Hormones and Regulation of Metabolism Flashcards
Diagram an overview of metabolic pathway interactions between organs
Describe the metabolic demands of specific tissues - brain, red blood cell, heart, muscle, kidney, liver, adipose tissue?
Brain, CNS -> uses only glucose OR KB after ~48hrs starvation
Red blood cell -> uses only glucose
Heart -> uses both glucose AND FA, but prefers FA
Muscle -> uses everything + KB; stores everything; supplise lactose and amino acids
Kidney -> uses everything + KB; stores everything; supplies everything
Liver -> uses everything; stores everything; supplies everything + KB
Adipose tissue -> uses FA, glucose; stores TAG; supplies FA + glycerol
“everything” = glucose, fatty acids, and amino acids
Describe key tissues in normal energy metabolism - Liver
Supplies: glucose, ketone bodies, fatty acids
Stores: glucose (glycogen), fatty acids (TAGs)
Uses everything (DOES NOT USE KB), supplies everything
Describe key tissues in normal energy metabolism - Muscle
Supplies: lactate, amino acids
Stores: glucose (glycogen), fatty acids (TAGs)
“selfish” - glycogen, TAG stores for own use
Describe key tissues in normal energy metabolism - Adipose Tissue
Supplies: fatty acids, glycerol
Stores: fatty acids (TAGs)
How are these metabolic interactions among organs coordinated?
Problem: complicating factors such as: variable diet (varies DAILY), variable needs (daily variations in activities); organ specialization: various organs/tissues have specific needs/roles
Solution: hormonal regulation
Hormonal Regulation of Metabolism - General characteristics, major classes of hormones, principles of action of the hormones
General: small signal -> large effect (biologic amplification)
Major classes:
- polypeptide hormone, ex: insulin and glucagon
- amino acid derivative, ex: epinephrine
- steroid, ex: cortisol
- eicosanoid hormones, ex: prostaglandins
Principles of action:
- effective at low concentrations -> amplified -> secondary signals -. target
- tissue specific: due to specific receptors on the various tissues
- different responses in different tissues: due to different receptor types; different isozymes respond to the signals
- self-limiting activity: due to rapid breakdown of the hormone (i.e. t1/2 = 5min for glucagon)
Insulin structure
Synthesized (RER) as: preproinsulin (inactive)
To Golgi as: proinsulin (inactive)
- lost leader (aka signal) sequence [via a protease] in rough ER
Released as: insulin (active)
- t1/2 = 5mins
- C-peptide (connecting peptide) - removed (again via a protease), but not degraded, and is released with insulin
* more stable, longer half life than insulin
* used for diagnostic purposes in early diabetes
Insulin Secretion and Receptor
Secretion - in response to HIGH BLOOD SUGAR from beta-cells of the pancreas
Receptor: ‘receptor-as-kinase’
structure of the insulin receptor: 2 alpha-subunits bind insulin; 2 beta-subunits cytosoilc domains are tyrosine kinases
Activation: insulin binds to extracellular alpha-subunits -> causes an intracellular conformational change of the receptor -> activates kinase domains
Rapid autophosphorylation of a specific tyrosine residue on each beta-subunit occurs
The autophosphorylated tyrosine kinase domains of the insulin receptor induce a cascade of cell-signaling responses - phosphorylate a family of proteins called insulin receptor substrates (IRS); ultimately activates phosphatases (cleave off phosphate groups); the phosphatases then dephosphorylate target proteins
General Rule of Insulin
Insulin dephosphorylates target proteins to typically ACTIVATE them
Insulin “Dp” ACTIVATES
- ex: HMG-CoA reductase, glycogen synthase, pyruvate dehydrogenase complex - all are active in the dephosphorylated state
- Exception: glycogen phosphorylase - dephosphorylated form is INACTIVE* [note: the exception is the enzyme’s ‘activity’ - not its phosphorylation state]
Insulin Target Tissues - Liver?
Synthetic processes and glycolysis [store excess sugars as TAGs]: STIMULATED
Gluconeogenesis/glycogen breakdown: INHIBITED (decrease glucose production - because liver doesn’t need to export glucose if plenty in blood already)
Insulin Target Tissues - Muscle?
Glucose uptake into muscle cells: STIMULATED
Synthetic processes (glycogen synthesis, sprotein synthesis, etc): STIMULATED
Insulin Target Tissues - Adipose Tissue?
Glucose uptake: STIMULATED
TAG synthesis (and other synthetic processes): STIMULATED
Downstream Effects of Insulin - Promotes?
Fuel uptake - glucose, TAG (i.e. fatty acids from chylomicrons and VLDLs), amino acids
Synthesis - TAG, glycogen, protein, cholesterol
Glucose metabolism - glycolysis in the liver (store excess glucose as fat)
Downstream Effects of Insulin - Inhibits?
Gluconeogenesis - in the liver
Glycogen breakdown - in the liver
Lipolysis - in adipose tissue; insulin is a potent inhibitor of lipolysis, even at very low insulin concentrations
Protein degradation - in muscle
Insulin Overall Effect on Plasma Levels
Glucose - Decrease (cells are taking glucose & liver removing excess glucose from blood)
Fatty Acids - Decrease
Amino Acids - Decrease
Ketone Bodies - Decrease
Insulin In General
Associated with FED STATE; acts to STORE ENERGY (acts as a ‘growth hormone’ because stimulates synthesis of many biological molecules)
Beckwith-Weideman Syndrome
increase insulin -> decrease glucose in blood -> hypoglycemia
Glucagon Structure
Synthesized (RER) as: preproglucagon (inactive)
To Golgi as: proglucagon (inactive)
- a protease cleaves off 20 amino acids from amino-terminus
Released as: glucagon (active)
- a protease cleaves off 8 amino acids from carboxy-terminus
- t1/2 = 5mins
Glucagon Secretion
In response to LOW BLOOD SUGAR from alpha-cells of the pancreas
Secretion mechanism - complex
- self-limiting reaction - as insulin produced, a signal to alpha-cells inhibits glucagon secretion
Glucagon Receptor
A Gs-protein coupled receptor
Mechanism of signal transduction:
Glucagon binds to the receptor and activates the receptor -> activates a Gs-Protein (GTP bound) -> releases Gs alpha-subunit (now active) -> the active Gs alpha-subunit -> activates adenylate cylcase -> increase cAMP -> activates protein kinases -> phosphorylate target proteins -> typically INACTIVATES the target proteins
General Hormone Rules
Insulin DEPHOSPHORYLATES target proteins to typically ACTIVATE them
- Ex: HMG-CoA reductase, glycogen synthase, pyruvate dehydrogenase complex - all are active in the dephosphorylated state
Glucagon PHOSPHORYLATES target proteins to typically INACTIVATE them
- Ex: HMG-CoA reductase, glycogen synthase, pyruvate dehydrogenase cmoplex - all are inactive in the phosphorylated state
Exceptions: glycogen phosphorylase and fructose 2,6-bisphosphatase (FBP2)
- dephosphorylated forms are INACTIVE
- phosphorylated forms are ACTIVE
Target tissues and downstream effects of glucagon - Liver?
Glucagon Promotes:
Gluconeogenesis; glycogen breakdown; ketone body synthesis (releases H2O soluble fuel sources to the blood)
Glucagon Inhibits:
Glycolysis; glycogen synthesis
Target tissues and downstream effects of glucagon - Adipose Tissue?
Glucagon Promotes:
- lipolysis (provides FAs to liver for ketone body synthesis)
Glucagon Inhibits:
- lipogenesis (TAG synthesis)
NOTE: glucagon does NOT act on muscle tissues
Glucagon In General
Associated with STARVED STATE; acts to promote glucose synthesis and fatty acid mobilization to promote ketone body synthesis to ensure water-soluble fuel sources available for all tissues
