11.1 Hormones

Hormones as metabolic chemistry

The Chemistry domain is 13% of NBCE Part I (Session 2). This section is the hormone slice of that domain: chemical classes, mechanisms of action, and metabolic effects on carbohydrate, lipid, and protein pathways. Endocrine physiology of tropic axes, pulsatility, and feedback lives in the physiology chapter. Here the exam question is usually of the form: given a fed, fasting, or stress state, which hormone, receptor, second messenger, and enzyme phosphorylation pattern fit?

A hormone is a chemical messenger released into blood (or a local paracrine/autocrine fluid) that changes target-cell enzyme activity or gene expression. For biochemistry items, classify every hormone three ways at once: chemical class, receptor location, and net effect on fuel metabolism.

Quick Answer: Insulin (peptide, receptor tyrosine kinase) is the only major anabolic hormone of the fed state. Glucagon, epinephrine, cortisol, growth hormone, and T3/T4 are catabolic or calorigenic overlays. Peptide and catecholamine signals start at the plasma membrane; steroids and thyroid hormone start in the nucleus.

Chemical classes: peptide, steroid, amine

Peptide and protein hormones are gene products. Ribosomes assemble a preprohormone with an N-terminal signal peptide that threads the chain into the rough endoplasmic reticulum. Cleavage of the signal peptide yields a prohormone; further cleavage in the Golgi and secretory granule yields the mature hormone plus any connecting peptides (C-peptide of proinsulin is the classic exam marker of endogenous insulin secretion). Peptides are stored in granules, are water-soluble, travel mostly unbound, have half-lives of minutes, and cannot cross the plasma membrane. They must use surface receptors. High-yield peptides for metabolic items: insulin, glucagon, growth hormone (GH), parathyroid hormone, calcitonin, adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), and the posterior-pituitary peptides antidiuretic hormone and oxytocin.

Steroid hormones are derived from cholesterol. Adrenal cortex and gonads do not store large hormone pools; they store cholesterol esters and synthesize hormone on demand. Steroids are lipid-soluble, travel bound to corticosteroid-binding globulin, sex hormone-binding globulin, or albumin, have half-lives of hours, and diffuse to intracellular receptors that act as ligand-activated transcription factors. High-yield metabolic steroids: cortisol, aldosterone (mineralocorticoid, less a fuel hormone than a Na+/K+ hormone), estradiol, progesterone, testosterone, and the secosteroid 1,25-dihydroxyvitamin D (calcitriol).

Amine hormones are tyrosine derivatives split into two very different families:

1. Catecholamines — dopamine, norepinephrine, epinephrine — synthesized in cytosol and chromaffin granules (tyrosine hydroxylase is rate-limiting; phenylethanolamine N-methyltransferase in the adrenal medulla converts norepinephrine to epinephrine and is induced by cortisol in the medullary portal blood). Catecholamines behave like peptides: stored, water-soluble, membrane G-protein-coupled receptors, seconds-long actions.
2. Thyroid hormones — thyroxine (T4) and triiodothyronine (T3) — iodinated tyrosines on thyroglobulin. They behave like steroids: protein-bound in plasma (thyroxine-binding globulin), long half-life, nuclear receptors, transcriptional effects over hours to days.

Mechanisms of action and second messengers

Membrane receptors change enzyme phosphorylation in seconds. Nuclear receptors change the amount of enzyme protein over hours. Mixing those clocks is a common wrong-answer pattern: cortisol does not translocate GLUT4 in two minutes; insulin does not induce PEPCK transcription as its primary hypoglycemic mechanism.

Insulin receptor is a receptor tyrosine kinase (RTK) tetramer (two alpha, two beta chains). Ligand binding autophosphorylates the beta chains, docks insulin-receptor substrate (IRS) proteins, and opens two branches: phosphoinositide 3-kinase (PI3K) → phosphatidylinositol-3,4,5-trisphosphate (PIP3) → Akt (protein kinase B) for metabolic effects, and a Ras-MAPK branch for growth. Akt phosphorylates AS160, allowing GLUT4 vesicles to fuse with the sarcolemma and adipocyte membrane. Akt also activates phosphodiesterase, lowering cAMP, so insulin chemically antagonizes glucagon at the second-messenger level, not only at plasma glucose.

Glucagon uses a hepatocyte Gs-coupled G-protein-coupled receptor (GPCR). Gs stimulates adenylyl cyclase → cyclic AMP (cAMP) → protein kinase A (PKA). PKA phosphorylates phosphorylase kinase (glycogenolysis), cAMP response element-binding protein (CREB) (gluconeogenic transcription), and the bifunctional enzyme phosphofructokinase-2 / fructose-2,6-bisphosphatase, which in liver is phosphorylated into the phosphatase form. Fructose-2,6-bisphosphate therefore falls. That single sugar phosphate is the reciprocal switch between glycolysis and gluconeogenesis: low fructose-2,6-bisphosphate turns phosphofructokinase-1 off and fructose-1,6-bisphosphatase on.

Epinephrine is not a second glucagon. Liver has both beta-2 (Gs-cAMP) and alpha-1 (Gq-Ca2+) adrenergic receptors, so hepatic glycogenolysis can be driven by PKA or by calcium-calmodulin activation of phosphorylase kinase. Skeletal muscle has no glucagon receptors. Muscle glycogenolysis during a fight-or-flight burst is epinephrine (and contraction-linked calcium), and the product is lactate for the Cori cycle, not free glucose, because muscle lacks glucose-6-phosphatase.

Insulin: the fed-state program

Insulin is released from pancreatic beta cells when glucose enters via GLUT2, is phosphorylated by glucokinase, and raises the ATP/ADP ratio, closing KATP channels, depolarizing the cell, and opening voltage-gated calcium channels. Incretins amplify the same path. Once in the blood, insulin rewrites fuel flow in three tissues.

Liver. Hepatocytes already have GLUT2, so insulin does not gate hepatic glucose uptake the way it gates muscle. It changes enzyme phosphorylation and transcription: induces glucokinase, acetyl-CoA carboxylase (ACC), fatty acid synthase, and HMG-CoA reductase; activates glycogen synthase by promoting dephosphorylation (protein phosphatase-1); inhibits glycogen phosphorylase, glucose-6-phosphatase, PEPCK, and hormone-sensitive lipase locally via lowered cAMP. Citrate and malonyl-CoA rise. Malonyl-CoA inhibits carnitine palmitoyltransferase-I (CPT-I), so newly made fatty acid is not immediately oxidized. Triacylglycerol is packaged as VLDL.

Skeletal muscle. GLUT4 translocation is the seconds-scale hypoglycemic event. Hexokinase phosphorylates glucose, glycogen synthase stores it, and amino acid uptake plus mTOR signaling support protein synthesis. Muscle does not release glucose into blood.

Adipose. GLUT4 plus glycolysis supply glycerol-3-phosphate. Insulin induces lipoprotein lipase on the capillary endothelium so chylomicron and VLDL fatty acids enter the adipocyte, and it dephosphorylates hormone-sensitive lipase, stopping lipolysis. Net: triacylglycerol storage, falling plasma free fatty acids.

Net protein effect is anabolic: decreased proteolysis, increased translation. That is why untreated insulin-deficient diabetes produces wasting plus hyperglycemia, not just a high glucose number.

Glucagon, epinephrine, cortisol, GH, and thyroid hormone

Glucagon (alpha cell; inhibited by insulin and glucose, stimulated by amino acids and sympathetic input) is a liver hormone. PKA-driven glycogenolysis covers the first overnight hours. As liver glycogen empties, glucagon plus falling insulin raise PEPCK, fructose-1,6-bisphosphatase, and glucose-6-phosphatase, and they lower malonyl-CoA so CPT-I delivers fatty acyl-CoA to mitochondria. Beta-oxidation generates NADH, FADH2, and acetyl-CoA. When oxaloacetate is diverted to gluconeogenesis, acetyl-CoA is shunted to ketone bodies (acetoacetate, 3-hydroxybutyrate). Muscle and brain (after adaptation) oxidize ketones; liver cannot because it lacks succinyl-CoA:acetoacetate CoA transferase.

Epinephrine is the acute-stress amplifier. In adipose, beta-adrenergic PKA phosphorylates hormone-sensitive lipase and perilipin, flooding plasma with free fatty acids. In muscle, it mobilizes glycogen. At the pancreatic islets, alpha-2 receptors inhibit insulin release and beta-2 receptors stimulate glucagon, stacking the deck toward glucose output. Exam trap: glucagon does not explain an exercising muscle's glycogen drop; epinephrine and calcium do.

Cortisol is the chronic-stress steroid. The glucocorticoid receptor translocates to the nucleus and binds glucocorticoid response elements. It induces PEPCK, glucose-6-phosphatase, and tyrosine aminotransferase, supplies gluconeogenic carbon by stimulating muscle proteolysis, and reduces peripheral glucose uptake (anti-insulin). Lipolysis increases, with central fat redistribution as a longer-term phenotype. Cortisol is permissive for glucagon and epinephrine: without it, the cAMP machinery is less effective. That is why Addisonian patients crash glucose under stress, and why Cushing physiology is diabetogenic.

Growth hormone uses JAK2-STAT signaling. Direct metabolic effects are lipolysis and decreased glucose uptake (the diabetogenic action). Indirect effects run through hepatic insulin-like growth factor-1 (IGF-1): amino acid uptake and protein synthesis, chondrocyte growth. GH is therefore simultaneously catabolic for fat and anabolic for protein — the opposite of cortisol's protein wasting.

T3/T4 bind the nuclear thyroid hormone receptor (often as a heterodimer with the retinoid X receptor) and induce Na+/K+-ATPase, respiratory enzymes, and uncoupling proteins. Basal metabolic rate, oxygen consumption, and heat rise. Fuel cycles speed in both directions: glycogenolysis and gluconeogenesis both increase, as do lipolysis and, with adequate insulin, glucose oxidation. Thyroid hormone up-regulates beta-adrenergic receptors, which is why hyperthyroid patients look sympathetically driven. Hypothyroidism lowers BMR and raises LDL because hepatic LDL-receptor expression falls.

Reciprocal enzyme switches worth memorizing

Fuel hormones rarely invent new reactions. They flip the same liver switches:

1. Fructose-2,6-bisphosphate — insulin raises it (PFK-1 on, FBPase-1 off); glucagon lowers it.
2. Glycogen synthase versus glycogen phosphorylase — insulin dephosphorylates (synthase on); glucagon/epinephrine phosphorylate (phosphorylase on).
3. Acetyl-CoA carboxylase — insulin dephosphorylates ACC (malonyl-CoA up, FA synthesis on, CPT-I off); glucagon phosphorylates ACC (the reverse).
4. Hormone-sensitive lipase — insulin off; glucagon/epinephrine/cortisol on.

If a stem says “hours of transcriptional change” think cortisol or T3. If it says “minutes after a meal” think insulin phosphorylation state and GLUT4. If it says “minutes after a scare, muscle glycogen falling” think epinephrine, not glucagon.

/practice/nbce-part1Practice questions with detailed explanations