Hormonal Regulation of Metabolic Pathways

• Metabolic pathways are coordinated by hormones, regulating energy storage and utilization based on nutrient availability
• Hormones regulate critical points in metabolic pathways to prevent conflicting reactions, known as reciprocal regulation
• Hormone actions align with the allosteric properties of individual enzymes

Insulin - A Hormone for Feasting

• Insulin is most effective in the liver, muscle, and adipose tissue
• Insulin facilitates fuel storage by promoting synthesis of glycogen in the liver and muscle, and triglycerides in the liver and adipose tissue
• Insulin activates energy-storing enzymes like glycogen synthase and inactivates energy-mobilizing enzymes like glycogen phosphorylase through dephosphorylation
• Insulin enhances glucose uptake in muscle and adipose tissue by relocating GLUT4 receptors to the cell surface
• Insulin increases K+ uptake by up-regulating the Na+/K+-ATPase membrane transporter
• Insulin is released by pancreatic β-cells in response to carbohydrate ingestion
• Proinsulin is cleaved to produce C peptide and active insulin, composed of disulfide-linked A and B chains
• Blood glucose concentration, certain amino acids (e.g., arginine), gastrointestinal peptides (gastric inhibitory peptide and glucagon-like peptide-1), and neural stimulation influence insulin release
• The insulin receptor, a tetramer with tyrosine kinase activity, is activated upon insulin binding
• Insulin binding initiates autophosphorylation of the cytosolic domain, followed by phosphorylation of a cytosolic signaling protein

Glucagon - A Hormone for Fasting

• Glucagon primarily affects the liver
• Glucagon’s overall effect is to promote glycogenolysis and gluconeogenesis
• This action helps prevent fasting hypoglycemia
• Glucagon secretion from pancreatic α-cells is stimulated by low circulating glucose levels (<70 mg/L)
• Glucagon receptors are coupled to stimulatory G-proteins, increasing intracellular cyclic adenosine monophosphate
• Protein kinase A, stimulated by phosphorylation, simultaneously activates some enzymes while inhibiting others
• Glycogen phosphorylase is stimulated to mobilize glycogen, while glycogen synthase, which stores glycogen, is inhibited
• Phosphorylation also stimulates hormone-sensitive lipase in adipose tissues

Epinephrine - A Hormone for Fleeing or Fighting

• Epinephrine's metabolic actions are most noticeable in muscle and adipose tissue, but it also affects the liver
• Along with norepinephrine, epinephrine works to mobilize energy for the flight-or-fight response
• Glycogenolysis in muscle and the liver, and fat mobilization in adipose tissue are mobilized
• Muscle and adipose tissue contain β-adrenergic receptors, which, like glucagon, trigger a wave of phosphorylation by stimulating adenylate cyclase
• Glucose is mobilized from glycogen for energy in muscle, and free fatty acids (FFAs) are mobilized from adipose tissue
• Liver cells have α₁-adrenergic receptors, which operate through Gq-proteins, activating phospholipase C and a Ca++-dependent protein kinase
• Glycogen phosphorylase activation occurs as seen with glucagon

Glucocorticoids - Hormones for Sustained Stress

• The adrenal glands produce glucocorticoids for tissues to respond to long-term metabolic stress
• Adrenocorticotropic hormone released from the pituitary triggers glucocorticoid synthesis
• Glucocorticoids have a slower response time, acting over days
• The overall effect is anti-insulin or "counter-regulatory" by down-regulating insulin receptor substrate
• Rather than using second messenger pathways, glucocorticoids affect nuclear DNA, changing the rates of enzyme synthesis

Key Points About Hormonal Influences on Metabolism

• Insulin and glucagon are key short-term regulators of blood glucose under normal conditions
• Insulin lowers blood glucose (hypoglycemic effect), while glucagon raises it (hyperglycemic effect)
• Insulin primarily dephosphorylates enzymes, while glucagon primarily phosphorylates them

The Well-Fed State

• Glucose influx from the gut primarily regulates metabolism in the well-fed state
• A high insulin/glucagon ratio marks up to 4 hours, caused by dietary glucose absorption

Liver Metabolism in the Well-Fed State

• In the well-fed state, insulin promotes glycogen, fat, and cholesterol synthesis in the liver
• To handle the high influx of glucose, glucokinase is adapted
• Glucokinase is active only at high glucose concentrations (10 to 20 mmol/L) and is not inhibited by G6P
• The less active phosphorylated form of glycogen synthase can quickly store increased G6P as glycogen
• Insulin triggers the conversion of glycogen synthase to its fully active dephospho- form, increasing phosphatase activity
• Abundant acetyl-CoA is produced from this pyruvate, which is used for FFA and cholesterol synthesis
• Pentose phosphate pathway substrate, increased G6P provides NADPH (nicotinamide adenine dinucleotide phosphate) which is required for FFA syntehsis
• FFAs are esterified as triglyceride and transported in VLDL (very-low-density lipoprotein) to adipose tissue
• Insulin stimulates the conversion of acetyl-CoA to cholesterol by activating β-hydroxy-β-methylglutaryl CoA reductase
• VLDL particles transport synthesized cholesterol and triglycerides to periphery tissues

Adipose Tissue Metabolism in the Well-Fed State

• A high insulin/glucagon ratio stimulates pathways leading to triglyceride synthesis and storage in adipose tissue after a meal
• GLUT4 increases glucose, which increases glycolysis for the production of glycerol 3-phosphate which is the backbone for FFA esterification
• Increased activity of pyruvate dehydrogenase provides acetyl-CoA
• Insulin inhibits hormone-sensitive lipase, which prevents fat mobilization
• Regulation of Lipoprotein lipase by insulin increases uptake of FFAs from VLDL and chylomicrons for incorporation into triglycerides

Muscle Metabolism in the Well-Fed State

• Energy storage in muscle is promoted by the high insulin/glucagon ratio
• GLUT4 and glycogen synthase is activated while increasing amino acid, leading to glycogen and protein formation resulting in muscle growth
• Muscle also is a source for carbon skeletons for hepatic gluconeogenesis during fasting

Brain Metabolism in the Well-Fed State

• The brain relies on aerobic glucose metabolism becaus it cannot use FFAs and has no stored glycogen reserves

The Fasting State

• Fuel absorption from the gut ends which is determined by decreasing glucose from the blood
• After the last meal (postprandial) which is approximately 3 hours, the fasting state begins which can extend from 4 to 5 days
• The declining insulin/glucagon ratio causes metabolism to increase reliance on glycogenolysis which is followed by gluconeogenesis to maintain blood glucose

Liver Metabolism in the Fasting State

• Glucagon causes glycogen breakdown (glycogenolysis) and glucose synthesis
• An increased in cyclic adenosine monophosphate is stimulated, leading to an increase in phosphorylation by protein kinase A
• Enzymes activate such as glycogen phosphorylase which are involved in glycogen degradation
• Fructose-2,6-bisphosphatase (F2,6-BP) becomes reduced leading to reverse glycolysis
• Pyruvate kinase becomes inactivated while amino acids from muscle degradation provides the carbon skeletons for gluconeogenesis
• The liver metabolizes increased concentrations of NH4+ resulting in excess urea excretion through urination
• Fatty acids derived from lipolysis gives energy for gluconeogenesis which raises acetyl-CoA and citrate concentrations
• Acetyl-CoA activates pyruvate carboxylase, which converts pyruvate to oxaloacetate.
• Increased ATP inhibits glycolysis while providing energy for gluconeogenesis.
• Adipose glycerol is taken up by the liver for hepatic gluconeogenesis

Adipose Tissue Metabolism in the Fasting State

• Epinephrine are released which lead to active hormone-sensitive lipase which then splits triglycerides into FFAs and glycerol
• Glycerol is converted to glycerol 3-phosphate in the liver and is a substrate for gluconeogenesis

Muscle Metabolism in the Fasting State

• Protein synthesis is not induced due to the absence of insulin which leads to degradation of protein. The aminos provide needed carbons for the hepatic gluconeogenesis
• Transport of Alanine creates the Alanine Cycle, which transports more pyruvate but creates no glucose
• FFAs are a major fuel source and glycogen degradation provides more glucose for short amounts of exertion (G6Pase is not produced to contribute to blood glucose)

Brain Metabolism in the Fasting State

• Hepatic glycogenolysis and gluconeogenesis helps maintain blood glucose concentrations so that the brain is constantly using glucose

The Starvation State

• Metabolic state cannot anticipate for the next meal because it shifts towards conserving blood glucose and spares protein due to no breaking down them to maintain glucose
• Fatty acids and ketone bodies allows the body to maintain blood glucose and save muscle protein because there is less urea excretion
• Ketosis is the result of increased hepatic production

Liver Metabolism in the Starvation State

• In the absence of insulin means Fatty acids continue to mobilize as the only spot for fat oxidation
• Ketones produced by ketogenesis supplies energy, but not the erythrocytes or the liver
• Gluconeogenesis slows as the bodies supply for amino acids decreases. The release of glycerol in adipose tissue keeps the low level of gluconegenesis in the liver

Adipose Tissue Metabolism in the Starvation State

• Hormone-sensitive lipase are activated due to the absence of insulin or high amount of epinephrine leading to mobilzed FFAs
• Liver and muscle does not burn erythrocyctes
• Glycerol released, from lipase activity, provides carbons for gluconeogenesis

Muscle Metabolism in the Starvation State

• Due to most of it's energy derived from FFA and ketone bodies, proteins can degrade less
• Muscle relies more on FFAs to save glucose and ketone for the brain

Brain Metabolism in the Starvation State

• Saving blood glucose, the brain uses ketone

The Untreated Type 1 Diabetic State

• Absent amount of Insulin is due to destruction of B-cell. Leading to similarities between states. Metabolic abnormalitlies include
  • Hyperglycemia by the increased output of glucose and no uptake by GLUT4 in Muscle
  • Muscle becomes degraded due to loss of muscle protein
  • Excessive amount of mobilization which creates Ketoacidosis
  • Lipoprotein is is decreased to cause Hypertriglyceridemia

Liver Metabolism in Type 1 Diabetes

• Leads to signaling of low glucose and stimulates the creation of excess glucose

Adipose Tissue Metabolism in Type 1 Diabetes

• leads to excess formation of Ketone to produce by the protein production via the liver
• Increased by lipoprotein prevents the amount of elevation

Muscle metabolism in Type 1 Diabetes

• Since transport of glucose for uptake cannot occur, protein synthesis cannot occur and is being degraded leading to abnormal concentrations of the blood.