Endocrinology

• Guanylate cyclase is a membrane receptor with enzymatic activity:

  1. Ligand binds to receptor guanylate cyclase
  2. Receptor catalyzes GTP > cGMP
  3. This acts as second messenger, binds protein kinase G (PKG)
  4. PKG phosphorylates serine or threonine residues
• Receptor tyrosine kinase (RTK):

  1. Ligand binds
  2. Receptors dimerize and autophosphorylate
  3. Phosphorylated receptors will activate protein kinases
  4. These will signal to Ras protein
  5. This binds GTP and becomes active
  6. It then phosphorylates MAPKKK > MAPKK > MAPK
  7. MAPK can phosphorylate other protein kinases, transcription factors, and proteins
• Serine/threonine kinase receptor:

  1. Ligand binds Type I receptor
  2. Receptor dimerizes with Type II receptor
  3. Type II receptor phosphorylates Type I receptor
  4. Activated Type I receptor phosphorylates a SMAD protein
  5. This will enter the nucleus and regulate gene expression
• The hypothalamus controls the adenohypophysis/anterior pituitary gland via the release of neurohormones:

  • TRH = thryotropin-releasing hormone
  • GnRH = gonadotropin-releasing hormone (releases FSH and LH)
  • CRH = ACTH-releasing hormone
  • GHRH = GH-releasing hormone and GHIH = GH-inhibiting hormone
• Information on GH:

  • release from anterior pituitary is stimulated by GHRH and inhibited by GHIH
  • moves to both liver and somatic tissues, which both release IGFs, promoting somatic growth
• Prolactin is a hormone released by the anterior pituitary; it stimulates milk synthesis and mammary gland development, as well as maternal behavior.
• Peptide hormones:

  • Synthesis: first as preprohormones, must be processed
  • Storage: in intracellular vesicles
  • Solubility: hydrophilic (water) / lipophobic
  • Receptors: transmembrane
  • Effects: rapid
  • Transport: dissolved in ECF
  • ex: GH, insulin, glucagon, prolactin, ACTH
• Steroid hormones:

  • Synthesis: derived from cholesterol
  • Storage: must be synthesized on demand
  • Solubility: hydrophobic (water) / lipophilic
  • Receptors: intracellular
  • Effects: slower b/c they affect transcription
  • Transport: protein-bound
  • ex: testosterone, estrogen
• Amine hormones:

  • Synthesis: derived from Tyrosine
  • Storage: can vary
  • Solubility: hydrophilic; thyroid hormones are hydrophobic
  • Receptors: transmembrane; sometimes intracellular
  • Effects: rapid OR slower
  • Transport: dissolved in ECF; sometimes protein-bound
  • ex: epinephrine, norepinephrine, thyroid hormones
• Cretinism is caused by insufficient thyroid hormone during fetal and neonatal development, and is a condition of severe mental retardation and growth defects.
• Thyroid hormones play a role in thermogenesis. In response to cold weather, these hormones will increase cellular metabolism at body tissues, thereby releasing heat.
• Information on adrenocorticotropic hormone, or ACTH:

  • release from anterior pituitary is stimulated by CRH
  • regulates secretion of cortisol from the adrenal cortex, which suppresses the immune system in response to stress
• Oxytocin and AVP are both secreted from the hypothalamus and are released from the posterior pituitary gland.
• Major hormones of the pancreas:

  • Insulin: produced by beta cells, triggered by high blood glucose and promotes absorption of glucose from the blood
  • Glucagon: produced by alpha cells, triggered by low blood glucose and promotes synthesis of glucose
  • Somatostatin: produced by delta cells, major inhibitory hormone
  • others include gastrin (stomach acid) and VIP (osmolarity)
• Anterior pituitary gland produces 6 major hormones: GH, PRL, TSH, ACTH, LH, and FSH
• IGF-1 is a peptide with 4 domains. A and B domains are very similar to insulin, and the hormone itself is released from the liver or somatic tissues.
• 98% of the pancreas consists of exocrine tissue that produces pancreatic enzymes and sodium bicarbonate, which are excreted by the pancreatic duct. The other 2% is endocrine tissue, which secretes insulin and glucagon.
• Somatostatin is a major inhibitory hormone that inhibits the release of GH, insulin and glucagon, prolactin, TSH, adenylyl cyclase, and exocrine secretion of the pancreas, among other things.
• Beta cells produce insulin; alpha cells produce glucagon.
• Pathways regulating insulin secretion (ex: you eat a meal, and then...):

  1. Detection of increase in blood glucose > stimulation of pancreatic beta cells > insulin
  2. Activation of glucose receptors in the digestive tract, which will secrete CCK > stimulation of beta cells, etc. (this happens before #1)
  3. Activation of stretch receptors in the digestive tract upon eating > stimulation of beta cells, etc. (feed-forward; does not need glucose)
• Synergism: when 2 or more hormones work together to increase target cell response much more than expected by additivity
• Type 1 diabetes is due to the loss of beta cells of the pancreas, resulting in little to no insulin production. It is mainly caused by autoimmunity, but could also be caused by trauma or damage to pancreatic cells or could be idiopathic.
• Type 1 diabetes can cause a diabetic coma when a person becomes hyperglycemic (not enough insulin) or hypoglycemic (took too much insulin).
• Type 1 diabetes can be treated with insulin replacement therapy, insulin agonists, or dietary control, but there is no cure available.
• Characteristics of type 2 diabetes include:

  • insensitivity to endogenous insulin
  • excess abdominal fat due to inflated fat cells
  • hyperplasia (proliferation) of beta cells (more insulin)
• Type 2 diabetes must be treated via natural methods such as lifestyle changes and controlled diet.
• The hypothalamic-pituitary-adrenal axis is the vertebrate stress response:

  • Hypothalamus: secretes CRH
  • Anterior pituitary: secretes ACTH
  • Adrenal cortex: secretes cortisol, which inhibits CRH and ACTH release
• Adrenal gland: 2 parts

  • medulla: catecholamines (epi and norepi)
  • cortex: corticosteroids (cortisol, aldosterone, androgens)
• Short term stress is well treated by cortisol, but long term or chronic stress can lead to inflammatory diseases due to suppression of the immune system.
• Addison's disease is a result of low cortisol levels (ACTH levels become high).
• Cushing's disease is a result of high cortisol levels, and could be ACTH-dependent (result of excessive ACTH) or ACTH-independent (result of excessive cortisol production for some other reason).
• Symptoms of Cushing's disease include obesity, skin changes (stretch marks), hypertension, and gonadal dysfunction.
• Symptoms of Addison's disease include weight loss, weakness and fatigue, nausea, vomiting, hypotension and hypoglycemia.
• The adrenal gland is involved in long-term stress response, mostly due to the effect of secreted glucocorticoids:

  • protein and fat break down > conversion > increased blood glucose
  • suppression of immune system
• Glucose is important in vertebrate stress response because it is the only energy source for neuronal cells in the brain.