Integration of Metabolism Flashcards
What 4 major tissues play a role in energy metabolism
- Liver, adipose, muscle, brain
- each specialized in storage, use of specialized fuels
- form a network in which one tissue provides substrates to another
- communication mediated by nervous system
Integration of energy metabolism is controlled by which two peptide hormones?
- Insulin and glucagon
- Secreted in response to changing substrate levels in blood
Catecholamines play a supporting role
- Epinephrine and norepinephrine- secreted in response to neutral signals from brain
Changes in conc. of two hormones allow what?
Body to store energy after eating, or make stored energy available during fasting, injury or fight or flight
Insulin vs. Glucagon
Insulin: inc. glucose ox., glycogen synthesis, fat synthesis, protein synthesis
Glucagon: inc. glycogenolysis, gluconeogenesis, ketogenesis
Insulin
Most important hormone controlling energy use by tissues
What are the metabolic effects of insulin?
Anabolic
- well fed state
- promotes storage of energy
- promotes synthesis of glycogen, fat and protein
Where is insulin synthesized
peptide hormone synthesized is the b-cells of islets of langerhans in the pancreas
Structure of Insulin
- Insulin is composed of 51 amino acids in two protein chains (A and B chain)
- The two chains are joined by 2 intermolecular disulfide bonds
- The A chain also contains an intramolecular disulfide bond
- mostly a-helical
Synthesis of Insulin
- Involves 2 inactive precursors: preproinsulin and proinsulin
- Precursors are sequentially cleaved to form mature insulin and c-peptide
- C-peptide is essential for protein folding
Where is Insulin stored
- Stored in cytosolic granules and released by exocytosis when glucose levels are high
Plasma half life of insulin
- 6 mins (short)
- Rapid turnover once released = rapid changes in circulated changes
Stimulation of Insulin Secretion
- Glucose
- Amino Acids
- Gastrointestinal hormone
(mirror images for spike of glucose corresponding to spike in insulin)
- Glucose
Inc. plasma glucose conc. is the most important signal for increased insulin secretion
- Amino Acids
Eating protein causes rise in plasma a.a, inducing insulin secretion (fatty acids have similar effect)
- Gastrointestinal Hormones
Ingestion of food causes the release of intestinal hormones that stimulate insulin secretion
Inhibition of Insulin Secretion
- Decreased food ingestion (lower blood glucose)
- Periods of physiological stress - injury or infection
- mediated by norepinephrine and epinephrine
- catecholamines cause rapid mobilization of energy-yielding fuels
- can override glucose-stimulated insulin release in emergency situations
Metabolic Effects of Insulin
- Insulin promotes nutrient storage in glycogen, TAG and protein and inhibits their mobilization
1. Effects on Carbohydrate metabolism
2. Effects on lipid metabolism
3. Effects on protein synthesis
- Effects on Carbohydrate metabolism
Most pronounced in liver, muscle, adipose
- In liver and muscle glycogen synthesis is increased
- in muscle and adipose glucose uptake is increased by inc. the number of glucose transporters in the membrane
- In liver glucose production is decreased through inhibition of glycogen degradation and gluconeogenesis
- Effects on lipid metabolism
- In adipose tissue release of FA is decreased by two mechanisms (inhibiting hormone sensitive lipase activity resulting in decreased TAG breakdown and increasing TAG synthesis by inc. glucose transport and metabolism in fat cells resulting resulting in inc. glycerol 3-P levels)
- Activity of lipoprotein lipase is inc. resulting in more FFA from lipoproteins (VLDL/chylomicrons) available for TAG formation
- Effects on protein synthesis
- Insulin stimulates entry of a.a into the cells
- Stimulates protein synthesis
Signal Transduction Pathway
Ways signals from outside the cell can change the overall activity of the cell
- External signal received by receptor, amplifies signal, transduction in pathways, results in respone
Insulin Receptor
- Insulin binds to specific receptor in cell membrane (can’t cross membrane on own)
- Insulin receptor is found on most tissues, including liver, adipose and muscle
- binding to receptor is firsts step that leads to cascade of rxns ultimately leading to diverse array of biological responses to insulin signal
Mechanism of Action
- Binding of insulin to the a-subunit activates the receptor, changing its shape
- Initiates signal transduction by autophosphorylation of Tyr on receptor - locks in active site
Insulin mechanism of action
- Signal transduction is a series of phosphorylation rxns of insulin receptor substrate proteins
- Signal stops when receptor is dephosphorylated
Insulin-Dependent Glucose Transport
- Muscle and adipose tissues experience inc. glucose uptake in response to insulin
- Mediated through inc. glucose transporters in the cell membrane in response to insulin
- Binding of insulin to insulin receptor causes intracellular glucose transporters to move to the cell membrane
- Inc. insulin dependent transport of glucose into cell
- Dec. insulin leads to internalization of glucose transporters untl more insulin is detected
Glucagon
- Peptide hormone secreted by a-cells of the pancreatic islets of Langerhans
- Glucagon (epinephrine/norepniphrine) oopose actions of insulin
Most important role of glucagon
Maintain blood glucose levels by activating glycogen degradation and gluconeogenesis in the liver
Structure of Glucagon
Glucagon is a signle peptide of 29 a.a
- similar to insulin it starts as preproglucagon and is converted to glucagon by a series of proteolytic cleavages
Stimulation of Glucagon Secretion
- Low blood glucose
- Amino Acids
- Catecholamines
- Low blood glucose
Dec. in plasma glucose conc. is primary stimulus for glucagon release, during overnight or prolonged fast, glucagon prevents hypoglycemia
- Amino Acids
Derived form protein rich meal. Glucagon prevents hypoglycemia that would other wise occur as a result of inc. insulin secretion
- Catecholamines
Elevated levels of epinephrine/norepinephrine increase glucagon secretion
- During periods of physiological stress, regardless of blood glucose level, glucagon is elevated in anticipation of inc. glucose use
Inhibition of Glucagon Secretion
Elevated blood glucose
- Insulin (both elevated after glucose or carbohydrate-rich meal)
Metabolic Effects of Glucagon
- Carbohydrate metabolism
- Lipid metabolism
- Protein metabolism
- effects are catabolic and promote the maintenance of blood glucose
- primary target is liver
- Carbohydrate metabolism(G)
glucagon stimulates breakdown of liver glycogen (not muscle) and inc. gluconeogenesis
- intravenous administration of glucagon results in rapid rise of blood glucose
- Lipid Metabolism(G)
glucagon increases ox. of fatty acids and formation of ketone bodies from acetyl CoA
- Protein metabolism(G)
glucagon increases uptake of a.a from the blood by liver
- Inc. C skeleton available for gluconeogenesis
- Plasma levels of a.a are decreased
Glucagon mechanism of action
- Glucagon binds to specific glucagon receptor in the cell
- Activates adenylyl cyclase in cell membrane (inc. conc. of cAMP a second messenger for glucagon’s metabolic action)
What does cAMP do?
activates cAMP-dependent kinase which phosphorylates specific protein that results in
- Inc. glycogen degradation
- Inc. gluconeogenesis
- Inc. Ketone body synthesis
- Inc. uptake of amino acids
- Dec. glycogenesis
