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295 Cards in this Set
- Front
- Back
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Thyroid hormones -
general or specific action? |
General -- maintain metabolic stability
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What is dietary iodide required for?
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Synthesis of thyroid hormones
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How to peripheral tissue help regulate thyroid hormones?
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Converts T4 into T3
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What kind of receptor do thyroid hormones bind to?
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Intracellular receptor -- become transcription factors to alter gene transcription
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What are the main effects of thyroid hormones?
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1. increase protein synthesis
2. increase cell growth and maturation 3. increase cellular respiration 4. increase oxygen consumption and metabolic rate 5. increase food intake 6. increase cardiac output and thermogenesis |
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How is thyroxin "permissive"?
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Thyroxin (thryoid hormones) increase the amount of EPI receptors in the cell, so EPI can have a greater effect
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What do underactive and overactive follicles of the thryoid look like?
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Underactive -- flattened thyroid epithelial cells and icnreased colloid
Overactive -- tall, columnar epithelial cells and reduced colloid |
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Describe the organization of follicular cells
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Polar epithelial cell
APICAL: faces colloid: endocytosis of colloid into droplets attached to lysosomes, transports it through cell out BASAL: end faces capillary - secretes colloid droplets into circulation |
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Early action of TSH
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1. Stimulates GPCR on thyroid follicluar cells
2. Activates adenylate cyclase 3. Endocytosis of colloid 4. Mitochondrial respiration and cell metabolism |
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Late action of TSH
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1. Iodide uptake
2. Protein synthesis 3. DNA replication and mitotic activity |
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Where is iodide stored?
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- normally goes from GI (food intake) to thryoid for storage, then secreted as hormones - into tissue, out urine.
1. Thyroid - 8,000ug 2. As hormones (T4 & T3) - 600ug 3. GI tract (dietary) - 500ug 4. Urine - 488ug 5. ECF - 250ug |
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Thyroglobulin
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= colloid -- dimer produced by thyroid epithelial cells
- used by thyroid to produce T4 & T3 - contains 135 tyrosines and 1% iodine - iodinated thryroglobulin is stored in lumen of thryoid folicle |
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Thyroxin-binding globulin
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Bindings to thyroxine (thyroid hormones)in circulation. One of 3 hormones that carries T3 & T4 in bloodstream. Highest affinity for T3/4, but present at [lowest]. Carries the majority of T4 in circulation. Single binding site.
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Thyroid peroxidase
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Large membrane protein located on apical (towards colloid) side of follicular cells.
Catalyze iodination of thyroglobulin into T4 - efficiency decreases when thryoglobulin already contains some bound iodine. |
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How is thyroxin released from thryglobulin (colloid)?
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Proteases! - Lysosomal degredation of colloid droplets
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Levels of iodine & regulation of T4 vs T3?
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Low levels of iodine = more T3
High levels of iodine = more T4 |
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Where is T4 converted into T3?
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Liver & Kidney
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Amounts of T3 & T4 secreted by thyroid?
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Thyroid produces mostly T4. It produces a tiny bit of T3 and rT3. Most T3 is made from conversion of T4 into T3 in liver and kidney.
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Regulation of thyroxine secretion / feedback -- HPT axis:
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Hypothalamus (TRH) --> Pituitary (TSH) --> stimulates T4 & T3 release from Thyroid
T4 & T3 inhibit Pituitary & Hypothalamus. Somatosatin (from hypothalamus) also inhibits pituitary release of TSH. |
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How does TSH stimulate thryoid?
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* Binds to GPLR on thyroid follicular cell surface.
1. activates adenylate cyclase & cAMP 2. influx of Na+, efflux of iodide. 3. release of Ca2+ & activation of CaM --> activates PKs 4. Iodination of thyroglobulin and thyroid-hormone release (due to increased H2O2) 5. Endocytosis of colloid droplets & increase microvilli at apical surface 6. Increased cell metabolism 7. Protein synthesis 8. Iodide influx into cell (requires new protein synth for activation) |
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T3 vs. T4 production
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Twice as much T4 produced as T3
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Amount of T3 vs. T4 from thyroid
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Five x as much T4
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Comparison of metabolic potency of T3 vs. T4
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T3 is 3x more potent compared to T4
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Serum concentration comparison of T3 vs. T4
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100 times more T4
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How much T3 and T4 are as hormone in free form?
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Much more T3 is free (0.03) compared to T4 (0.002)
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How much T3 vs. T4 is intracellular?
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About 3x as much T3 is intracellular compared to T4
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What is the half life of T3 and T4?
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T3 = 0.75
T4 = 7.0 |
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What are the 3 Thyroid Binding Proteins?
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1. Thyroxine-binding globulin
2. Transthyretin 3. Albumin |
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Which cells synthesize thyroxine?
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Follicular/principle cells of thyroid
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Effects of Thyroxine:
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1.Increases cardiac output
2.Increases heart rate 3.Increases ventilation rate 4.Increases basal metabolic rate 5.Potentiates brain development 6.Thickens endometrium in females |
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T4 binding capacity of:
1. Thyroxin-binding globulin 2. Transthyretin 3. Albumin |
1. 21
2. 350 3. 50,000! |
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What are deiodonases?
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Enzymes that convert T4 into T3
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3 Types of iodothyronin deiodinase
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(1) Provides T3 for circulation. Inactivates T4 and T3. Degrades rT3.
(2)Provides intracellular T3 in pituitary, brain, adipose, & for circulation. (3)Inactivates T4 and T3. |
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Type 1 Iodothyronin Deiodinase
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- Provides T3 for circulation.
- Inactivates T4 and T3 - Degrades rT3 * Located in liver, kidney, and brain * prefers rT3>>T4>T3 |
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Type 2 Iodothyronin Deiodinase
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- Provides intracellular T3 in pituitary, brain, brown adipose
- Provides T3 for circulation * Located in pituitary, brain, adipose, placenta, thryoid, muscle * T4>=T3 * Decreases in response to hormone excess |
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Type 3 Iodothyronin Deiodinase
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Inactivates T4 and T3
* Located in brain, placenta, skin * T3>T4 * Increases in response to hormone excess |
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TRb1
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Thyroid hormone receptor
- liver, kidney, thyroid |
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TRb2
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Thyroid hormone receptor
- pituitary, hypothalamus, retina, inner ear |
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TRb3
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Thyroid hormone receptor
- heart and kidney |
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TRa1
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Thyroid hormone receptor
- heart, bone, brain |
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TRa2 and TRa3
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Thyroid hormones receptors which do not bind hormone
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Which thyroid hormone receptors do not bind hormone?
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TRa2 and TRa3
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How do thyroid hormone receptors work?
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T3 binds to receptor -- receptor forms heterdimer with unoccupied retinoid X receptor; zinc fingers attach to DNA; recruit coactivator --> act as transcription factor
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What kind of dimers does the thyroid hormone receptor form to become an active transcription factor?
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- Homodimers
- Heterdimers with retinoid receptor |
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What is the promoter sequence of the thyroid hormone receptor transcription factor?
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TRE -- thyroid hormone response element. It's located on the promoter of the T3 target gene.
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What does the thyroid hormone receptor do in the absence of T3?
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Binds to TRE and represses basal transcription. Co-repressors may also bind to the TR and limit access to transcription machinery.
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What do co-activators of TR do?
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Make chromatin more accessible to transcription.
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What does it mean that thyroxin is "permissive"?
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Thyroxin binds to thyroid hormone receptor -- increases transcription of epinephrine receptor on cells. Makes epinephrine able to bind to more receptors and increase activity.
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What happens to growth when there is no thyroid hormone?
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Normal whole body growth does not occur in the absence of TH, even when GH is present.
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5 effects of thyroid hormones
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1. Necessary for growth
2. Enhances growth hormone production by increasing GH txn in pituitary 3. Effects thermogenesis and tempterature 4. Promotes protein synthesis 5. Affects most aspects of carbo and lipid metabolism |
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Which bone region does not have any thyroid receptors?
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Hypertrophic zone
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What hormone regulates frog metamorphosis?
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thyroxine!
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When is there an increase in thyroxine in developing frog?
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Change from tadpole to frog
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What happens during perinatal period if deprived of thyroid hormone or iodine?
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sever mental & physical retardation; deafness, paralysis (cretinism)
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What disease is caused by lack of iodine perinatally?
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Cretinism (form of paralysis
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What is sporadic cretinism?
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Athyrotic (no thyroid) fetus developing in a normal mother
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What is autoimmune thyroiditis / Hashimoto's thyroditis?
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Low thyroxin, elevated TSH
- short stature - delayed skeletal maturation |
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What is a disease where there is low thyroxine and elevated TSH?
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Autoimmune thyroiditis / Hashimoto's thyroiditis
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What are 5 clinical symptoms of hypothyroidism?
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1. appearance - weight gain, corse skin, puffy due to glycosaminoglycans in skin and muscle; maybe goitre
2. disposition - cold, lethargic, depressed 3. neuromuscular function - changed tendon reflexes 4. Reduced cardiac output; slow pulse 5. altered gonadotrophin secretion (b/c of impaired estrogen metabolism) |
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Clinical symptoms of hyperthyroidism
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1. Weight loss
2. Goiter (maybe) 3. Agitated, easily fatigueable 4. Heat intolerance 5. Tachycardia / atrial fibrillation 6. Muscle weakness, loss of muscle mass |
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What is Graves disease?
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A form of hyperthyroidism
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Name diseases associated with hyperthyroidism and hypothyroidism
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hyper:
Graves disease hypo: Cretinism (also due to low iodine) |
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What is Graves disease?
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Hyperthyroidism:
- exessive and unregulated synthesis of iodothyroglobulin |
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What is one anti-thyroid drug and how does it work?
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Propylithiuracil / mercaptoimidazole
- blocks iodination of thyroglobulin by antagonizing thyroid peroxidase - results in the reducted production of T3 and T4 |
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What is thyroid peroxidase?
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Enzyme that iodinates thyroglobulin to form T3 and T4
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What are clinical characteristics of Graves Disease?
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1. Elevated T4 in serum
2. Increased uptake of radioiodine 3. Supressed levels of TSH in serum 4. Increased appetite but weight loss |
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Normal feedback mechanisms of thyroid hormone release
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T3/T4 inhibit pituitary (TSH release) and Hypothalamus (TRH release)
- if you give patient TRH you will see rise in TSH |
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Feedback mechanism seen in hyperthyroidism
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If you give patient TRH you do not see resulting rise in TSH
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How is energy stored?
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In the form of glycogen and fat
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What are two phases of metabolism?
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Anabolic and catabolic phase
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What is the main anabolic signaling hormone from the hypothalamus?
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NPY
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What is the main catabolic hormone from the hypothalamus?
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CRH
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What is one long term satiety signal?
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leptin from adipocyte to hypothalamus
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What is one short term satiety signal?
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CCK from gut through vagus to hypothalamus
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Which exocrine secretions come from the stomach?
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1. HCl - activates pepsin from pepsinogen. Solubalizes food particles, kills microbes
2. Pepsin - protein digesting 3. Mucus - lubricates / protects epithelial surface |
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What does the liver secrete?
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1. Bile salts - solubalizes fats
2. Bicarbonate - neutralizes HCl from stomach 3. Organic waste products and trace materials |
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What are enteroendocine cells?
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Singly distrubuted throughout gastrointestinal epithelium. Constitute the largest endocrine "organ"
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What hormones are produced by the pyloric antrum?
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1. gastrin (G cell) - stimulates HCL and pepsinogen release
2. Glucagon (A cells) - promotes conversion of glycogen to glucose in liver |
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What hormones are produced in the duodenum and iejunum?
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1. CCK (I cells) - stimulate pancreate enzyme release and gallbladder contraction
2. GIP (K cells) - stimulate insulin secretion 3. Motilin (Mo and EC cells) - stimulates gastroinestinal motility. 4. Secretin (S cells) - stimulates bicarbonate and water secretion by pancreaatic duct cells |
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Where is gastrin produced and what does it do?
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G cells of pyloric antrum.
Stimulates release of HCL and pepsinogen. |
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Where is glucagon produced and what does it do?
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A cells of pyloric antrum.
Promotes conversion of glycogen to glucose in the liver |
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Where is CCK produced and what does it do?
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I cells of duodenum and iejunum
Stimulates pancreatic enzyme release and gallbladder contraction |
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Where is motilin produced and what does it do?
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Mo and EC cells of duodenum and iejunum
Stimulates gastrointestinal motility |
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Where is secretin produced and what does it do?
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S cells of duodenum an diejunum
Stimulates bicarbonate and water secretion by pancreatic duct cells |
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What hormone is produced in the Ileum?
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Neurotensim (from N cells) - inhibits gastroinestinal motility
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What is neurotensin and where is it produced?
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N cells of Ileum
inhibits gastroinestinal motility |
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What hormone is produced in the large intestin?
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Glicentin (L cells) - promotes conversion of glycogen to glucose in the liver
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What is glicentin and where is it produced?
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L cells of large intestine
promotes conversion of glycogen to glucose in the liver |
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What hormones are produced in the stomach, small intestine, and large intestine?
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Somatostatin (D cells) - inhibits local secretion of gastrin, motilin, secretin, and GIP
Serotonin (EC cells) - stimulates gastroinestinal motility Substance P (EC cells) - stimulates intestinal motility |
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What does somatostatin do in the stomach/small intestine / large intestine?
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inhibits local secretion of:
- gastrin - motilin - secretin - GIP |
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Where in the GI tract is somatostatin secreted?
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D cells of stomach, small and large intestine
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Where in the GI tract is serotonin secreted?
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EC cells of stomach, sm/lg intestine
- stimulates GI motility |
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Where in the GI tract is substance P secreted and what does it do?
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EC cells of stomach, sm/lg intestine
- stimulates intestinal motility |
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Where is glicentin secreted and what does it do?
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L cells of large intestine
- promotes conversion of glycogen to glucose in the liver |
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Which two main hormones help convert glycogen into glucose?
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glucagon & glicentin
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What are 3 phases/stimuli for HCl secretion?
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1. SCephalic phase - parasympathetic nerves to enteric nervous system
- sight/smell/taste/chewing 2. Gastric phase - long and short neural reflexes and direct stimulation of gastrin secretion - distension / peptides / reduced 3. Intestinal phase - long and short neural reflexes; secretin; CCK; other duodenal hormones - distension/acidity/osmolarity/nutrient contents |
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Which mouse has a null mutation in the leptin gene?
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Genetically obese and diabeteic Ob/Ob mouse
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What regulates secretion of parietal cells?
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1. Gastrin
2. Histamine 3. ACh 4. Somatostatin 5. Gastrin releasing peptide |
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What does increased fatty acids and amino acids signal to the small intestine?
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Increase CCK secretion
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What does increased acid from the stomach signal to the small intestine?
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Increase secretin secretion
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What does increased plasma CCK (secreted from small intestine in response to intestinal fatty acids and amino acids) do?
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Signal pancreas to increase enzyme secretion
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What happens when pancreas increases enzyme secretion (in response to increased plasma CCK)?
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more digestion!
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What kind of feedback turns of secretin secretion in the small intestine?
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neg feedback from increased neutralization of intestinal acid (from bicarbonate)
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What cells of the pancreas secrete digestive enzymes?
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Exocrine cells
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What does increased plasma CCK do?
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Increases bile flow
1. Contracts gallbladder 2. Relaxes sphincter of Oddi |
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What regulates bile flow into small intestine?
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plasma CCK (which increases in duodenum due to increased fatty acids)
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Which hormones are members of the secretin family of peptides?
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1. Secretin
2. VIP (vasointestinal peptide) 3. GIP (gastroinestinal peptide) 4. glucagon |
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What are some peripheral signals of energy balance?
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1. leptin
2. insulin 3. ghrelin 4. PYY 5. OXM 6. GLP-1 7. PP 8. CCK |
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How much does an adrenal weigh?
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4-6g
tends to be larger in adolescence |
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What percent of the adrenal is cortex & medulla?
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cortex - 80-90%
medulla - 10-20% |
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From which cells is the adrenal derived?
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medulla - neural crest cells
cortex - mesodermal cells |
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Which cells produce epinephrine and norepinephrine?
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Chromaffin cells
- actually the adrenal produces 80% epinephrine |
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Effects of epinephrine
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Sympathomimetic - produces effects similar to those induced by having the sympathetic NS activated
- increased heart rate, BP, reduced blood to viscera, stimulates conversion of glycogen to glucose... |
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What are the layers of the adrenal gland?
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outer = capsule
cortex glomerulosa fasciculata retularis medulla |
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What do chromaffin cells produce and where are they?
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Adrenal medulla - produce 80% epinephrine, 20% norepinephrine
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Which layer of adrenal are mineralocorticoids produced?
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Cortex: zona glomerulosa
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Which layer of adrenal are glucocorticoids produced?
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Cortex: zona fasciculata
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Which layer of adrenal are gonadocorticoids produced?
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Cortex: zona fasciculata
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Which cells of adrenal produce epinephrine?
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chromaffin cells of medulla
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Which cells of adrenal produce norepinephrine
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chromaffin cells of medulla
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What does the adrenal medulla do?
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It is a modified sympathetic ganglion with postganglionic cells but not axons
- specialized to secrete catecholamines from chromaffin cells |
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What does one splanchnic nerve fiber innervate?
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Innervates many medullary cells -- can therefore cause massive discharge of catecholamines
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What are epinephrine-secreting chromaffin cells like?
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Less densely stained granules
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What are norepinephrine-secreting chromaffin cells like?
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Contain granules with very dense cores
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Of NE and EPI chromaffin cells, which are dense core and which are less dense?
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EPI - Less dense
NE - More dense |
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What is the starting material for NE and EPI?
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Tyrosine.
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Enzymes converting tyrosine into dopamine?
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1. Tyrosine hydroxylase
2. DOPA decarboxylase |
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Enzyme converting dopamine into norepinephrine
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DOPA-b-hydroxylase
(in granule) |
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Enyzyme converting norepinephrine into epinephrine
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PNMT (in cytoplasm)
(Phenylethanolamine N-methytransferase) |
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2 Enzymes that can be regulated in the production of Epinephrine
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1. Tyrosine Hydroxylase (by phosphorylation)
2. PNMT (under regulation of cortisol) |
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What are the 3 Major actions of epinephrine?
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1. Stress/arousal response
2. metabolic action 3. cardiovascular |
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How does release from chromaffin cells occur?
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- ACh comes in, depolarizes cell.
- Causes Ca2+ influx - exocytosis of EPI, DBE (dopa-b-hydroxylase), ATP, and chromagranin - NE is produced in cytosplasm |
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What are the effects of a-adrenergic receptor?
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1. Vasoconstriction
2. Iris dilation 3. Intestinal relaxation 4. Intestinal sphincter contraction 5. Pilomotor contraction 6. Bladder sphincter contraction |
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What are the effects of b-adrenergic receptors?
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b1:
1. cardioacceleration 2. Increased myocardial strength 3. lipolysis b2: 1. Vasodilation 2. Intestinal relaxation 3. Uterus relaxation 4. Bronchodilatation 5. Calorigenesis 6. Glycogenolysis 7. Bladder wall relaxation |
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What are some effects of b-adrenergic receptors?
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1. Vasodilation
2. Intestinal relaxation 3. Uterus relaxation 4. Bronchodilatation 5. Calorigenesis 6. Glycogenolysis 7. Bladder wall relaxation |
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What are some effects of a-adrenergic receptors?
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1. cardioacceleration
2. Increased myocardial strength 3. lipolysis |
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What does thyroxine do for adrenergic receptors?
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"permissive" -- increases their expression to increase the function of NE
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What is a "beta blocker"
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Actually blocks b-adrenergic receptors to help relieve increased blood pressure
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Name 6 things that increase food intake
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1. NPY
2. NE a-receptor 3. Melanin Concentrating hormone (MCH) 4. GHRH 5. Galanin 6. Opioid peptides |
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Name 9 things that decrease food intake
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1. DA
2. NE - b-receptors 3. 5-HT 4. CRF 5. Urocortin 6. Glucagon-like peptide 7. CCK 8. Insulin 9. Leptin |
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Does NPY increase or decrease food intake?
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Increase
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Does NE a-receptor increase or decrease food intake?
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Increase
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Does NE b-receptor increase or decrease food intake?
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Decrease
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Which NE receptor increases food intake?
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a-receptor
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Which NE decreases food intake?
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b-receptor
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Does 5-HT increase or decrease food intake?
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Decrease
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Does GHRH increase or decrease food intake?
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Increase
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Does urocortin increase or decrease food intake?
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Decrease
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Do opioid peptides increase or decrease food intake?
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Increase
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Does galanin increase or decrease food intake?
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Increase
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Does CRF increase or decrease food intake?
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Decrease
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Does glucagon-like peptide increase or decrease food intake?
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Decrease
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Does melanin concentrating hormone increase or decrease food intake?
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Increase
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Does CCK increase or decrease food intake?
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Decrease
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Does insulin increase or decrease food intake?
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Decrease
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Does urocortin increase or decrease food intake?
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Decrease
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Does ghrelin increase or decrease food intake?
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Increase
Ghrelin is produced and secreted by the stomach in response to food, but also spikes before mealtime = hunger signal |
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What is secretin?
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First hormone to be discovered. Secreted by small intestine in response to acid released from stomach.
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Where does digestion of fats begin?
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Intestine. Pancreatic lipase breaks down dietary triglycerides which have been emulsified by detergent actions of bile salts from gall bladder.
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What is the benefit of having diffuse distribution of ECL cells along GI tract?
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Ensures that hormone release is regulated by integrated sampling of mixed luminal content rather than specific stimulus that might exist transiently at only one point.
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What hormones comprise the gastrin family?
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Gastrins & CCKs
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What hormones comprise the secretin family?
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Secretin, glucagon, VIP, GIP.
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Name one similarity between gastrin and CCK?
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Gastrin and CCK have identicle C-terminal sequences.
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What kinds of cells synthesize GI hormones?
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enterochromaffinlike (ECL) cells
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What is ghrelin?
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Stimulates hunger: produced and secreted by stomach in response to food -- stimulates:
brainstem - automatic processes hypothalamus - metabolism midbrain - mesolimbic reward * Spikes before mealtime as a hunger signal |
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What is the role of ghrelin in gastric bypass surgery?
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Remove part of the stomach so less ghrelin is secreted. Since ghrelin is a hunger signal, producing less of it will decrease.
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What is the feedback/long term signal of ghrelin?
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Produce more GHRH
- if you eat a lot, you should signal the production of more muscle mass. |
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Do people with anorexia have a lot of ghrelin?
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Yes! They have high ghrelin levels (very hungry) -- must suppress.
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What are the levels of GH and ACTH in obese people?
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Low GH
High ACTH |
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What are the exocrine cells of the pancreas and what do they do?
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Acinar cells. Stain dark red. Secrete digestive enzymes
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What types of cells comprise the endocrine pancreas?
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a-cells: glucagon (periphery)
b-cells: insulin (central) d-cells: somatostatin (periphery) |
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Describe the biosynthesis of insulin
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(pre)pro-insulin synthesized in RER
Packaged into vesicles in golgi pro-insulin converted to insulin (requires Zn2+ to compact granules) Insulin is secreted in Ca2+/energy - dependent manner |
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What is required to compact granules for the secretion of insulin?
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Zinc
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Describe how glucose stimulates insulin secretion
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Glucose enters cells through Glut2 transporter (facilitated diffusion)
Glucose is converted to pyruvate; also produces ATP ATP closes K+ channels Closing of K+ channels cause small depolarization of cell Depolarization opens voltage-gated Ca2+ Channel Ca2+ enters cell Exocytosis of insulin from vesicles (Ca2+/energy dependent) |
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Name 8 things that increase insulin production
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1. Increased blood glucose
2. amino acids (i.e. breakdown of protein) 3. glucagon 4. gastrin (from stomach -- prepares b-cells to release insulin) 5. CCK 6. GIP 7. Sympathetic innervation (a-receptors) 8. Parasympathetic innervation (cholinergic) |
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Name 4 Factors that decrease insulin secretion
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1. Low blood glucose
2. Sympathetic innervation (b-receptors) 3. Somatostatin 4. Stress |
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Of a- and b-receptors, which increases and which decreases insulin secretion
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a-receptors increases insulin secretion
b-receptors decrease insulin secretion |
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(How) can you identify pancreatic cell types without specific antibodies?
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Yes
pink outer = a-cells -- glucagon purple center = b-cells - insulin |
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How is it that when you ingest food you stimulate more insulin secretion?
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* Requires less glucose*
- Food stimulates many receptor types; glucose only stimulates insulin secretion by directly entering through Glut2 transporter EX: incretins in intestinal wall increase insulin even before blood glucose levels elevate |
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What is GLP-1 (glucagon-like peptide 1)
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Made from the same gene as glucagon
- inhibits glucagon - very susceptible to proteolytic degredation (2-3min) - stimulates insulin secretion - lowers blood glucose |
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What is a peptide which is a major target for pharmaceuticals because it lowers blood glucose?
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GLP-1 = glucagon-like peptide
Good at lowering blood glucose but very susceptible to proteolytic degredation. |
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How does increases in insulin cause removal of glucose from blood?
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LIVER:
-- Insulin binds to membrane receptor on liver (Glut2) -- Increases glycogen synthase -- Removal of glucose from blood: storage as glycogen ADIPOCYTE/MUSCLE -- Insulin binds to membrane receptor (Glut4) -- Exocytosis and activation of glycose transporters -- Glucose uptake -- Removal of glucose from blood: storage as glycogen |
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Where are Glut2 and Glut4?
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Glut2 = liver (causes increase in glycogen synthase)
Glut4 = adipocyte & muscle cells (cause glucose uptake and storage) |
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What happens when you have decreased blood glucose?
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1. Release of glucagon -- binds to membrane receptors
2. Increase cAMP 3. Activation of glycogen phosphorylase (a kinase) 4. Causes inhibition of glycogen synthase 5. Glycogen is degraded into glucose -- released into the blood |
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How are insulin and growth hormone receptors similar?
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Both Tyrosine Kinase Receptors
a-subunits: extracellular b-subunits: transmembrane * both a- and b- subunits are encoded by 1 gene!* |
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How does activation of Glut4 work?
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Insulin TRK receptor -- located on muscle and adipocyte, the amount of receptors are directly related to presence of insulin
* Insulin binds to TRK receptor, causes vesicles containing Glut4 to fuse w/ plasma membrane to increase Glut4 expression * When insulin is down, transporters are endocytoses and stored in vesicles |
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What is glycogen synthase?
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An enzyme that turns glucose into glycogen for storage
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What is glycogen phosphorylase?
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Enzyme that breaks glycogen down to give free glucose
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In terms of glucose / glycogen, what does increased cAMP signal?
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Increased cAMP stimulates glycogen breakdown and prevents glycogen synthesis
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In terms of glucose/glycogen, what does decreases in cAMP signal?
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Decreases in cAMP inhibits glycogen breakdown and stimulates glycogen synthase
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What type of receptor does glucagon (and family) bind to?
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GPLRs
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Type 1 Diabetes
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Insulin-dependent diabetes
* autoimmune attack on b-cells! * generally juvenile-onset * low/absent endogenous insulin * partially genetic: 35% mono concord. |
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Type 2 Diabetes
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Generally insulin-independent
* change in receptor #/Glut4/glucose transport * May be increase, decrease, or normal insulin * Strongly genetic (60-90% mono concord) |
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What pathway is activated when insulin binds to receptor?
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Ras-MAP pathway -- regulates glucose in circulation
* Binding to TRK receptor causes phosphorylation of IRS protein |
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What mediates the effects of insulin on glucose metabolism?
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Protein kinase B -- activation results in increase of glucose transport from blood, translocation of glucose to plasma membrane in fat and muscle, and activation of glycogen synthase
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What happens when insulin binds in fat cells?
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Causes increase translocation of Glut4 to plasma membrane (which results in increased transport of glucose into fat -- storage!
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Which enzymes are responsible for glycogen storage and breakdown?
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Glycogen synthase (storage; glucose -- glycogen)
Glycogen phosphorylase (breakdown into glucose) |
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How are glycogen levels regulated?
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cAMP levels
- up = stimulate glycogen breakdown; inhibit glycogen synthesis - down = inhibits glycogen breakdown; stimulate glycogen synthesis |
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What are two major sites of gluconeogensis, and from which amino acids are they made?
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Kidney (made from glutamin)
Liver (made from alanine) |
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When amino acids are released from muscle breakdown into amino acids, what happens to the amino acids?
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Glutamine -- goes to kidney where gluconeogenesis produces glucose
Alanin -- goes to liver where gluconeogenesis produces glucose |
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Which type of diabetes has low or absent levels of endogenous insulin?
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Insulin-dependent diabetes mellitus
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What are insulin levels like in non-insulin dependent diabetes?
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Can be normal, high, or low, although as disease progresses there is generally hyperinsulemia and insulin resistance
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Do you likely have insulin defiency or glucagon excess if you have
under utilization of glucose |
Insulin defiency
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Do you likely have insulin defiency or glucagon excess if you have
Overproduction of glucose |
Glucagon excess
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Do you likely have insulin defiency or glucagon excess if you have
Increased release of amino acids |
Insulin defiency
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Do you likely have insulin defiency or glucagon excess if you have
Increased lipolysis |
Insulin Defiency
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Do you likely have insulin defiency or glucagon excess if you have
Increased hepatic ketogenesis |
Glucagon excess
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What are some tissues susceptible to damage by high glucose levels?
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1. Nerve/lens
2. Erythrocytes 3. Lens of eye 4. Vitreous humour of eye 5. Kidney, leucocytes |
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How does overproduction of ketone in diabetes happen?
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CNS signals increase in glucagon production. Glucose is produced by the liver, at the same time ketones are released.
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What happens to the kidney in diabetes?
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Thickening of the basal lamina
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How can diabetes damage the retina?
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Osmotic damage can cause some retinal capillaries to close of or form dilated segments (microaneurysms)
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In a post-meal state, what's the major hormone controlling blood glucose?
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Insulin
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In a fasting state, what's the major hormone controlling blood glucose?
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Glucagon
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How many people in the US have diabetes?
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18 million
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What kind of disease would you characterize type1 diabetes?
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autoimmune disease
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What happens with diabetics who have inherited DR3
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Develop diabetes at an older age.
Tend to have antibodies against pancreatic beta cells but not against insulin. More likely to develop autoimmune disease |
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What happens with diabetics who have inhertied DR4?
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Tend to develop diabetes earlier in life.
Have immune rxn against insulin |
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What happens with diabetics who inherit both DR3 and DR4?
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Develop diabetes at the youngest age.
Have the highest levels of antibodies against insulin |
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In terms of inherited alleles, who has it worst for diabetes?
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D3 and D4
Develop young, have the highest levels of antibodies against insulin |
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What is the general progression of type 2 diabetes?
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Too much food + not enough exercise + genes that make you hungry + genes that make pancreatic islets ware out early
Leads to obesity, need extra insulin b/c of more fat, body becomes resistant, fatty deposits in pancreas causes even more damage, body needs even more insulin b/c cannot produce it... |
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What kind of changes occur in pancreatic islets in type 2 diabetes?
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amyloid build-up in pancreatic islets
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What happens to a- vs. b-cells of pancreatic islets in non-diabetic obesity?
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More b-cells! (Need to produce more insulin because of increased fat production)
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How does type 2 insulin resistance work?
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1. Decrease in insulin receptor
2. Decrease in Glut-4 transporter 3. Or, defect in signaling from insulin receptor to Glut-4 Causes diminished glucose uptake |
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How much does an adrenal gland weigh?
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4-6g in adults
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From what type of tissue is the adrenal gland derived?
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Ectodermal neural crest cells = medulla
Mesodermal cells = cortex |
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What are the 4 layers of the adrenal?
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Cortex:
1. Glomerulosa 2. Fasciculata 3. Retiularis 4. Medulla (also surrounded by capsule) |
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Ganglion cells of adrenal are derived from neural crest cells. What prevents them from forming neurons?
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High cortisol levels inhibit projection formation
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What cells of adrenal secrete mineralocorticoids?
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Zona glomerulosa cells
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What cells of the adrenal secrete glucocorticoids and gonadocorticoids?
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Zona reticularis of cortex
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Which cells of the adrenal secrete catecholamines?
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medulla
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What do zona glomerulosa cells secrete?
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mineralocorticoids
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What do zona reticularis cells secrete?
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Glucocorticoids and gonadocorticoids
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Adrenal chromaffin cells of medulla secrete EP and NE. Which type of granules secrete each?
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EPI -- less intesnsly staining granules
NE -- granules with very dense cores |
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Explain the synthesis of catecholamines
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Tyrosine converted to DOPA by TH
DOPA converted to DA by L-amino acid decarboxylase DA converted to NE by DA-b-hydroxylase NE converted to EPI by PNMT |
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What signals EPI / NE secretion from chromaffin cells of adrenal medulla
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Cholinergic innervation
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What are 3 Major actions of EPI?
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1. Stress/arousal response
2. Metabolic action 3. Cardiovascular action |
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What is the b-adrenergic receptor like?
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7TM GPCR (** Gs **) -- ligand binding site is in hydrophobic pocket.
Gs: activates adenylyl cyclase * increase cAMP, activates PKA |
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What type of receptor does alpha2-adrenergic bind to?
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Gi GPCR
causes inhibition of adenylyl cyclase and a reduction of cAMP, which inhibits PKA |
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What type of receptor does alpha1 receptor bind to?
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Gq GPCR
activates PLC which results in activation of PKC (by DAG) and increased intracellular calcium by IP3 |
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What happens when EPI normally binds to receptor on smooth muscle?
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Generally will activate a-receptor since it is "dominant" -- results in smooth muscle contraction.
If a-receptor is blocked, then b-receptor will be activated resulting in smooth muscle relaxation |
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Describe the concept of "silent" receptors?
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On smooth muscle, there are both b-adrenergic and a-adrenergic receptors. They antagonize each other (a=contraction, b=relax). a-receptors are dominant - higher affinity/more receptors, so unless they are blocked, the b-receptors are "silent"
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How do adrenergic receptors desensitize?
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Activation causes increased cAMP - PKA. Sustained PKA phosphorylates a region on the C-terminus of the receptor, inactivating it. Also, this can target receptor for internalization.
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Mechanism of adrenergic receptor internalization
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Sustained PKA activation phosphorylates c-terminus, which inactivates it. P-sites also target b-arrestin binding, which can cause clathrin-mediated endocytosis.
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Describe thyroxine recptor
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T3/T4 are able to enter nucleus (lipo-hilic tryosine derivative).
Upon binding, Thyroxine receptor dimerizes (homo- or hetero- with RXR) and becomes active txn factor |
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Where do the initial steps of catecholamine synthesis take place?
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Cytoplasm
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Where do the final steps of EPI/NE synthesis take place?
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Storage granules
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What are chromogranins and where are they synthesized?
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Regulated secretory proteins synthesized on RER and packaged within hormone vesicles
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Does thyroxine biosynthesis require synthesis and modification of thyroglobulin?
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Yes
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Does thyroxine production require transport of iodine across the plasma membrane?
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Yes
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Does thyroxine production require the presence of peroxidase and hydrogen peroxide?
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Yes
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Does thyroxine production require iodination of tyrosine residues of thyroglubulin?
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Yes
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Does thyroxine production require digestion of colloid in the luminal space of the follicle?
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No.
Colloid gest engulfed by follicular cell processes and transported into cells which later act as lysosomes. |
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What are the cells of the exocrine pancreas?
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Acinar cells.
Source of enzymes which digest food arriving in small intestine |
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What does the gall bladder do?
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Secretes bile salts to emulsify lipids
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What enzymes first digest carbohydrates in the mouth?
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ptyalin (= a-amylase)
* There are other a-amylases in small intestine which are secreted by exocrine pancreas |
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Where does protein digestion begin?
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Stomach -- by pepsins which cleave peptide linkages
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Which cells secrete pepsinogen (precursor to pepsin)?
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Chief cells of the stomach.
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What converts pepsinogen into pepsin?
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gastric hydrochloric acid released from parietal or oxyntic cells of gastric glands
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What cleaves short peptides?
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Trypsin and chymotrypsin released from the pancreas which act in the small intestine
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What enzymes cleave small peptides into individual amino acids?
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pancreatic carboxypeptidases, intestinal aminopeptidases, and dipeptidases
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What type of transport gets freed amino acids (which are cleaved by pancreatic & intestinal carboxypeptidases) into the bloodstream?
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Active transport gets free amino acids across intestinal lumen and into bloodstream
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Where does the digestion of fats begin?
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Intestine.
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What enzyme begins the digestion of fats and where?
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Panreatic lipases in the intestine free amino acids from dietary triglycerides.
Act on fats that have been emulsified by bile salts |
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Which type of cells secrete HCl?
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Parietal cells
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What are 2 functions of CCK?
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1. Slows down emptying of stomach by acting on pyloric sphincter
2. Stimulates bile release from gallbladder and secretion of pancreatic enzymes |
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What are 2 functions of Secretin (in intestine)?
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1. Stimulates pancreatic bicarbonate secretion
2. Enhances insulin secretion by b-cell of islets of langerhans |
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What are 3 functions of Gastrin?
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1. Stimulates secretion of HCl by parietal cells of stomach
2. Stimulates insulin secretion by b-cells of pancreas 3. Stimulates gastric motility and growth of mucosal cells |
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What does increased CCK do to gallbladder and sphincter of oddi?
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Contracts gallbladder - allows bile to flow into duct
Relaxes sphincter -- allows bile to flow from duct into intestines |
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Where are gastrin receptors located and what does their activation do?
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Located on parietal cell of stomach.
Causes released of HCl into stomach |
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What 5 hormones/NTs regulate Parietal cells (HCl secretion)?
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1. Histamine
2. ACh 3. Gastrin 4. Somatostatin 5. Gastrin-releasing peptide |
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Which cells secrete pepsinogen?
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Chief cells of stomach
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Which cells secrete HCl?
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Parietal cells of stomach
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What are the two secretory cells of stomach?
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Chief cells - pepsinogen
Parietal cells - HCl |
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What are the 3 phases of HCl secretion?
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1. Cephalic - parasympathetic: increase HCl secretion
2. Gastric - long and short neural reflexes and direct gastrin stimulation: increase HCl secretion 3. Intestinal - long and short neural reflexes, secretin, CCK: decrease HCl secretion |
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Gastrin
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stimulates release of HCl and pepsinogen
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Glucagon
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Promotes conversion of glycogen to glucose in the liver
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CCK
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Stimulates pancreatic enzyme release and elicits gallbladder contractions
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GIP
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Stimulates insulin secretion
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Motilin
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Stimulates GI motility
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Secretin
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Stimulates bicarbonate and water secretion by pancreatic duct cells
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Neurotensin
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Inhibits GI motility
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Glicentin
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Promotes conversion of glycogen to glucose in the liver
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Somatostatin
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Inhibits local secretion of gastrin, motilin, secretin, and GIP
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Serotonin
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Stimulates GI motility
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What is intrinsic factor and where is it secreted?
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Necessary for absorption of vitamin B12. Secreted by parietal cells of stomach
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What are two iodine deficiency disorders?
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Goiter & Cretinism
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What is cretinism?
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Defiency of TH or iodine during perinatal period
= mental and physical retardation, deafness, paralysis |
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What does thyroid hormone do to growth hormone?
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Enhances growth hormone by increasing txn of GH gene in pituitary
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Name on example of permissive action?
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Thyroid hormone and epinephrine!
Causes increased expression of epinephrine receptors. |
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What do co-activators do to Thyroid hormone receptors?
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Renders chromatin more accessible to txn
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What does thyroid hormone receptor do in the absence of T3/T4?
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Binds to TRE site and represses basal transcription
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Which thyroid hormone receptors do not bind hormone?
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TRa2 and TRa3
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Name 3 thyroid hormone binding proteins
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1. Thyroxine-binding globulin
2. Transthyretin 3. Albumin |
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What are the major sites of T4 to T3 conversion?
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Liver and kidney
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How does thyroxine get released from thyroglobulin?
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Lysosomal degradation:
thyroglobulin gets endocytosed from colloid center of cell; stored in vesicles, sorted into lysosomes. Lysosomes get degraded by proteases in the follicular cells of thyroid gland |
