Pathway: Glucagon-like Peptide-1 (GLP1) regulates insulin secretion
Reactions in pathway: Glucagon-like Peptide-1 (GLP1) regulates insulin secretion :
Glucagon-like Peptide-1 (GLP1) regulates insulin secretion
Glucagon-like Peptide-1 (GLP-1) is secreted by L-cells in the intestine in response to glucose and fatty acids. GLP-1 circulates to the beta cells of the pancreas where it binds a G-protein coupled receptor, GLP-1R, on the plasma membrane. The binding activates the heterotrimeric G-protein G(s), causing the alpha subunit of G(s) to exchange GDP for GTP and dissociate from the beta and gamma subunits.
The activated G(s) alpha subunit interacts with Adenylyl Cyclase VIII (Adenylate Cyclase VIII, AC VIII) and activates AC VIII to produce cyclic AMP (cAMP). cAMP then has two effects: 1) cAMP activates Protein Kinase A (PKA), and 2) cAMP activates Epac1 and Epac2, two guanyl nucleotide exchange factors.
Binding of cAMP to PKA causes the catalytic subunits of PKA to dissociate from the regulatory subunits and become an active kinase. PKA is known to enhance insulin secretion by closing ATP-sensitive potassium channels, closing voltage-gated potassium channels, releasing calcium from the endoplasmic reticulum, and affecting insulin secretory granules. The exact mechanisms for PKA's action are not fully known. After prolonged increases in cAMP, PKA translocates to the nucleus where it regulates the PDX-1 and CREB transcription factors, activating transcription of the insulin gene.
cAMP produced by AC VIII also activates Epac1 and Epac2, which catalyze the exchange of GTP for GDP on G-proteins, notably Rap1A.. Rap1A regulates insulin secretory granules and is believed to activate the Raf/MEK/ERK mitogenic pathway leading to proliferation of beta cells. The Epac proteins also interact with RYR calcium channels on the endoplasmic reticulum, the SUR1 subunits of ATP-sensitive potassium channels, and the Piccolo:Rim2 calcium sensor at the plasma membrane.
The activated G(s) alpha subunit interacts with Adenylyl Cyclase VIII (Adenylate Cyclase VIII, AC VIII) and activates AC VIII to produce cyclic AMP (cAMP). cAMP then has two effects: 1) cAMP activates Protein Kinase A (PKA), and 2) cAMP activates Epac1 and Epac2, two guanyl nucleotide exchange factors.
Binding of cAMP to PKA causes the catalytic subunits of PKA to dissociate from the regulatory subunits and become an active kinase. PKA is known to enhance insulin secretion by closing ATP-sensitive potassium channels, closing voltage-gated potassium channels, releasing calcium from the endoplasmic reticulum, and affecting insulin secretory granules. The exact mechanisms for PKA's action are not fully known. After prolonged increases in cAMP, PKA translocates to the nucleus where it regulates the PDX-1 and CREB transcription factors, activating transcription of the insulin gene.
cAMP produced by AC VIII also activates Epac1 and Epac2, which catalyze the exchange of GTP for GDP on G-proteins, notably Rap1A.. Rap1A regulates insulin secretory granules and is believed to activate the Raf/MEK/ERK mitogenic pathway leading to proliferation of beta cells. The Epac proteins also interact with RYR calcium channels on the endoplasmic reticulum, the SUR1 subunits of ATP-sensitive potassium channels, and the Piccolo:Rim2 calcium sensor at the plasma membrane.
Many hormones that affect individual physiological processes including the regulation of appetite, absorption, transport, and oxidation of foodstuffs influence energy metabolism pathways. While insulin mediates the storage of excess nutrients, glucagon is involved in the mobilization of energy resources in response to low blood glucose levels, principally by stimulating hepatic glucose output. Small doses of glucagon are sufficient to induce significant glucose elevations. These hormone-driven regulatory pathways enable the body to sense and respond to changed amounts of nutrients in the blood and demands for energy.
Glucagon and Insulin act through various metabolites and enzymes that target specific steps in metabolic pathways for sugar and fatty acids. The processes responsible for the long-term control of fat synthesis and short term control of glycolysis by key metabolic products and enzymes are annotated in this module as six specific pathways:
Pathway 1. Glucagon signalling in metabolic pathways: In response to low blood glucose, pancreatic alpha-cells release glucagon. The binding of glucagon to its receptor results in increased cAMP synthesis, and Protein Kinase A (PKA) activation.
Pathway 2. PKA mediated phosphorylation:PKA phosphorylates key enzymes, e.g., 6-Phosphofructo-2-kinase /Fructose-2,6-bisphosphatase (PF2K-Pase) at serine 36, and regulatory proteins, e.g., Carbohydrate Response Element Binding Protein (ChREBP) at serine 196 and threonine 666.
In brief, the binding of insulin to its receptor leads to increased protein phosphatase activity and to hydrolysis of cAMP by cAMP phosphodiesterase. These events counteract the regulatory effects of glucagon.
Pathway 3: Insulin stimulates increased synthesis of Xylulose-5-phosphate (Xy-5-P). Activation of the insulin receptor results indirectly in increased Xy-5-P synthesis from Glyceraldehyde-3-phosphate and Fructose-6-phosphate. Xy-5-P, a metabolite of the pentose phosphate pathway, stimulates protein phosphatase PP2A.
Pathway 4: AMP Kinase (AMPK) mediated response to high AMP:ATP ratio: In response to diet with high fat content or low energy levels, the cytosolic AMP:ATP ratio is increased. AMP triggers a complicated cascade of events. In this module we have annotated only the phosphorylation of ChREBP by AMPK at serine 568, which inactivates this transcription factor.
Pathway 5: Dephosphorylation of key metabolic factors by PP2A: Xy-5-P activated PP2A efficiently dephosphorylates phosphorylated PF2K-Pase resulting in the higher output of F-2,6-P2 that enhances PFK activity in the glycolytic pathway. PP2A also dephosphorylates (and thus activates) cytosolic and nuclear ChREBP.
Pathway 6: Transcriptional activation of metabolic genes by ChREBP: Dephosphorylated ChREBP activates the transcription of genes involved in glucose metabolism such as pyruvate kinase, and lipogenic genes such as acetyl-CoA carboxylase, fatty acid synthetase, acyl CoA synthase and glycerol phosphate acyl transferase.
The illustration below summarizes this network of events. Black lines are metabolic reactions, red lines are negative regulatory events, and green lines are positive regulatory events (figure reused with permission from Veech (2003) - Copyright (2003) National Academy of Sciences, U.S.A.).
Glucagon and Insulin act through various metabolites and enzymes that target specific steps in metabolic pathways for sugar and fatty acids. The processes responsible for the long-term control of fat synthesis and short term control of glycolysis by key metabolic products and enzymes are annotated in this module as six specific pathways:
Pathway 1. Glucagon signalling in metabolic pathways: In response to low blood glucose, pancreatic alpha-cells release glucagon. The binding of glucagon to its receptor results in increased cAMP synthesis, and Protein Kinase A (PKA) activation.
Pathway 2. PKA mediated phosphorylation:PKA phosphorylates key enzymes, e.g., 6-Phosphofructo-2-kinase /Fructose-2,6-bisphosphatase (PF2K-Pase) at serine 36, and regulatory proteins, e.g., Carbohydrate Response Element Binding Protein (ChREBP) at serine 196 and threonine 666.
In brief, the binding of insulin to its receptor leads to increased protein phosphatase activity and to hydrolysis of cAMP by cAMP phosphodiesterase. These events counteract the regulatory effects of glucagon.
Pathway 3: Insulin stimulates increased synthesis of Xylulose-5-phosphate (Xy-5-P). Activation of the insulin receptor results indirectly in increased Xy-5-P synthesis from Glyceraldehyde-3-phosphate and Fructose-6-phosphate. Xy-5-P, a metabolite of the pentose phosphate pathway, stimulates protein phosphatase PP2A.
Pathway 4: AMP Kinase (AMPK) mediated response to high AMP:ATP ratio: In response to diet with high fat content or low energy levels, the cytosolic AMP:ATP ratio is increased. AMP triggers a complicated cascade of events. In this module we have annotated only the phosphorylation of ChREBP by AMPK at serine 568, which inactivates this transcription factor.
Pathway 5: Dephosphorylation of key metabolic factors by PP2A: Xy-5-P activated PP2A efficiently dephosphorylates phosphorylated PF2K-Pase resulting in the higher output of F-2,6-P2 that enhances PFK activity in the glycolytic pathway. PP2A also dephosphorylates (and thus activates) cytosolic and nuclear ChREBP.
Pathway 6: Transcriptional activation of metabolic genes by ChREBP: Dephosphorylated ChREBP activates the transcription of genes involved in glucose metabolism such as pyruvate kinase, and lipogenic genes such as acetyl-CoA carboxylase, fatty acid synthetase, acyl CoA synthase and glycerol phosphate acyl transferase.
The illustration below summarizes this network of events. Black lines are metabolic reactions, red lines are negative regulatory events, and green lines are positive regulatory events (figure reused with permission from Veech (2003) - Copyright (2003) National Academy of Sciences, U.S.A.).
Metabolic processes in human cells generate energy through the oxidation of molecules consumed in the diet and mediate the synthesis of diverse essential molecules not taken in the diet as well as the inactivation and elimination of toxic ones generated endogenously or present in the extracellular environment. The processes of energy metabolism can be classified into two groups according to whether they involve carbohydrate-derived or lipid-derived molecules, and within each group it is useful to distinguish processes that mediate the breakdown and oxidation of these molecules to yield energy from ones that mediate their synthesis and storage as internal energy reserves. Synthetic reactions are conveniently grouped by the chemical nature of the end products, such as nucleotides, amino acids and related molecules, and porphyrins. Detoxification reactions (biological oxidations) are likewise conveniently classified by the chemical nature of the toxin.
At the same time, all of these processes are tightly integrated. Intermediates in reactions of energy generation are starting materials for biosyntheses of amino acids and other compounds, broad-specificity oxidoreductase enzymes can be involved in both detoxification reactions and biosyntheses, and hormone-mediated signaling processes function to coordinate the operation of energy-generating and energy-storing reactions and to couple these to other biosynthetic processes.