH2-terminal alanine 2 residue, resulting in the generation of the inactive GLP-1 9-36amide or GLP-1 9 ‚Äď37. |
|
Formal Description Interaction-ID: 75163 |
|
| Drugbank entries | Show/Hide entries for DPP4 |
| Comment | The degradation of GLP-1 is achieved by the dipeptidylpeptidase 4 (DPP-IV), which cleaves native GLP-1 at the NH2-terminal alanine 2 residue, resulting in the generation of the inactive GLP-1 9-36amide or GLP-1 9 ‚Äď37. |
|
Formal Description Interaction-ID: 75165 |
|
| Drugbank entries | Show/Hide entries for DPP4 |
| Comment | The glucose-dependent insulinotropic polypeptide (GIP) is a 42-amino acid protein secreted from K cells in the mucosa of the duodenum and jejunum. GIP was originally identified based on its ability to inhibit gastric acid secretion, an observation that initially classified this hormone as the gastric inhibitory polypeptide (GIP). Based on its ability to stimulate insulin secretion in a glucose-dependent manner, GIP was renamed glucose-dependent insulinotropic polypeptide. |
|
Formal Description Interaction-ID: 75167 |
gene/protein is_expressed_in tissue/cell line enteroendocrine K-cell |
| Comment | The glucose-dependent insulinotropic polypeptide (GIP) is a 42-amino acid protein secreted from K cells in the mucosa of the duodenum and jejunum. GIP was originally identified based on its ability to inhibit gastric acid secretion, an observation that initially classified this hormone as the gastric inhibitory polypeptide (GIP). Based on its ability to stimulate insulin secretion in a glucose-dependent manner, GIP was renamed glucose-dependent insulinotropic polypeptide. |
|
Formal Description Interaction-ID: 75170 |
|
| Comment | Similar to GLP-1, GIP also signals through a specific cognate G protein-coupled surface receptor. Ligand induced activation of the GIP receptor (GIPR) leads to activation of adenylate cyclase and an increase in intracellular cAMP. |
|
Formal Description Interaction-ID: 75171 |
|
| Comment | Similar to GLP-1, GIP also signals through a specific cognate G protein-coupled surface receptor. Ligand induced activation of the GIP receptor (GIPR) leads to activation of adenylate cyclase and an increase in intracellular cAMP. |
|
Formal Description Interaction-ID: 75172 |
|
| Comment | Despite similar mechanism in action, the insulinotropic effect of GIP and GLP-1 is additive in healthy humans but notably different in type 2 diabetes. When administered in physiological doses, patients with type 2 diabetes show an impaired insulinotropic response to GIP, much less so for GLP-1. |
|
Formal Description Interaction-ID: 75173 |
|
| Comment | As an incretin, GIP enhances glucose-stimulated insulin secretion and therefore indirectly modulates glucagon secretion via this insulinotropic effect. |
|
Formal Description Interaction-ID: 75181 |
|
| Comment | In healthy humans, GIP suppresses glucagon secretion under conditions of hyperglycemia but increases glucagon secretion during hypoglycemia or euglycemia. Similar results are reported in patients with type 2 diabetes, in which GIP counteracts insulin-induced hypoglycemia and increases postprandial glucagon levels, implying that it is a bifunctional regulator of islet hormone secretion. |
|
Formal Description Interaction-ID: 75182 |
gene/protein decreases_activity of process |
| Comment | In healthy humans, GIP suppresses glucagon secretion under conditions of hyperglycemia but increases glucagon secretion during hypoglycemia or euglycemia. Similar results are reported in patients with type 2 diabetes, in which GIP counteracts insulin-induced hypoglycemia and increases postprandial glucagon levels, implying that it is a bifunctional regulator of islet hormone secretion. |
|
Formal Description Interaction-ID: 75183 |
gene/protein increases_activity of process |
| Comment | The mechanisms by which glucose regulates glucagon release seems to include a direct effect as well as indirect effects via paracrine signals from adjacent islet cell populations. Paracrine signals affecting glucagon release include insulin, GABA, amylin, zinc, and somatostatin. |
|
Formal Description Interaction-ID: 75191 |
|
| Comment | The mechanisms by which glucose regulates glucagon release seems to include a direct effect as well as indirect effects via paracrine signals from adjacent islet cell populations. Paracrine signals affecting glucagon release include insulin, GABA, amylin, zinc, and somatostatin. |
|
Formal Description Interaction-ID: 75197 |
|
| Comment | The mechanisms by which glucose regulates glucagon release seems to include a direct effect as well as indirect effects via paracrine signals from adjacent islet cell populations. Paracrine signals affecting glucagon release include insulin, GABA, amylin, zinc, and somatostatin. |
|
Formal Description Interaction-ID: 75198 |
|
| Comment | The mechanisms by which glucose regulates glucagon release seems to include a direct effect as well as indirect effects via paracrine signals from adjacent islet cell populations. Paracrine signals affecting glucagon release include insulin, GABA, amylin, zinc, and somatostatin. |
|
Formal Description Interaction-ID: 75199 |
|
| Comment | Endocrine signals from the central nervous system (CNS), the gastrointestinal (GI) tract, and the liver regulate glucagon secretion. Such endocrine factors include free fatty acids (FAA), certain amino acids (most prominently L-arginine), and the gastrointestinal peptide hormones GLP-1 and GIP. |
|
Formal Description Interaction-ID: 75200 |
|
| Comment | Endocrine signals from the central nervous system (CNS), the gastrointestinal (GI) tract, and the liver regulate glucagon secretion. Such endocrine factors include free fatty acids (FAA), certain amino acids (most prominently L-arginine), and the gastrointestinal peptide hormones GLP-1 and GIP. |
|
Formal Description Interaction-ID: 75203 |
|
| Comment | Endocrine signals from the central nervous system (CNS), the gastrointestinal (GI) tract, and the liver regulate glucagon secretion. Such endocrine factors include free fatty acids (FAA), certain amino acids (most prominently L-arginine), and the gastrointestinal peptide hormones GLP-1 and GIP. |
|
Formal Description Interaction-ID: 75204 |
|
| Comment | In the liver, glucagon stimulates the production of the neuropeptide kisspeptin1 via cAMP-PKA-CREB signaling. Kisspeptin1 then acts on beta-cells to suppress glucose-stimulated insulin secretion. |
|
Formal Description Interaction-ID: 75206 |
|
| Comment | In the liver, glucagon stimulates the production of the neuropeptide kisspeptin1 via cAMP-PKA-CREB signaling. Kisspeptin1 then acts on beta-cells to suppress glucose-stimulated insulin secretion. |
|
Formal Description Interaction-ID: 75207 |
gene/protein decreases_activity of |
| Comment | Amylin’s physiological effects include the regulation of glucose metabolism via paracrine effects on the pancreas and through modulation of gastric motility as well as the regulation of body weight via central modulation of food intake and energy expenditure. Amylin is further reported to have anti-psychotic effects and positively affects neurodegeneration in patients with Alzheimer’s disease. |
|
Formal Description Interaction-ID: 75208 |
|
| Comment | Amylin’s physiological effects include the regulation of glucose metabolism via paracrine effects on the pancreas and through modulation of gastric motility as well as the regulation of body weight via central modulation of food intake and energy expenditure. Amylin is further reported to have anti-psychotic effects and positively affects neurodegeneration in patients with Alzheimer’s disease. |
|
Formal Description Interaction-ID: 75209 |
|
| Comment | Amylin’s physiological effects include the regulation of glucose metabolism via paracrine effects on the pancreas and through modulation of gastric motility as well as the regulation of body weight via central modulation of food intake and energy expenditure. Amylin is further reported to have anti-psychotic effects and positively affects neurodegeneration in patients with Alzheimer’s disease. |
|
Formal Description Interaction-ID: 75210 |
|
| Comment | Amylin’s physiological effects include the regulation of glucose metabolism via paracrine effects on the pancreas and through modulation of gastric motility as well as the regulation of body weight via central modulation of food intake and energy expenditure. Amylin is further reported to have anti-psychotic effects and positively affects neurodegeneration in patients with Alzheimer’s disease. |
|
Formal Description Interaction-ID: 75212 |
|
| Comment | Amylin is produced and co-secreted with insulin from the pancreatic beta-cells and is thus released into the general circulation in response to nutrient, and especially glucose stimuli. Circulating levels of amylin are, like insulin, decreased under conditions of hypoglycemia, largely absent in individuals with type 1 diabetes and, dependent on the severity of the disease, elevated or decreased under conditions of type 2 diabetes. |
|
Formal Description Interaction-ID: 75215 |
|
| Comment | Amylin is produced and co-secreted with insulin from the pancreatic beta-cells and is thus released into the general circulation in response to nutrient, and especially glucose stimuli. Circulating levels of amylin are, like insulin, decreased under conditions of hypoglycemia, largely absent in individuals with type 1 diabetes and, dependent on the severity of the disease, elevated or decreased under conditions of type 2 diabetes. |
|
Formal Description Interaction-ID: 75218 |
|
| Comment | Amylin is produced and co-secreted with insulin from the pancreatic beta-cells and is thus released into the general circulation in response to nutrient, and especially glucose stimuli. Circulating levels of amylin are, like insulin, decreased under conditions of hypoglycemia, largely absent in individuals with type 1 diabetes and, dependent on the severity of the disease, elevated or decreased under conditions of type 2 diabetes. |
|
Formal Description Interaction-ID: 75221 |
|
| Comment | The release of amylin is further, similar to insulin, abolished by preinfusion of somatostatin. |
|
Formal Description Interaction-ID: 75222 |
|
| Comment | Somatostatin (SST) is a peptide hormone derived from prosomatostatin (pro-SST) and exists in two active forms, comprising either 14 or 28 amino acids. Purified from hypothalamic extracts, SST was first identified as a potent inhibitor of growth hormone (GH) secretion in cultured pituitary cells. |
|
Formal Description Interaction-ID: 75223 |
|
| Comment | Centrally regulated effects of somatostatin (SST) include the inhibition of thyroid-stimulating hormone (TSH) and growth hormone (GH) secretion from the pituitary, while the most predominant peripheral effects of SST are the inhibition of gastric motility and intestinal fluid absorption, as well as inhibition of glucagon and insulin secretion from the pancreas. |
|
Formal Description Interaction-ID: 75226 |
|
| Comment | Centrally regulated effects of somatostatin (SST) include the inhibition of thyroid-stimulating hormone (TSH) and growth hormone (GH) secretion from the pituitary, while the most predominant peripheral effects of SST are the inhibition of gastric motility and intestinal fluid absorption, as well as inhibition of glucagon and insulin secretion from the pancreas. |
|
Formal Description Interaction-ID: 75228 |
|
| Comment | Centrally regulated effects of somatostatin (SST) include the inhibition of thyroid-stimulating hormone (TSH) and growth hormone (GH) secretion from the pituitary, while the most predominant peripheral effects of SST are the inhibition of gastric motility and intestinal fluid absorption, as well as inhibition of glucagon and insulin secretion from the pancreas. |
|
Formal Description Interaction-ID: 75229 |
|
| Comment | The machinery regulating the secretion of somatostatin (SST) from the delta-cells is similar to those regulating the secretion of insulin and glucagon. Accordingly, the delta-cells express K-ATP channels that when blocked generate a membrane potential that entails opening of VDCC. The resulting Ca2+ influx subsequently stimulates fusion of the SST granules with the plasma membrane and secretion of SST into the circulation. In contrast, opening of K-ATP channels using, e.g., diazoxide, renders a membrane potential that entails closing of VDCC, decrease of Ca2+ influx, and thus inhibition of SST secretion. The secretion of SST from delta-cells is stimulated by glucose, amino acids, and GLP-1, while norepinephrine and insulin inhibit its release. |
|
Formal Description Interaction-ID: 75230 |
complex/PPI ATP-sensitive potassium channel complex affects_activity of process |
| Comment | The machinery regulating the secretion of somatostatin (SST) from the delta-cells is similar to those regulating the secretion of insulin and glucagon. Accordingly, the delta-cells express K-ATP channels that when blocked generate a membrane potential that entails opening of VDCC. The resulting Ca2+ influx subsequently stimulates fusion of the SST granules with the plasma membrane and secretion of SST into the circulation. In contrast, opening of K-ATP channels using, e.g., diazoxide, renders a membrane potential that entails closing of VDCC, decrease of Ca2+ influx, and thus inhibition of SST secretion. The secretion of SST from delta-cells is stimulated by glucose, amino acids, and GLP-1, while norepinephrine and insulin inhibit its release. |
|
Formal Description Interaction-ID: 75231 |
|
| Comment | The machinery regulating the secretion of somatostatin (SST) from the delta-cells is similar to those regulating the secretion of insulin and glucagon. Accordingly, the delta-cells express K-ATP channels that when blocked generate a membrane potential that entails opening of VDCC. The resulting Ca2+ influx subsequently stimulates fusion of the SST granules with the plasma membrane and secretion of SST into the circulation. In contrast, opening of K-ATP channels using, e.g., diazoxide, renders a membrane potential that entails closing of VDCC, decrease of Ca2+ influx, and thus inhibition of SST secretion. The secretion of SST from delta-cells is stimulated by glucose, amino acids, and GLP-1, while norepinephrine and insulin inhibit its release. |
|
Formal Description Interaction-ID: 75232 |
|
| Comment | The machinery regulating the secretion of somatostatin (SST) from the delta-cells is similar to those regulating the secretion of insulin and glucagon. Accordingly, the delta-cells express K-ATP channels that when blocked generate a membrane potential that entails opening of VDCC. The resulting Ca2+ influx subsequently stimulates fusion of the SST granules with the plasma membrane and secretion of SST into the circulation. In contrast, opening of K-ATP channels using, e.g., diazoxide, renders a membrane potential that entails closing of VDCC, decrease of Ca2+ influx, and thus inhibition of SST secretion. The secretion of SST from delta-cells is stimulated by glucose, amino acids, and GLP-1, while norepinephrine and insulin inhibit its release. |
|
Formal Description Interaction-ID: 75233 |
|
| Comment | The machinery regulating the secretion of somatostatin (SST) from the delta-cells is similar to those regulating the secretion of insulin and glucagon. Accordingly, the delta-cells express K-ATP channels that when blocked generate a membrane potential that entails opening of VDCC. The resulting Ca2+ influx subsequently stimulates fusion of the SST granules with the plasma membrane and secretion of SST into the circulation. In contrast, opening of K-ATP channels using, e.g., diazoxide, renders a membrane potential that entails closing of VDCC, decrease of Ca2+ influx, and thus inhibition of SST secretion. The secretion of SST from delta-cells is stimulated by glucose, amino acids, and GLP-1, while norepinephrine and insulin inhibit its release. |
|
Formal Description Interaction-ID: 75234 |
|
| Comment | The machinery regulating the secretion of somatostatin (SST) from the delta-cells is similar to those regulating the secretion of insulin and glucagon. Accordingly, the delta-cells express K-ATP channels that when blocked generate a membrane potential that entails opening of VDCC. The resulting Ca2+ influx subsequently stimulates fusion of the SST granules with the plasma membrane and secretion of SST into the circulation. In contrast, opening of K-ATP channels using, e.g., diazoxide, renders a membrane potential that entails closing of VDCC, decrease of Ca2+ influx, and thus inhibition of SST secretion. The secretion of SST from delta-cells is stimulated by glucose, amino acids, and GLP-1, while norepinephrine and insulin inhibit its release. |
|
Formal Description Interaction-ID: 75235 |
|
| Comment | The machinery regulating the secretion of somatostatin (SST) from the delta-cells is similar to those regulating the secretion of insulin and glucagon. Accordingly, the delta-cells express K-ATP channels that when blocked generate a membrane potential that entails opening of VDCC. The resulting Ca2+ influx subsequently stimulates fusion of the SST granules with the plasma membrane and secretion of SST into the circulation. In contrast, opening of K-ATP channels using, e.g., diazoxide, renders a membrane potential that entails closing of VDCC, decrease of Ca2+ influx, and thus inhibition of SST secretion. The secretion of SST from delta-cells is stimulated by glucose, amino acids, and GLP-1, while norepinephrine and insulin inhibit its release. |
|
Formal Description Interaction-ID: 75236 |
|
| Comment | The machinery regulating the secretion of somatostatin (SST) from the delta-cells is similar to those regulating the secretion of insulin and glucagon. Accordingly, the delta-cells express K-ATP channels that when blocked generate a membrane potential that entails opening of VDCC. The resulting Ca2+ influx subsequently stimulates fusion of the SST granules with the plasma membrane and secretion of SST into the circulation. In contrast, opening of K-ATP channels using, e.g., diazoxide, renders a membrane potential that entails closing of VDCC, decrease of Ca2+ influx, and thus inhibition of SST secretion. The secretion of SST from delta-cells is stimulated by glucose, amino acids, and GLP-1, while norepinephrine and insulin inhibit its release. |
|
Formal Description Interaction-ID: 75237 |
|
| Comment | Somatostatin promotes its biological action through binding to somatostatin receptors, which are G protein-coupled receptors, of which six subtypes (SSTR1-6) have so far been identified. In the human pancreas, the beta-cells preferably express SSTR1 and SSTR5, whereas SSTR2 predominates in the alpha-cells and SSTR5 in the delta-cells. In line with the distribution of the SST receptors in the endocrine pancreas, insulin secretion is inhibited by selective SSTR1 agonists whereas SSTR2 agonists inhibit the release of glucagon. |
|
Formal Description Interaction-ID: 75238 |
|
| Drugbank entries | Show/Hide entries for SSTR1 |
| Comment | Somatostatin promotes its biological action through binding to somatostatin receptors, which are G protein-coupled receptors, of which six subtypes (SSTR1-6) have so far been identified. In the human pancreas, the beta-cells preferably express SSTR1 and SSTR5, whereas SSTR2 predominates in the alpha-cells and SSTR5 in the delta-cells. In line with the distribution of the SST receptors in the endocrine pancreas, insulin secretion is inhibited by selective SSTR1 agonists whereas SSTR2 agonists inhibit the release of glucagon. |
|
Formal Description Interaction-ID: 75239 |
|
| Drugbank entries | Show/Hide entries for SSTR2 |
| Comment | Somatostatin promotes its biological action through binding to somatostatin receptors, which are G protein-coupled receptors, of which six subtypes (SSTR1-6) have so far been identified. In the human pancreas, the beta-cells preferably express SSTR1 and SSTR5, whereas SSTR2 predominates in the alpha-cells and SSTR5 in the delta-cells. In line with the distribution of the SST receptors in the endocrine pancreas, insulin secretion is inhibited by selective SSTR1 agonists whereas SSTR2 agonists inhibit the release of glucagon. |
|
Formal Description Interaction-ID: 75240 |
|
| Comment | Somatostatin promotes its biological action through binding to somatostatin receptors, which are G protein-coupled receptors, of which six subtypes (SSTR1-6) have so far been identified. In the human pancreas, the beta-cells preferably express SSTR1 and SSTR5, whereas SSTR2 predominates in the alpha-cells and SSTR5 in the delta-cells. In line with the distribution of the SST receptors in the endocrine pancreas, insulin secretion is inhibited by selective SSTR1 agonists whereas SSTR2 agonists inhibit the release of glucagon. |
|
Formal Description Interaction-ID: 75241 |
|
| Comment | Somatostatin promotes its biological action through binding to somatostatin receptors, which are G protein-coupled receptors, of which six subtypes (SSTR1-6) have so far been identified. In the human pancreas, the beta-cells preferably express SSTR1 and SSTR5, whereas SSTR2 predominates in the alpha-cells and SSTR5 in the delta-cells. In line with the distribution of the SST receptors in the endocrine pancreas, insulin secretion is inhibited by selective SSTR1 agonists whereas SSTR2 agonists inhibit the release of glucagon. |
|
Formal Description Interaction-ID: 75242 |
|
| Drugbank entries | Show/Hide entries for SSTR5 |
| Comment | Somatostatin promotes its biological action through binding to somatostatin receptors, which are G protein-coupled receptors, of which six subtypes (SSTR1-6) have so far been identified. In the human pancreas, the beta-cells preferably express SSTR1 and SSTR5, whereas SSTR2 predominates in the alpha-cells and SSTR5 in the delta-cells. In line with the distribution of the SST receptors in the endocrine pancreas, insulin secretion is inhibited by selective SSTR1 agonists whereas SSTR2 agonists inhibit the release of glucagon. |
|
Formal Description Interaction-ID: 75243 |
|
| Comment | Somatostatin promotes its biological action through binding to somatostatin receptors, which are G protein-coupled receptors, of which six subtypes (SSTR1-6) have so far been identified. In the human pancreas, the beta-cells preferably express SSTR1 and SSTR5, whereas SSTR2 predominates in the alpha-cells and SSTR5 in the delta-cells. In line with the distribution of the SST receptors in the endocrine pancreas, insulin secretion is inhibited by selective SSTR1 agonists whereas SSTR2 agonists inhibit the release of glucagon. |
|
Formal Description Interaction-ID: 75244 |
|
| Drugbank entries | Show/Hide entries for SSTR1 |
| Comment | Somatostatin promotes its biological action through binding to somatostatin receptors, which are G protein-coupled receptors, of which six subtypes (SSTR1-6) have so far been identified. In the human pancreas, the beta-cells preferably express SSTR1 and SSTR5, whereas SSTR2 predominates in the alpha-cells and SSTR5 in the delta-cells. In line with the distribution of the SST receptors in the endocrine pancreas, insulin secretion is inhibited by selective SSTR1 agonists whereas SSTR2 agonists inhibit the release of glucagon. |
|
Formal Description Interaction-ID: 75245 |
|
| Drugbank entries | Show/Hide entries for SSTR5 |
| Comment | Somatostatin promotes its biological action through binding to somatostatin receptors, which are G protein-coupled receptors, of which six subtypes (SSTR1-6) have so far been identified. In the human pancreas, the beta-cells preferably express SSTR1 and SSTR5, whereas SSTR2 predominates in the alpha-cells and SSTR5 in the delta-cells. In line with the distribution of the SST receptors in the endocrine pancreas, insulin secretion is inhibited by selective SSTR1 agonists whereas SSTR2 agonists inhibit the release of glucagon. |
|
Formal Description Interaction-ID: 75246 |
|
| Drugbank entries | Show/Hide entries for SSTR2 |
| Comment | Somatostatin promotes its biological action through binding to somatostatin receptors, which are G protein-coupled receptors, of which six subtypes (SSTR1-6) have so far been identified. In the human pancreas, the beta-cells preferably express SSTR1 and SSTR5, whereas SSTR2 predominates in the alpha-cells and SSTR5 in the delta-cells. In line with the distribution of the SST receptors in the endocrine pancreas, insulin secretion is inhibited by selective SSTR1 agonists whereas SSTR2 agonists inhibit the release of glucagon. |
|
Formal Description Interaction-ID: 75247 |
|
| Drugbank entries | Show/Hide entries for SSTR5 |
| Comment | Somatostatin promotes its biological action through binding to somatostatin receptors, which are G protein-coupled receptors, of which six subtypes (SSTR1-6) have so far been identified. In the human pancreas, the beta-cells preferably express SSTR1 and SSTR5, whereas SSTR2 predominates in the alpha-cells and SSTR5 in the delta-cells. In line with the distribution of the SST receptors in the endocrine pancreas, insulin secretion is inhibited by selective SSTR1 agonists whereas SSTR2 agonists inhibit the release of glucagon. |
|
Formal Description Interaction-ID: 75248 |
|
| Drugbank entries | Show/Hide entries for SSTR1 |
| Comment | Somatostatin promotes its biological action through binding to somatostatin receptors, which are G protein-coupled receptors, of which six subtypes (SSTR1-6) have so far been identified. In the human pancreas, the beta-cells preferably express SSTR1 and SSTR5, whereas SSTR2 predominates in the alpha-cells and SSTR5 in the delta-cells. In line with the distribution of the SST receptors in the endocrine pancreas, insulin secretion is inhibited by selective SSTR1 agonists whereas SSTR2 agonists inhibit the release of glucagon. |
|
Formal Description Interaction-ID: 75249 |
|
| Drugbank entries | Show/Hide entries for SSTR2 |
| Comment | Insulin stimulates somatostatin release in the hypothalamus but inhibits its release in the gut and in islets. |
|
Formal Description Interaction-ID: 75250 |
|
| Comment | Glucagon promotes its biological action through binding and activating the glucagon receptor (GcGR), a seven transmembrane GPCR located on the cell surface. GcGR is predominantly expressed in the liver, but small amounts can also be found in the kidney, adipose tissue, lymphoblasts, spleen, pancreas, brain, the adrenal gland, and the gastrointestinal tract. In the pancreas, GcGR is expressed in both alpha- and beta-cells. |
|
Formal Description Interaction-ID: 75251 |
|
| Drugbank entries | Show/Hide entries for GCGR |
| Comment | Binding of glucagon to its receptor leads to activation of at least two classes of G proteins, a cAMP stimulatory G protein (G -s-alpha) and a G-q signaling G protein that signals via inositol 1,4,5-trisphosphate (IP3). The activation of G-q leads to activation of the phospholipase C (PLC) and subsequently to an increase in IP3, which in turn entails activation of downstream signaling cascades via enhanced Ca2+ release from the ER. |
|
Formal Description Interaction-ID: 75252 |
|
| Drugbank entries | Show/Hide entries for GCGR |
| Comment | Binding of glucagon to its receptor leads to activation of at least two classes of G proteins, a cAMP stimulatory G protein (G -s-alpha) and a G-q signaling G protein that signals via inositol 1,4,5-trisphosphate (IP3). The activation of G-q leads to activation of the phospholipase C (PLC) and subsequently to an increase in IP3, which in turn entails activation of downstream signaling cascades via enhanced Ca2+ release from the ER. |
|
Formal Description Interaction-ID: 75253 |
|
| Drugbank entries | Show/Hide entries for GCGR or PLC |
| Comment | Binding of glucagon to its receptor leads to activation of at least two classes of G proteins, a cAMP stimulatory G protein (G -s-alpha) and a G-q signaling G protein that signals via inositol 1,4,5-trisphosphate (IP3). The activation of G-q leads to activation of the phospholipase C (PLC) and subsequently to an increase in IP3, which in turn entails activation of downstream signaling cascades via enhanced Ca2+ release from the ER. |
|
Formal Description Interaction-ID: 75254 |
gene/protein increases_quantity of drug/chemical compound |
| Drugbank entries | Show/Hide entries for GCGR |
| Comment | Binding of glucagon to its receptor leads to activation of at least two classes of G proteins, a cAMP stimulatory G protein (G -s-alpha) and a G-q signaling G protein that signals via inositol 1,4,5-trisphosphate (IP3). The activation of G-q leads to activation of the phospholipase C (PLC) and subsequently to an increase in IP3, which in turn entails activation of downstream signaling cascades via enhanced Ca2+ release from the ER. |
|
Formal Description Interaction-ID: 75255 |
drug/chemical compound increases_activity of process |
| Comment | Glucagon-induced hyperglycemia is induced by a marked increase in liver glycogenolysis while at the same time glycogenesis is inhibited. |
|
Formal Description Interaction-ID: 75256 |
|
| Comment | Glucagon-induced hyperglycemia is induced by a marked increase in liver glycogenolysis while at the same time glycogenesis is inhibited. |
|
Formal Description Interaction-ID: 75257 |
|
| Comment | Apart from the ability to rapidly increase blood glucose through stimulation of glycogen breakdown and inhibition of glycogen synthesis, glucagon also enhances de novo glucose production via stimulation of hepatic gluconeogenesis and inhibition of glycolysis. |
|
Formal Description Interaction-ID: 75258 |
|
| Comment | Apart from the ability to rapidly increase blood glucose through stimulation of glycogen breakdown and inhibition of glycogen synthesis, glucagon also enhances de novo glucose production via stimulation of hepatic gluconeogenesis and inhibition of glycolysis. |
|
Formal Description Interaction-ID: 75337 |
|
| Comment | Binding of glucagon to its receptor results in activation of adenylate cyclase (AC), which in turn leads to an increase in cAMP and subsequently to the activation of PKA. |
|
Formal Description Interaction-ID: 75339 |
|
| Drugbank entries | Show/Hide entries for GCGR |
| Comment | Activated PKA leads to phosphorylation of glycogen phosphorylase kinase (GPK) and to activation of glycogen phosphorylase (GP). The activated GP promotes glycogen breakdown (glycogenolysis) and production of glucose-6-phosphate (G-6-P), which serves as the substrate for the G-6-Pase to produce glucose. |
|
Formal Description Interaction-ID: 75340 |
complex/PPI Protein kinase A increases_phosphorylation of complex/PPI Glycogen phosphorylase kinase |
| Comment | Activated PKA leads to phosphorylation of glycogen phosphorylase kinase (GPK) and to activation of glycogen phosphorylase (GP). The activated GP promotes glycogen breakdown (glycogenolysis) and production of glucose-6-phosphate (G-6-P), which serves as the substrate for the G-6-Pase to produce glucose. |
|
Formal Description Interaction-ID: 75341 |
complex/PPI Glycogen phosphorylase kinase increases_activity of complex/PPI Glycogen phosphorylase |
| Comment | Activated PKA leads to phosphorylation of glycogen phosphorylase kinase (GPK) and to activation of glycogen phosphorylase (GP). The activated GP promotes glycogen breakdown (glycogenolysis) and production of glucose-6-phosphate (G-6-P), which serves as the substrate for the G-6-Pase to produce glucose. |
|
Formal Description Interaction-ID: 75342 |
|
| Comment | Activated PKA leads to phosphorylation of glycogen phosphorylase kinase (GPK) and to activation of glycogen phosphorylase (GP). The activated GP promotes glycogen breakdown (glycogenolysis) and production of glucose-6-phosphate (G-6-P), which serves as the substrate for the G-6-Pase to produce glucose. |
|
Formal Description Interaction-ID: 75344 |
|
| Comment | Activated PKA leads to phosphorylation of glycogen phosphorylase kinase (GPK) and to activation of glycogen phosphorylase (GP). The activated GP promotes glycogen breakdown (glycogenolysis) and production of glucose-6-phosphate (G-6-P), which serves as the substrate for the G-6-Pase to produce glucose. |
|
Formal Description Interaction-ID: 75345 |
|
| Comment | Apart from promoting glycogen breakdown via the PKA-GPK pathway, glucagon also increases the activity of G-6-Pase, which catalyzes the conversion of G-6-PO4 to glucose during gluconeogenesis, and promotes the expression of the G-6-Pase via the PKA-CREB-CRTC2 pathway. |
|
Formal Description Interaction-ID: 75347 |
|
| Comment | Apart from promoting glycogen breakdown via the PKA-GPK pathway, glucagon also increases the activity of G-6-Pase, which catalyzes the conversion of G-6-PO4 to glucose during gluconeogenesis, and promotes the expression of the G-6-Pase via the PKA-CREB-CRTC2 pathway. |
|
Formal Description Interaction-ID: 75351 |
|
| Comment | Apart from promoting glycogen breakdown via the PKA-GPK pathway, glucagon also increases the activity of G-6-Pase, which catalyzes the conversion of G-6-PO4 to glucose during gluconeogenesis, and promotes the expression of the G-6-Pase via the PKA-CREB-CRTC2 pathway. |
|
Formal Description Interaction-ID: 75358 |
|
| Comment | Glucagon decreases glycogen production (glycogenesis) by inhibiting the activity of glycogen synthase (GS). |
|
Formal Description Interaction-ID: 75359 |
|
| Comment | Glucagon increases mRNA levels of PEPCK via the PKA-CREB-CRTC2 pathway. Accordingly, glucagon-mediated activation of PKA leads to phosphorylation of a CREB. The phosphorylated CREB then binds to the DNA and promotes expression of its target genes, such as PGC1-alpha, hepatocyte nuclear factor-4 (HNF-4), and PEPCK. |
|
Formal Description Interaction-ID: 75363 |
|
| Drugbank entries | Show/Hide entries for PCK1 |
| Comment | Glucagon-induced activation of PKA leads to inhibition of the phosphofructokinase-2 (PFK-2). The lower activity of PFK-2 leads to enhanced activity of fructose-2,6-bisphosphatase (FBPase-2), which results in lower levels of fructose-2,6-bisphosphate [F(2,6)P2]. The lower levels of F(2,6)P2 enhance the activity of fructose-1,6-bis-phosphatase (FBPase-1) and hence increase gluconeogenesis while they simultaneously decrease the activity of phosphofructokinase-1 (PFK-1) and thus inhibit glycolysis. |
|
Formal Description Interaction-ID: 75364 |
|
| Comment | Glucagon-induced activation of PKA leads to inhibition of the phosphofructokinase-2 (PFK-2). The lower activity of PFK-2 leads to enhanced activity of fructose-2,6-bisphosphatase (FBPase-2), which results in lower levels of fructose-2,6-bisphosphate [F(2,6)P2]. The lower levels of F(2,6)P2 enhance the activity of fructose-1,6-bis-phosphatase (FBPase-1) and hence increase gluconeogenesis while they simultaneously decrease the activity of phosphofructokinase-1 (PFK-1) and thus inhibit glycolysis. |
|
Formal Description Interaction-ID: 75366 |
|
| Comment | Glucagon-induced activation of PKA leads to inhibition of the phosphofructokinase-2 (PFK-2). The lower activity of PFK-2 leads to enhanced activity of fructose-2,6-bisphosphatase (FBPase-2), which results in lower levels of fructose-2,6-bisphosphate [F(2,6)P2]. The lower levels of F(2,6)P2 enhance the activity of fructose-1,6-bis-phosphatase (FBPase-1) and hence increase gluconeogenesis while they simultaneously decrease the activity of phosphofructokinase-1 (PFK-1) and thus inhibit glycolysis. |
|
Formal Description Interaction-ID: 75367 |
|
| Drugbank entries | Show/Hide entries for FBP1 |
| Comment | Glucagon-induced activation of PKA leads to inhibition of the phosphofructokinase-2 (PFK-2). The lower activity of PFK-2 leads to enhanced activity of fructose-2,6-bisphosphatase (FBPase-2), which results in lower levels of fructose-2,6-bisphosphate [F(2,6)P2]. The lower levels of F(2,6)P2 enhance the activity of fructose-1,6-bis-phosphatase (FBPase-1) and hence increase gluconeogenesis while they simultaneously decrease the activity of phosphofructokinase-1 (PFK-1) and thus inhibit glycolysis. |
|
Formal Description Interaction-ID: 75369 |
|
| Comment | Glucagon decreases food intake and promotes body weight loss in a variety of species, including rodents and humans. Glucagon’s physiological effect to suppress feeding is mediated via the liver-vagus-hypothalamus axis. The liver informs the brain via sensory fibers of the vagus nerve of changes in circulating levels of glucagon. The brain responds to increased glucagon concentrations by suppressing food intake via a decrease in meal size, without affecting meal frequency. Glucagon-induced inhibition of food intake is mediated by enhanced satiety rather than taste aversion and is not related to changes in postprandial behavior. |
|
Formal Description Interaction-ID: 75370 |
|
| Comment | Glucagon decreases food intake and promotes body weight loss in a variety of species, including rodents and humans. Glucagon’s physiological effect to suppress feeding is mediated via the liver-vagus-hypothalamus axis. The liver informs the brain via sensory fibers of the vagus nerve of changes in circulating levels of glucagon. The brain responds to increased glucagon concentrations by suppressing food intake via a decrease in meal size, without affecting meal frequency. Glucagon-induced inhibition of food intake is mediated by enhanced satiety rather than taste aversion and is not related to changes in postprandial behavior. |
|
Formal Description Interaction-ID: 75371 |
|
| Comment | In rats, a single subcutaneous administration of glucagon causes a rapid transient increase in metabolic rate, with a peak 1 h post-injection and return to baseline levels after 4h. An increase in resting metabolic rate following glucagon infusion has also been shown in hypoinsulinemic humans. Low levels of insulin seem a prerequisite for glucagon’s thermogenic effect, since glucagon’s effect on metabolic rate can be blocked by simultaneous infusion of insulin. |
|
Formal Description Interaction-ID: 75372 |
|
| Comment | Several lines of evidence indicate that glucagon enhances metabolic rate through activation of brown adipose tissue (BAT). Oxygen consumption and BAT temperature increase in rats following glucagon administration, and glucagon stimulates oxygen consumption in BAT-derived cells. Plasma levels of glucagon increase in rats and humans upon cold exposure, and cold-acclimatized rats have increased levels of glucagon in both plasma and BAT. Administration of norepinephrine increases BAT glucagon levels, and pretreatment of rats or hamsters with the beta-adrenergic receptor blocker propranolol blocks glucagon’s thermogenic effect. |
|
Formal Description Interaction-ID: 75374 |
|
| Comment | Several lines of evidence indicate that glucagon enhances metabolic rate through activation of brown adipose tissue (BAT). Oxygen consumption and BAT temperature increase in rats following glucagon administration, and glucagon stimulates oxygen consumption in BAT-derived cells. Plasma levels of glucagon increase in rats and humans upon cold exposure, and cold-acclimatized rats have increased levels of glucagon in both plasma and BAT. Administration of norepinephrine increases BAT glucagon levels, and pretreatment of rats or hamsters with the beta-adrenergic receptor blocker propranolol blocks glucagon’s thermogenic effect. |
|
Formal Description Interaction-ID: 75375 |
|
| Comment | Several lines of evidence indicate that glucagon enhances metabolic rate through activation of brown adipose tissue (BAT). Oxygen consumption and BAT temperature increase in rats following glucagon administration, and glucagon stimulates oxygen consumption in BAT-derived cells. Plasma levels of glucagon increase in rats and humans upon cold exposure, and cold-acclimatized rats have increased levels of glucagon in both plasma and BAT. Administration of norepinephrine increases BAT glucagon levels, and pretreatment of rats or hamsters with the beta-adrenergic receptor blocker propranolol blocks glucagon’s thermogenic effect. |
|
Formal Description Interaction-ID: 75376 |
drug/chemical compound increases_quantity of gene/protein |
| Comment | Administration of glucagon lowers circulating levels of cholesterol in humans, rodents, and dogs. |
|
Formal Description Interaction-ID: 75377 |
|
| Comment | Glucagon inhibits de novo fatty acid synthesis, as indicated by diminished incorporation of radioactive labeled acetate, glucose, or fructose into fatty acids. |
|
Formal Description Interaction-ID: 75378 |
|
| Comment | In adipocytes, glucagon stimulates lipolysis by enhancing the activity of hormone-sensitive lipase (HSL), the key lipolytic enzyme stimulating triglyceride hydrolysis. |
|
Formal Description Interaction-ID: 75379 |
|
| Comment | In adipocytes, glucagon stimulates lipolysis by enhancing the activity of hormone-sensitive lipase (HSL), the key lipolytic enzyme stimulating triglyceride hydrolysis. |
|
Formal Description Interaction-ID: 75380 |
|
| Comment | Glucagon’s ability to directly stimulate triglyceride breakdown, as demonstrated in isolated rat liver slices, hepatocytes, and adipocytes, is complemented by its indirect action to modulate lipid metabolism via secretion of lipolytic hormones such as growth hormone, cortisol, and epinephrine. |
|
Formal Description Interaction-ID: 75381 |
|
| Comment | Glucagon’s ability to directly stimulate triglyceride breakdown, as demonstrated in isolated rat liver slices, hepatocytes, and adipocytes, is complemented by its indirect action to modulate lipid metabolism via secretion of lipolytic hormones such as growth hormone, cortisol, and epinephrine. |
|
Formal Description Interaction-ID: 75382 |
|
| Comment | Glucagon’s ability to directly stimulate triglyceride breakdown, as demonstrated in isolated rat liver slices, hepatocytes, and adipocytes, is complemented by its indirect action to modulate lipid metabolism via secretion of lipolytic hormones such as growth hormone, cortisol, and epinephrine. |
|
Formal Description Interaction-ID: 75383 |
|
| Comment | Glucagon’s ability to directly stimulate triglyceride breakdown, as demonstrated in isolated rat liver slices, hepatocytes, and adipocytes, is complemented by its indirect action to modulate lipid metabolism via secretion of lipolytic hormones such as growth hormone, cortisol, and epinephrine. |
|
Formal Description Interaction-ID: 75384 |
|
| Comment | Glucagon’s ability to directly stimulate triglyceride breakdown, as demonstrated in isolated rat liver slices, hepatocytes, and adipocytes, is complemented by its indirect action to modulate lipid metabolism via secretion of lipolytic hormones such as growth hormone, cortisol, and epinephrine. |
|
Formal Description Interaction-ID: 75385 |
|
| Comment | Glucagon’s ability to directly stimulate triglyceride breakdown, as demonstrated in isolated rat liver slices, hepatocytes, and adipocytes, is complemented by its indirect action to modulate lipid metabolism via secretion of lipolytic hormones such as growth hormone, cortisol, and epinephrine. |
|
Formal Description Interaction-ID: 75386 |
|
| Comment | Glucagon enhances degradation of LDL by increasing LDL-receptor activity and cholesterol uptake in primary hepatocytes. In another report, glucagon-induced changes in the lipoprotein profile were assessed in either normally fed, fasted, or cholesterol-fed rats. This study suggests that glucagon appears to mainly affect apoE-rich lipoproteins. |
|
Formal Description Interaction-ID: 75387 |
|
| Comment | Glucagon effects on lipid metabolism are not restricted to only the regulation of triglyceride and cholesterol metabolism but also include a direct effect to enhance hepatic ketogenesis. Under prolonged periods of fasting, and thus limited endogenous energy supply, ketone bodies represent a predominant energy substrate and account for upwards of two-thirds of the brain’s energy source. |
|
Formal Description Interaction-ID: 75388 |
|
| Comment | There is accumulating evidence indicating that glucagon promotes its biological action through mechanisms that depend on fibroblast growth factor 21 (FGF21). Consistent with the liver being the major site of glucagon action, FGF21 is primarily produced in hepatocytes, from which it is secreted into circulation under conditions of fasting, notably a condition where the concentration of glucagon in the portal vein peaks. Apart from its ability to lower blood glucose via insulin-independent mechanisms, FGF21 promotes weight loss by increasing energy expenditure without affecting food intake and when combined with leptin, FGF21 reverses resistance to leptin in DIO mice. Accumulating evidence indicates that glucagon acts in the liver as an endogenous FGF21 secretagogue and as such stimulates FGF21 secretion under conditions of starvation. |
|
Formal Description Interaction-ID: 75389 |
|