Integration of energy metabolism (Homo sapiens)
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Description
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.). View original pathway at Reactome.
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.). View original pathway at Reactome.
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DataNodes
type V or VI: G-protein beta
gamma Complex(pancreatic beta
cell)(s):GTP:Adenylate
cyclasePP2A-ABdeltaC
complextetramer:ABCC8
tetramerAcetylcholine Receptor M3:Acetylcholine
Complexvoltage-gated channels (beta
cell, closed)voltage-gated channels (beta
cell, open)closed (pancreatic
beta cell)open (pancreatic
beta cell)Calcium Channels (pancreatic beta
cell)Calcium Channels
Type Cav1 (closed)Calcium Channels
Type Cav1 (open)Annotated Interactions
type V or VI: G-protein beta
gamma Complex(pancreatic beta
cell)(s):GTP:Adenylate
cyclase(s):GTP:Adenylate
cyclasePP2A-ABdeltaC
complextetramer:ABCC8
tetramerAcetylcholine Receptor M3:Acetylcholine
ComplexAcetylcholine Receptor M3:Acetylcholine
Complexvoltage-gated channels (beta
cell, closed)voltage-gated channels (beta
cell, open)closed (pancreatic
beta cell)open (pancreatic
beta cell)This reaction takes place in the 'nucleus'.
This reaction takes place in the 'nucleus'.
This reaction takes place in the 'nucleus'.
This reaction takes place in the 'nucleus' and is mediated by the 'phosphatidate phosphatase activity' of 'PP2A-ABdeltaC complex'.
This reaction takes place in the 'cytosol' and is mediated by the 'phosphatidate phosphatase activity' of 'PP2A-ABdeltaC complex'.
This reaction takes place in the 'nucleus' (Ma et al. 2005, Havula et al. 2012).
This reaction takes place in the 'nucleus' (Ma et al. 2006).
This reaction takes place in the 'nucleus' (Ma et al.2007).
This reaction takes place in the 'cytosol' and is mediated by the 'phosphatidate phosphatase activity' of 'PP2A-ABdeltaC complex'.
This reaction takes place in the 'nucleus'.
This reaction takes place in the 'nucleus' and is mediated by the 'phosphatidate phosphatase activity' of 'PP2A-ABdeltaC complex'.
In the particular case of insulin granules in beta cells, the SNARE protein on the granule is Synaptobrevin2/VAMP2 and the SNARE protein on the plasma membrane is Syntaxin1A in a complex with SNAP-25. Unc18-1 binds Syntaxin1A and thereby prevents association with Synaptobrevin2 until dissociation of Unc18-1. Syntaxin 4 is also involved and binds filamentous actin but its exact role is unknown.
Insulin exocytosis occurs in two phases: 1) a rapid release of about 100 of the 1000 docked granules within the first 5 minutes of glucose stimulation and 2) a subsequent slow release over 30 minutes or more due to migration of internal granules to the plasma membrane. Data from knockout mice show that Syntaxin 1A is involved in rapid release but not slow release, whereas Syntaxin 4 is involved in both types of release.
Calcium dependence of membrane fusion is conferred by Synaptotagmin V, which binds calcium ions and associates with the Syntaxin1A-Synaptobrevin2 pair. The exact mechanism of Synaptotagmin's action is unknown. The migration of internal granules to the plasma membrane during slow release is also calcium dependent.
Microscopically, exocytosis is seen to occur as a "kiss and run" process in which the membrane of the secretory granule fuses transiently with the plasma membrane to form a small pore of about 4 nm between the interior of the granule and the exterior of the cell. Only a portion of the insulin in a granule is secreted after which the pore closes and the vesicle is recaptured back into the cell. Dynamin-1 and NSF may play a role in recapture but the mechanism is not fully known.
The major effect of adrenaline and noradrenaline on insulin secretion is the inhibition of exocytosis of pre-existing insulin secretory granules. The inhibition occurs at a "distal site", that is, the effect is most pronounced on granules already near the cytosolic face of the plasma membrane. The effect is caused by the Gi/o alpha:GTP complex but the exact mechanism by which Gi/o alpha:GTP inhibits exocytosis is unknown. On release, the higher pH in the extracellular region favours dissociation of Zn2+ from insulin. The insulin hexamer becomes unstable at this higher pH and it dissociates into the active insulin monomer.
Mouse and human beta cells are known to contain L type channels Cav1.2 and Cav1.3, both of which have been shown to physically associate with docked insulin granules via Syntaxin1A. Cav1.2 and Cav1.3 predominate in the initial rapid release of insulin. Human beta cells also contain the P/Q type channel Cav2.1 and the R type channel Cav2.3. Cav2.3 is involved in regulating the second, sustained phase of insulin release but signaling and regulatory differences between the two phases of secretion are not fully characterized. Human cells also exhibit T-type (brief burst) calcium currents but the responsible channel has not been identified.
The KATP channels in the beta cell are inwardly rectifying (allowing potassium ions to pass out of the cell) and are partially responsible for maintaining the resting potential of the cell, about -70 mV. Closure of the KATP channels causes a depolarization (a reduction in the voltage differential) across the plasma membrane.
The antidiabetic activity of sulfonylurea drugs such as acetohexamide, tolbutamide, glipzide, glibenclamide, and glimepiride is due to their binding ABCC8 (SUR1) subunits and inhibiting potassium efflux.
Epac2 interacts with the calcium sensor Piccolo in a complex with Rim2 at the cell membrane. This may influence exocytosis of insulin. Epac2 also interacts with the ryanodine-sensitive calcium channel on the ER membrane and may cause release of calcium from the ER into the cytosol.
Epac1 also interacts with the calcium sensor Piccolo in a complex with Rim2 at the cell membrane. This may influence exocytosis of insulin.
Activation by cAMP occurs when each regulatory subunit binds 2 molecules of cAMP, causing dissociation of the catalytic subunits. The active catalytic subunits are thereby released to phosphorylate their target proteins.
Prolonged exposure to increased cAMP levels results in translocation of the active catalytic subunits to the nucleus, where they regulate the PDX-1 and CREB transcription factors and cause increased transcription of the insulin gene.
Other effects of RAP1A :GTP may include regulating beta cell proliferation through activation of the Raf/MEK/ERK mitogenic cascade and activation of the PI3 Kinase/PDK/PKC cell growth pathway.
ATP-binding cassette sub-family C member 8 (ABCC8) is a subunit of the beta-cell ATP-sensitive potassium channel (KATP). KATP channels play an important role in the control of insulin release. Elevation of the ATP:ADP ratio closes KATP channels leading to cellular depolarisation, calcium influx and exocytosis of insulin from its storage granules. Defects in ABCC8 can cause dysregulation of insulin secretion resulting in hyperglycemias or hypoglycemias.
Defects in ABCC8 can cause permanent neonatal diabetes mellitus (PNDM; MIM:606176). Wild-type ABCC8 confers a lower open-channel probability (Po) than activating mutations of ABCC8, where overactive KATP channels reduce insulin secretion, resulting in hyperglycemia, diagnosed within the first months of life. PNDM requires lifelong therapy. Mutations causing PNDM include P132L, L213R, N72S, A1185E and E382K (Proks et al. 2006, Babenko et al. 2006, Ellard et al. 2007).
Defects in ABCC8 can also cause transient noenatal diabetes mellitus 2 (TNDM2; MIM:610374). Babies are born with intrauterine growth retardation and present within the first 6 weeks of life with severe failure to thrive, hyperglycemia, and dehydration. The condition usually resolves within the first 6 months after birth but there is a predisposition to type 2 diabetes later in life (Naylor et al. 2011). Activating mutations causing TNDM2 are R1379C and L582V (Babenko et al. 2006). These mutations confer a higher open-channel probability (Po) than wild-type ABCC8, keeping the KATP channel open thus not allow cellular depolarisation to occur with the end result of reduced insulin secretion and hyperglycemia.
Adiponectin (ADIPOQ, also known as 30-kDa adipocyte complement-related protein ACRP30) is an adipocyte-derived hormone that acts as an antidiabetic and anti-atherogenic adipokine. ADIPOQ blood levels are decreased under conditions of obesity, insulin resistance and type 2 diabetes. ADIPOQ can form a wide range of multimers from trimers to high molecular weight (HMW) multimers (Waki et al. 2003). The trimeric form is shown here. Through binding adiponectin receptor proteins 1 and 2 (ADIPOR1 and 2), ADIPOQ trimer stimulates AMPK phosphorylation and activation in the liver and the skeletal muscle, enhancing glucose and fatty-acid utilisation. ADIPOR1 is abundantly expressed in skeletal muscle, whereas ADIPOR2 is predominantly expressed in the liver (Yamauchi et al. 2003). ADIPORs are thought to function as homo- or hetero-multimers. For simplicity, the combinations annotated here are shown as homodimers. Although ADIPOR1 and 2 are predicted to contain seven transmembrane domains, they are structurally, topologically and functionally distinct from GPCRs.
Calcium Channels (pancreatic beta
cell)Calcium Channels
Type Cav1 (closed)Calcium Channels
Type Cav1 (closed)Calcium Channels
Type Cav1 (open)