SF4 Exam 2 General Flashcards
PTH Related Protein (PTHrP)
Sequence homology with PTH on N-terminal end. Paracrine/autocrine regulatory effect.
Function: Regulates Calcium flux through placenta (mom->child) during development. No calcium homeostasis effect in healthy adults
Fate of Mature Osteoblasts
- 50-70% undergo apoptosis
- Lining Cells covering new bone
- Osteocytes
Cortisol Effects on Lipid Metabolism
- Induces synthesis of hormone sensitive lipase
- Enhances Epinephrine/GH stimulation of Lipolysis
- Promotes fat deposition (excess Cortisol via appetite)
How do Glucosteroids usually effect the processes in target tissues?
Mostly has a permissive role in regulating function rather than initiating it
DIT + DIT
T4
Malonyl CoA
Blocks entrance of Fatty Acids into Mitochondria
- Increased by Insulin
- Decreased by Glucagon
Converts Dopamine to Norepinephrine within Secretory Granule
DBH
Layers of Adrenal Gland by Primary Secretion
Adrenal Cortex:
- Zona Glomerulosa – Aldosterone
- Zona Fasciulata – Glucocorticoids
- Zona Reticularis – Androgens
Adrenal Medulla: Catecholamines
Transports Iodide from Blood to Thyroid Gland
Na/I Symporter (NIS)
Utilizes gradient created by Na/K-ATPase
Major Source of IGF-1
Liver
Thyroid-Associated Opthalmopathy
Sign of Thyrotoxicosis assocciated typically with Graves Disease but also other Thyrotoxicosis
Characteristics:
- Periorbital Edema
- Proptosis (Graves Specific; not from TH)
- Lid Retraction (Other forms of Thyrotoxicosis too)
Lineage of Osteoclsts
Precursor cells derived from Monocyte/Macrophage lineage recruited from circulation and activated.
Mononuclear cells fuse to form Multinucleated Preosteoclasts
These then differentiate into Osteoclasts
Physiological Roles of Iodothyronine Deiodinases
- Maintain circulating pool of T3
- Local regulation of T3 production (target tissue)
- Thyroid Hormone Inactivation
Cell converting Proglucagon into Glucagon
Pancreatic α Cells
Chronic Effects of ACTH Release
- Increased Growth/Cell Prolif. in Zona Fasciculata and Reticularis
- Increased Synthesis of Steroidogenic enzymes, LDL receptors, Other proteins
DNA Sequence THRs bind to
Thyroid Hormone Response Elements (TREs)
Stress/Vasopressin Effect on Cortisol Release
Stress induces AVP’s release by CRH-secreting neurons. It potentiates CRH-mediated ACTH (has no effect itself however)
Decrease IGFBP Affinity for IGF1
- Binding to target cells
2. Degradation by IGFBP Proteases
GLUT2
Bidirectional transporter with low affinity for glucose. Takes in glucose when levels in portal system high.
When hepatic glucose high (blood glucose < 5mM), glucose exits cell via GLUT 2
Provide Docking Sites in IGF-1 Receptor Pathway
- Phosphotyrosines on Receptor
2. Insulin Receptor Substrate-1 (IRS-1)
Products of Proinsulin Cleavage
- Insulin
2. C Peptide
Promotes Fatty Acid Synthesis in Liver
Insulin
ACTH Receptor in Adrenal Cortex
Melanocortin-2 Receptor (MC2R)
Inhibits OPG Production
PTH
Metabolic Processes Suppressed by GH
- Glucose Uptake & Oxidation
2. Protein Breakdown (Fed State)
Nuclear Localization Signal
Domain on Steroid Hormone receptors allowing it reside in nucleus or translocate to the nucleus when activated
Incretin Defect in T2DM
Incretin secretion intact; β cell response is impaired
Inhibits RANK-L Expression
Estradiol
Insulin Receptor
Receptor Tyrosin Kinase
α subunit inhibits β subunit’s tyrosine kinase activity in ABSENCE of insulin.
β subunit autophosphorylates its other residues and other intracellular tyrosines
Increases Glucokinase expression
Insulin
Mechanism of Reabsorption: Distal Convoluted Tubules
Transcellular (Saturable Active Transport)
Regulated by PTH (TRPV5)
Enzyme necessary to export glucose after gluconeogenesis
Glucose 6-phosphatase
Cause of Hyperinsulinemia
GH Excess
Glucose Transporter in β Cells
GLUT2
Matrix Digestion Products from Bone Resorption
Serve as markers in serum/urine
- CTX (C-Terminal Telopeptides of Type 1 Collagen)
- NTX (N-Terminal Telopeptides of Type 1 Collagen)
Mechanism for Genes Repressed by T3 Binding
- Transcription is stimulated in the absence of T3/THR
2. T3/THR bind to negative TRE to repress transcription
Iodothyronines
- Thyroxine (T4)
- Triiodothyronine (T3)
- Reverse T3 (rT3)
Calcium-Sensing Receptors (CaSR)
G-protein coupled receptor on Chief Cells. Monitor changes in Serum Ca.
Gi: Inhibit Adenylyl Cyclase
Gq: Activate Phospholipase C
Action: Phosphorylase Kinase and Inhibitor 1
Induce conversion of Phosphorylase b to Phosphorylase a, promoting Glycogenolysis
Precursor of Glucagon
Preproglucagon
Major Organ Involved in Calcium Homeostasis
1) Skeleton
2) Small Intestine
3) Kidneys
4) Parathyroid Glands
Enzyme Phosphorylating Glucose in β Cells
Glucokinase
Indicator of Daily Cortisol Output
24-hour urinary excretion of unmetabolized cortisol (even though 99% of urinary cortisol is metabolized)
Principal Targets of Insulin
- Liver
- Skeletal Muscle
- Adipose Tissue
GH Excess in Adulthood
Acromegaly
Serine Phosphorylation and Insulin
- Reduce signal intensity by serine phosphorylation on Insulin Receptor
- Phosphorylation of IRS proteins has inhibitory effect on transduction
Thyroid Hormone effects on Growth Hormone
- Synergistic/Permissive effect on action of Growth Hormone and others
- Stimulates Growth Hormone synthesis/release at Pituitary Gland
Rate-Limiting Step in Steroid Biogenesis
Transfer of Cholesterol to Inner Mitochondrial Membrane. See StAR protein
Cortisol Effects on Carbohydrate Metabolism
- Prevents Hypoglycemia
- Promotes Hepatic Gluconeogenesis
- Permissive Effect on Glycogen Formation
- Decrease GLUT-4 Translocation
Functions of IGF Binding Proteins (IGFBP)
- Provide circulating reserve of IGF
- Increase half-life of IGF
- Modulate bioavailability
- Potentiate/Inhibit IGF action
Mechanism of H+ Secretion by Osteoclasts
Membrane-Associated H+-ATPase. Dissolves Hydroxyapatite crystals in bone matrix
Catecholamine Transport in Blood
- Albumin (59%)
2. Free Catecholamines
Clinical markers of Hashimoto Thyroidits
- Anti-TPO antibodies
2. Anti-TG Antibodies
Signaling Pathway Activated by IGF-1
Ras/Map Kinase Pathway
PI-3 Kinase / Akt Signal Transduction Pathway
Part of Insulin effects. Activated Pi-3 kinase phosphorylates Phosphoinositides on cytoplasmic face of membrane.
Resulting Pi 3-phosphates serve as docking sites for signaling proteins, including PKB/Akt
Causes of Hypoglycemia
- Drugs potentiating effects of insulin or interfering with gluconeogenesis
- Insulinomas
- Rapid Gastric Emptying
- Adrenal/Pituitary Insufficiency
- Liver Disease
- Inborn error of Carb. Metabolism
Effects of IGF-1 Binding
- Stimulation of DNA, RNA and Protein Synthesis
- Cell Proliferation
- Insulin-like Effects on Adipose/Muscle Cells
(Adrenal) Medullary Plexus
Former from merging of Medullary Arterioles and Cortical Sinusoids
Lid Retraction
Occurs in Thyrotoxicosis due to over-activity of Sympathetic Nervous System. Not just in Graves Disease but other Thyrotoxicosis
Cushing Syndrome and Causes (ordered by importance)
Excessive Cortisol secretion
- Ingestion of Pharmacological Glucocorticoids
- Excessive Secretion of ACTH (Cushing Disease)
- Ectopic Non-Endocrine ACTH-secreting Tumor
- Adrenal Cortex Tumor
Secondary Aldosteronism
Caused by inappropriate activation of Renin-Angiotensin System
Glucose Transporter in Skeletal Muscle
GLUT4
Mechanism of Matrix Protein Digestion by Osteoclasts
Cathepsin K (Protease) secretion
Innervation of Adrenal Medulla
Cholinergic Preganglionic Fibers
24,25(OH)2D
Second most abundant circulating metabolite of Vitamin D.
Formed from 25(OH)D by 24-hydroxylase, expressed in the Kidney and 1,25(OH)2D target tissue
Insulin Effects on Carbohydrate Metabolism in Liver
- Promotes Glycogen Storage
- Promote Glycolysis
- Inhibits Glycogenolysis
- Prevents Release of Glucose
- Inhibits Gluconeogenesis
- Stimulates Fatty Acid Synthesis
Endemic Gioter
Low iodide intake common in third wold countries. Decreased Thyroid Hormone production leads to increased TSH output
Secondary Adrenocortical Insufficiency and Causes
Insufficient ACTH Production. Note: this wouldn’t affect Aldosterone
- Prolonged Administration of Pharmacological Glucocorticoids (negative inhibition of Axis, depression of ACTH leads to Adrenal Atrophy)
- Pituitary Lesion (associated with Panhypopituitarism)
Usually associated with Renin and Renal Insufficiency
Stimulates Production of IGF-Binding Proteins in the Liver
Growth Hormone
Definition: Sensitivity
Ability of target cell to recognize and respond to hormone in proportion to intensity of signal
Affect Circulating TBG Levels
- Malnutrition
- Liver/Kidney Disease
- Synthesis Stimulated by Estrogens
Mechanism of Reabsorption: Ascending Limb, Loop of Henle
Passive Paracellular and Transcellular
Phosphate Uptake in Small Intestine
Na+-Phosphate (Na+/Pi) Cotransporter (NaPi-IIb) on Apical Membrane.
Active transporter, using energy from Na/K-ATPase Na gradient.
Expression increased by:
1) Vitamin D3
2) Low Dietary Phosphate
Location of Magnocellular Cells
Supraoptic and Paraventricular Nuclei (Hypothalamus)
TRPV5
Epithelial Calcium Channel. Apical/luminal side in active Calcium Reabsorption in the Kidneys.
PTH induces its transcription and inhibits its removal from the plasma membrane.
Anions Competing for Sites on NIS
- Perchlorate (HCLO4-)
- Thiocyanate (CNS-)
- Pertechnetate (TcO4-)
Lipoprotein Lipase
Synthesis induced by Insulin in fat and skeletal muscle cells.
LPL is translocated to Endothelial cells and breaks down TAGs associated with circulating Chylomicrons and VLDLs.
Converts them to Fatty Acids and Glycerol
Primary Hypothyroidism and Causes
Failure of the Thyroid Gland
- Hashimoto’s Thyroiditis (95% in US)
- Inadequate Dietary Iodine
- Surgical Removal, Radioactive Iodine Treatment, Antithyroid Drug Administration
P450c17
Enhances 17,20-lyase activity. Protein expressed in Zona Fasciulata and Zona Reticularis.
Zona Reticularis has cofactors enhancing P450c17/17,20-lyase activity which mean it synthesizes mainly androgens and only small amounts of glucocorticoids.
Adrenocorticotropic Hormone Precursor found in all three zones of the Adrenal Cortex
All three can synthesis pregnenolone and progesterone from cholsterol
Clinical indicator of Adrenal Androgen Release
DHEA and DHEAS in plasma
Thyroid Hormone Levels during Fast
- T4 levels remain constant
2. T3 drops due to decrease in T4->T3 conversion
Bigger Effect: Thyroid Hormone Negative Feedback on Hypothalamus or Pituitary Gland?
Pituitary Gland
Definition: Threshold
Minimum concentration to produce detectable response
Release Pattern of Thyroid-Stimulating Hormone
Pulsatile with Circadian Pattern. Higher late in evening
Principal Regulator of PTH Secretion
Concentration of ionic calcium in Extracellular Fluid (Chief cells are very sensitive to 2-3% deviations)
Intracellular Mechanism of GHRH Binding
G protein activation of Adenylyl Cyclase. cAMP/PKA mechanism activates voltage-gated Ca2+ channels.
Mechanism for Genes Activated by T3 Binding
- Unoccupied receptor binds to TRE and functions as a repressor of gene transcription.
- Histone Deacetylase (HDAC) and Corepressor Proteins (CoR) recruited
- Binding promotes dissociation and association of separate Coactivator Protein Complex
Physiological Stimuli of GH Release
- Exercise
- Stress
- Sleep
- Postprandial Hypoglycemia
- Protein Rich Meal / IV infusion (Arginine esp)
- Sex Steroids
- Ghrelin
Apical membrane Calcium Channels in Small Intestine
- TRPV6
- TRPV5
Synthesis increased by Vitamin D3
Anti-Inflammatory Effects of Cortisol
- Blocks expression of pro-inflammatory Cytokine Genes (TNFα, Interleukin-1)
- Inhibits Phospholipase A2
- Inhibits NO Synthase expression
- Inhibits release of Histamine and Serotonin from Mast Cells
- Inhibits release of Proteolytic Enzymes from damage tissues/phagocytes
Primary Cause of Growth Hormone Excess
Pituitary Adenoma
Rate-Limited Step in Catecholamine Synthesis
Conversion of Tyrosine to DOPA by Tyrosine Hydroxylase
Cell Type Secreting PTH
Chief Cells
Trigger of Calcitonin Secretion
- Plasma Ca rising above 9 mg/dL
2. Gastrin (supraphysiological levels)
Somatomammotropin Family of Hormones
Single chain proteins containing intrachain disulfide bridges
Pituitary Hormones:
- Growth Hormone (GH)
- Prolactin (PRL)
Placental Hormones:
- Placental GH (hGH-V)
- Chorionic Somatomammotropin (hCS) / Placental Lactogen (hPL)
Dissociation Constant
Concentration when 1/2 of receptors occupied; Kd = [H] and also 1/Ka
Primary Source of Norepinephrine in Circulation
Nerve terminals
Release Structures for Anterior Pituitary Gland Secretion
- Primary Capillary Plexus of Median Eminence (Hypothalamus)
- Carried to Anterior Pituitary via Hypothalamohypophyseal Portal Vessels
- Terminate in Secondary Capillary Plexus in Anterior Pituitary
Principal Adrenal Androgen Released by Zona Reticularis
Dehydroepiandrosterone (DHEA). Primarily released as DHEA Sulfate (DHEAS)
Also small amounts of Androstenedione
Multiple blood samples of this hormone are taken at timed intervals and combined to test levels
Integrated GH Concentration
Mechanisms of Calcium Uptake in Small Intestines
Transcellular (affected by Vitamin D) and Paracellular
Paracrine Regulator in Pancreas Inhibiting Insulin and Glucagon Release
Somatostatin
Metabolic Processes Stimulated by GH
- Lipolysis (esp. Visceral fat)
- Gluconeogenesis
- Glycogenolysis
- Protein Production (Fed State)
- Pancreatic Cell Growth / Function
Cell converting Proglucagon to GLP-1, GLP-2
Intestinal L Cells
Fasting Actions of Glucagon
- Stimulates Glycogenolysis
- Inhibits Glycogen Synthase
- Inhibits Glycolysis
- Promote Glucogenesis
Location of Thyroid Gland
Two lobes either side of the trachea, below the Larynx
Summary of PTH Effects:
- Stimulates Calcium Reabsorption
- Stimulates Phosphate Excretion
- Stimulates Vitamin D Synthesis
- Serum/Urine Calcium: Increases
- Serum Phosphate: Decreases
- Urine Phosphate: Increases
Adrenal Hormone whose main stimulator is not ACTH
Aldosterone (Angiotensin II and K to lesser degree)
Prolongs lifespan of Osteoclasts
RANK/RANK-L system inhibits apoptosis in Osteoclasts
Steroid Hormone Transport in Blood
- Coritcosteroid-Binding Globulin (CBG)
- Sex Steroid-Binding Globulin (SHBG)
- Vitamin D-Binding Globulin
- Albumin (non-specific, low affinity)
- Free fraction
Intracellular Mechanism: β1,2,3-adrenergic receptors
increased cAMP
Hepatic Glycogenolysis
Mobilizes glycogen into glucose. Action mediated by cAMP
PKA Phosphorylates:
- Phosphorylase Kinase (activate)
- Inhibitor 1 (activate)
- Pathway inhibiting Glycogen Synthase Activity
Alkaline Phosphatase
Diffuse into blood and used as indicator of bone formation.
Levels elevated during childhood growth, following major fracture, and in certain bone destroying disease.
Transports Epinephrine back into Secretory Granule after conversion from NE
VMAT (again)
Mechanism to Regulate Quantity of PTH Released
Degradation of stored PTH in Secretory Vesicles. Increase in release of inactive C-terminal fragments when PTH not needed
Neuroglycopenia
Deficient supply of glucose to CNS
Precursor of Insulin
Proinsulin
P450scc
Side-chain cleave enzyme which converts Cholesterol to Pregnenolone.
Located in Inner Mitochondrial Membrane
Factors Controlling Osteoblast Growth/Differentiation
- Bone Morphogenic Proteins
- Growth Factors (ex: IGF-1)
- Cytokines (ex: Interleukins 1 and 6)
- Mechanical Forces
Propylthiouracil
Blocks iodination of Thyroglobulin and inhibits conversion of T4 to T3.
Antithyroid drug which could the cause of Primary Hypothyroidism
Humoral Hypercalcemia of Malignancy (HHM)
Tumors release humoral agents into circulation promoting resorption. Associated with a variety of malignant tumors.
PTHrP is the most common mediator
Causes of Symptoms of Hypoglycemia
- Sympathetic Activation
2. Neurogylcopenia
Neurons releasing Hypophysiotropic Hormones
Parvicellular Neurons (Hypothalamus)
Corticotrope (Hypothalamic and Anterior Pituitary Hormones)
Hypothalamic Hormones:
- Corticotropin-Releasing Hormone (CRH) [++, Gs]
- Arginine Vasopressin (AVP) [++, Gq]
Anterior Pituitary Hormones:
- Adrenocorticotropic Hormone (ACTH)
- Beta-Lipotropin (β-LPH)
Diabetic Ketoacidosis
First indicator in children/adolescents with T1DM (not always.
- Uncontrolled hyperglycemia
- Metabolic acidosis
- ketosis
Serious Acute Complications in T1DM
- Diabetic Ketoacidosis
2. Hyperosmolar Hyperglycemic State (HHS)
PTH Effect on Vitamin D Metabolism
Induces 1α-renal hydroxylase activity in the Proximal Tubules (conversion of 25(OH)D3 to 1,25(OH)2D3)
Organification of Thyroglobulin
Binding of Oxidized Iodide to Thyroglobulin
Hormone Abnormality leads to Hypercholsterolemia
Hypothyroidism
Phospholipase A2
Catalyzes synthesis of inflammatory agents such as Prostaglandins, Thromboxanes, and Leukotrienes from Arachidonic Acid
Synthesis inhibited by Cortisol
Stimulates RANK-L Expression
PTH
Test Most Commonly Used when Endocrine Gland Hyperfunctional
Suppression Test
Cells Secreting Catecholamines into Blood Stream
Chromaffin Cells
Enzyme Hydroxylating 25(OH)D to 1,25(OH)2D
Renal 1α-hydroxylase
Action of Thyroid Hormone in Prolonged Fast
15-20% decrease in basal metabolic rate
Wolff-Chaikoff Effect
Thyroid Gland Autoregulation.
Ingestion of excessive amounts of iodine suppresses thyroid hormone synthesis. Suppresses expression of NIS and Thyroid Peroxidase.
Type of Neurons Posterior Pituitary Gland Axons Originate from
Unmyelinated axons from Magnocellular Neurons
Definition: Maximum Response
Effect produced by a saturating concentration of hormone
Neurophysin Domain
Found on the prohormone of ADH/Oxytocin.
Cleaved off and acts as a Intraneuronal Carrier, binding the hormone. Released alongside the hormones by with no physiological function.
Bone Resorption Initiation
Binding of hormones, cytokines, or other factors to receptors on Osteoblasts.
- Osteoblasts degrade unmineralized osteoid
- Increase expression of RANK-L
- Synthesize and release M-CSF
Cell Secreting Calcitonin
Parafollicular Cells (C Cells of Thyroid)
Effects of Chronically-Elevated Insulin Levels (on Insulin Receptors)
- Increased rate of receptor-mediated endocytosis
2. Decreases rate of Insulin Receptor synthesis
Blood Transport of Glucocorticoids
- Corticosteroid Binding Globulin (CBG) (75%)
- Albumin (15%)
- Free Cortisol
Steroid Hormone Receptors when Unoccupied
Form complexes with Chaperone Proteins (Heat-Shock Proteins). When steroid binds it dissociates.
Conversion Products of DHEA and Androstenedione Peripherally
- Testosterone
2. Dihydrotestosterone
Gonadotrope (Hypothalamic and Anterior Pituitary Hormones)
Hypothalamic Hormone:
1. Gonadotropin-Releasing Hormone (GnRH) [++, Gq]
Anterior Pituitary Hormone:
- Follicle Stimulating Hormone (FSH)
- Lutenizing Hormone (LH)
Majority Source of Circulating T3 and rT3
Peripheral Metabolism of T4
Especially: Liver and Kidney
Stimulates OPG Production
Estradiol
Thyroid Hormone Effects on Metabolism
Potentiates Catecholamine Effects on:
- Lipolysis
- Glycogenolysis
- Gluconeogenesis
Likely by β-adrenergic receptor upregulation
Catalytic Activity of GH Receptor
No intrinsic activity; relies on Janus Kinases (JAK2)
Main IGF Binding Protein
IGFBP-3
How are the two forms of Growth Hormone produced
Differential splicing of mRNA
Thyroid Hormone Negative Feedback
Hypothalamus:
1. T3 inhibits prepro-TSH gene expression
Pituitary (Major):
- Negative Response Element for Thyroid Hormone Receptor for TSH Subunit genes
- Intracellular T3 downregulates TSH Receptor
Mediators of Glucagon Release during Hypoglycemia
- Sympathetic Stimulation
2. Rise in Circulating Catecholamines (β2 receptor)
Sympathetic Nervous System Effect on Insulin Release
Exercise and stress inhibit insulin release.
Mediated by α2-adrenergic receptors coupled to Gi protein
Promotes Transcription of Tyrosine Hydroxylase
Acetlycholine
Adrenal Hormones with Negative Feedback Inhibition of ACTH Release
Only Cortisol.
Androgens and Aldosterone do not.
Compact Bone
80% of total bone mass. Densely packed matrix making it firm and strong. Forms the shafts of long bones. Covers ends of long bones and surfaces of other bones.
Primary Target of Glucagon
Liver
- Glycogenolysis
- Gluconeogenesis
Non-Autoimmune Causes of Thyrotoxicosis
Ordered by Occurrence
- Toxic Multinodular Goiter (incidence higher in iodine deficient areas; hyperfunctioning nodules)
- Toxic Adenoma (single hyperfunctioning nodule; Gain-in-Function TSH Receptor Mutation)
- Secondary Hyperthyroidism from TSH-Secreting Pituitary Adenoma
Paracrine Suppressors of Glucagon
Insulin and Somatostatin