12.2. Hormones
Page 1: Metabolic effects of Insulin and Glucagon
Insulin and glucagon play a dominant role in fuel metabolism
Four major organs involved: liver, adipose, muscle, and brain
These organs have unique sets of enzymes specialized for storage, use, or generation of specific fuels
These organs form a network where one tissue may provide substrates to another or process compounds produced by other organs
Page 3: Changes in circulating levels of hormones
Changes in hormone levels allow the body to store or make stored energy available
Hormones regulate energy storage and availability during different situations like abundance of food, survival crises, severe injury, and fight-or-flight situations
Page 4: Insulin production and metabolic effects
Insulin is a polypeptide hormone produced by the β cells of the islets of Langerhans in the pancreas
Insulin is the most important hormone coordinating the use of fuels by tissues
Insulin's metabolic effects are anabolic, favoring synthesis of glycogen, triacylglycerols, and protein
Page 5: Structure of insulin
Insulin is composed of 51 amino acids arranged in two polypeptide chains (A and B) linked by disulfide bridges
Insulin molecule contains an intramolecular disulfide bridge between amino acid residues of the A chain
Page 6: Different types of insulin
Pig and beef insulin differ from human insulin at one and three amino acid positions, respectively
Use of non-human insulin in humans can lead to the development of antibodies
Human recombinant insulin has eliminated this problem
Page 7: Insulin biosynthesis and storage
Insulin biosynthesis involves two inactive precursors, preproinsulin and proinsulin, which are sequentially cleaved to form the active hormone and C-peptide
C-peptide is essential for proper insulin folding and a good indicator of insulin production and secretion
Insulin is stored in cytosol granules and released by exocytosis when stimulated
Page 8: Intracellular movements and degradation of insulin
Insulin is degraded by the insulin-degrading enzyme insulinase in the liver and kidneys
Insulin has a short plasma half-life of approximately 6 minutes, allowing rapid changes in circulating levels
Page 9: Regulation of insulin secretion
Insulin secretion is closely coordinated with the release of glucagon by pancreatic α cells
Stimulation of insulin secretion occurs in response to various stimuli, including glucose, amino acids, and gastrointestinal hormones
Inhibition of insulin secretion is primarily mediated by epinephrine during stress or extreme exercise
Page 10: Stimulation of insulin secretion by glucose
Glucose is the most important stimulus for insulin secretion
Glucose also increases the expression of the gene for insulin
Page 12: Stimulation of insulin secretion by amino acids
Ingestion of protein causes a transient rise in plasma amino acid levels, leading to immediate insulin secretion
Elevated plasma arginine stimulates insulin secretion
Page 13: Stimulation of insulin secretion by gastrointestinal hormones
Gastrointestinal hormones like cholecystokinin, glucagon-like peptide-1 (GLP-1), and gastric-inhibitory polypeptide (GIP) favor insulin release
These hormones, known as "incretins," are released from the small intestine after food ingestion and cause an anticipatory rise in insulin levels
Page 14: Inhibition of insulin secretion by epinephrine
Epinephrine, secreted during stress or extreme exercise, inhibits insulin secretion
Epinephrine overrides the normal glucose-stimulated release of insulin, with the sympathetic nervous system replacing glucose concentration as the controlling influence
Page 16: Metabolic effects of insulin on carbohydrate metabolism
Insulin promotes glucose storage in liver, muscle, and adipose tissues
In the liver and muscle, insulin increases glycogen synthesis
In muscle and adipose tissues, insulin increases glucose uptake by increasing the number of glucose transporters GLUT-4
Page 19: Effects of insulin on lipid metabolism
Insulin decreases the release of fatty acids from adipose tissue
Insulin inhibits the activity of hormone-sensitive lipase, which degrades triacylglycerol
Insulin increases triacylglycerol synthesis by promoting glucose metabolism and increasing lipoprotein lipase activity
Page 22: Effects of insulin on protein synthesis
Insulin stimulates the entry of amino acids into cells and protein synthesis
Insulin activates factors required for translation, promoting protein synthesis
Page 24: Insulin receptor
Insulin receptor is synthesized as a single polypeptide and cleaved into α and β subunits
Binding of insulin to the receptor induces conformational changes and auto phosphorylation of specific tyrosine residues on the β subunits
Page 27: Signal transduction of insulin
Autophosphorylation of the insulin receptor initiates a cascade of cell signaling responses
Insulin receptor substrates (IRS) are phosphorylated and play a role in insulin signaling
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Phosphorylated IRS proteins interact with other signaling molecules through specific domains
Activates pathways that affect gene expression, cell metabolism, and growth
Insulin actions are terminated by dephosphorylation of the receptor
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Insulin binds to specific, high-affinity receptors in the cell membrane of most tissues
First step in a cascade of reactions leading to diverse biologic actions
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Insulin increases glucose transport in skeletal muscle and adipocytes
Promotes recruitment of insulin-sensitive glucose transporters (GLUT-4) from intracellular vesicles
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Two alternative processes for dephosphorylation of the insulin receptor
Dephosphorylation on the plasma membrane by dissociation of insulin
Internalization into the cytoplasm, degradation of insulin, and transport back to the plasma membrane
Receptor regulation
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Tissues not affected by insulin for glucose uptake: intestinal mucosa, red blood cells, β-cells of the pancreas, nervous tissue, kidney tubules, hepatocytes, cornea
Tissues that require insulin for glucose uptake: adipose tissue and resting skeletal muscle
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Long-acting modified forms of medical insulins
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Insulin binding leads to immediate increase in glucose transport into adipocytes and skeletal muscle cells
Insulin-induced changes in enzymic activity occur over minutes to hours
Insulin increases the amount of many enzymes, requiring hours to days
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Glucagon is a polypeptide hormone secreted by the α cells of the pancreatic islets of Langerhans
Glucagon opposes many actions of insulin
Glucagon maintains blood glucose levels through hepatic glycogenolysis and gluconeogenesis
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Glucagon is composed of 29 amino acids arranged in a single polypeptide chain
Glucagon amino acid sequence is the same in all mammalian species examined
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Glucagon is synthesized as a large precursor molecule (preproglucagon)
Converted to glucagon through selective proteolytic cleavages
Preproglucagon is processed into different products in different tissues
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Glucagon secretion is responsive to stimuli signaling hypoglycemia
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Glucagon secretion is increased by amino acids derived from protein meals
Prevents hypoglycemia resulting from increased insulin secretion after a protein meal
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Elevated levels of epinephrine stimulate glucagon release
Glucagon levels are elevated in anticipation of increased glucose use during stress, trauma, or severe exercise
Insulin levels are depressed in these situations
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Glucagon secretion is decreased by elevated blood glucose and insulin
Both substances are increased following ingestion of glucose or a carbohydrate-rich meal
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Glucagon activates lipolysis in adipose tissue
Free fatty acids released are taken up by the liver and oxidized for ketone body synthesis
Glucagon increases blood glucose through breakdown of liver glycogen and gluconeogenesis
Glucagon increases amino acid uptake by the liver, decreasing plasma levels of amino acids
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Glucagon binds to high-affinity G protein-coupled receptors on hepatocytes
Receptors for glucagon are distinct from those for insulin or epinephrine
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Glucagon receptors are not found on skeletal muscle
Glucagon binding activates adenylyl cyclase, leading to a rise in cAMP and activation of cAMP-dependent protein kinase
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Increasing enzymic activities through phosphorylation-mediated activation or inhibition of key regulatory enzymes in carbohydrate and lipid metabolism
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Hypoglycemia is characterized by CNS symptoms, blood glucose level ≤ 40 mg/dl, and resolution of symptoms with glucose administration
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Glucagon stimulates hepatic glycogenolysis and gluconeogenesis
Epinephrine promotes glycogenolysis and lipolysis, inhibits insulin secretion, and prevents glucose uptake by muscle and adipose tissues
Glucagon and epinephrine are critical in preventing or correcting hypoglycemia
Cortisol and growth hormone play a role in long-term glucose metabolism management
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Hypoglycemia is a medical emergency due to the CNS's requirement for continuous glucose supply
Elevated glucagon and epinephrine, combined with diminished insulin release, combat hypoglycemia
Hypoglycemia occurs when blood glucose levels fall below 4 mmol/L (72 mg/dL)
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Adrenergic symptoms of hypoglycemia include anxiety, palpitation, tremor, and sweating
Mediated by epinephrine release regulated by the hypothalamus
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Neuroglycopenic symptoms of hypoglycemia result from impaired glucose delivery to the brain
Symptoms include headache, confusion, slurred speech, seizures, coma, and death
Page 54: Insulin-induced hypoglycemia
Hypoglycemia occurs frequently in patients with diabetes receiving insulin treatment.
Mild hypoglycemia in conscious patients is treated with oral administration of carbohydrates.
Patients with hypoglycemia who are unconscious or unable to swallow are treated with glucagon, administered subcutaneously or intramuscularly.
Page 55: Postprandial hypoglycemia
Postprandial hypoglycemia is caused by an exaggerated insulin release following a meal.
It results in transient hypoglycemia with mild adrenergic symptoms.
The plasma glucose level returns to normal even without feeding.
Treatment usually involves eating frequent small meals instead of three large meals.
Page 56: Fasting hypoglycemia
Fasting hypoglycemia during fasting is rare but can be a serious medical problem.
It may result from a reduction in the rate of glucose production by hepatic glycogenolysis or gluconeogenesis.
Alternatively, it may be caused by an increased rate of glucose use by peripheral tissues due to overproduction of insulin.
Rare pancreatic tumors can also cause fasting hypoglycemia.
Page 57: Alcohol metabolism
Alcohol is metabolized in the liver through oxidation reactions.
Ethanol is converted to acetaldehyde by alcohol dehydrogenase.
Acetaldehyde is further oxidized to acetate by aldehyde dehydrogenase.
Disulfiram, an enzyme inhibitor, can cause the accumulation of acetaldehyde in the blood, leading to flushing, tachycardia, hyperventilation, and nausea.
Page 59: Alcoholic liver disease
Chronic alcohol consumption can result in alcoholic fatty liver.
Increased synthesis of triacylglycerols and decreased fatty acid oxidation contribute to the development of alcoholic fatty liver.
Alcoholic fatty liver can progress to alcoholic hepatitis and then to