organ systems: glucose regulation

this lecture focused on glucose metabolism: specifically, the interplay of insulin and glucagon secretion and their effect of glucose metabolism and storage in different organs and tissues. the pancreatic islets of langerhans secrete glucagon from alpha cells, insulin from beta cells, and somatostatin from delta cells. glucagon is secreted in response to low blood sugar and has a variety of effects which ultimately serve to raise blood glucose levels. in the liver, glycogenolysis is initiated, freeing glucose units from storage (see the biochem chapter on glycogen for more detail), gluconeogenesis creates glucose from non-carbon precursors such as amino acids. additionally, triacylglyceride stores are converted into fatty acids, which can be cleaved into ketone bodies, which are used as an alternative fuel source. glucagon is released in response to hypoglycemic (low blood sugar) conditions. other mechanisms are in place to raise blood sugar: sympathetic stimulation, cortisol, growth hormone. the symptoms from severe hypoglycemia are caused by these mechanisms; hunger by the hypothalamus and anxiety/tremors/sweating by sympathetic stimulation.

on the other hand, insulin is released in hyperglycemic conditions (high blood sugar) and facilitates uptake of glucose into cells. it accomplishes this by binding to receptors that translocate glucose transport proteins to surface of cell membranes, thereby allowing glucose to enter. there are 5 categories of glucose transport proteins, with different affinities for glucose and found in different locations of the body (see the carb digestion biochem chapter for some more physiology of the GLUT transporters): GLUT1 are found everywhere in the body and also present in placenta. GLUT2 transporters are in the pancreas, liver, kidney, and intestine. GLUT3 transporters are everywhere in the body. GLUT4 transporters are in muscle and adipose tissue and are the only insulin dependent glucose transporters. GLUT5 transporters are in the jejunum.

insulin has a variety of actions on organs and tissues; in the liver it initiates glycogen storage, fatty acid synthesis and subsequent triacylglyceride synthesis. in adipose tissue it stimulates uptake of glucose, triacylglyceride synthesis, and triacylglyceride release (through VLDL's). in muscle it stimulates uptake of glucose and amino acids and promotes glycogen storage from the excess glucose. insulin release is stimulated by a variety of factors- primarily high blood glucose levels, but also via parasympathetic stimulation, amino acids, growth hormone, and various GI hormones. insulin release is inhibited by catecholamines, somatostatin, and glucagon. note: glucagon and insulin reciprocally regulate each other- the release of one inhibits the release of the other. in addition, the release of somatostatin inhibits the release of both insulin and glucagon- preventing "rapid nutrient exhaustion".

diabetes type I is caused by an autoimmune destruction of pancreatic beta cells, resulting in low insulin levels and therefore low glucose metabolism and therefore a shift to ketone body metabolism. this also results in increased glucose levels in the urine, which can cause polyuria (excess urine volume), polydipsia (excess thirst), and polyphagia (excess hunger). type II diabetes is a resistance to insulin that is associated with high visceral fat deposits with high lipolytic activity (releasing fatty acids into the bloodstream) that are resistant to the anti-lipolytic properties of insulin. this can be induced by high free fatty acid, cortisol, or testesterone levels.

questions
glucagon...
1. what are the three types of cells in the pancreatic islets of langerhans and what do they secrete?
2. describe glucagon's effect on the liver.
3. what are the specific processes that occur that release glucose and ketones from the liver?
4. what is glucagon release from alpha cells stimulated by?
5. what is glucagon release from alpha cells inhibited by?
6. how does somatostatin "prevent rapid nutrient exhaustion"?
7. glucagon corrects...
8. what are the other ways that the body corrects for hypoglycemia?
9. what are the symptoms of severe hypoglycemia and what are they caused by?
10. what is reactive hypoglycemia and what is it caused by?

insulin...
11. describe the general function of insulin.
12. how does insulin facilitate the uptake of glucose into cells?
13. where are GLUT1-GLUT5 found?
14. which glucose transporter protein requires insulin?
15. describe insulin's action on muscle.
16. describe insulin's action on the liver.
17. describe insulin's action on adipose tissue.
18. what are some factors that facilitate release of insulin from the pancreas?
19. what are inhibitors of insulin release?

hormonal regulation...
20. describe the "reciprocal regulation" of insulin and glucagon.
21. describe the concept of a "basin of attraction" in regards to glucose regulation.

diabetes...
22. what is IDDM? what is it caused by?
23. what do high glucose levels in urine cause?
24. what is type II diabetes? what is it caused by and what does it result in?

answers
1. alpha cells secrete glucagon, beta cells secrete insulin, delta cells secrete glucagon.
2. increases glucose and ketone production and secretion.
3. glycogenolysis, gluconeogenesis, lipolysis, ketogenesis.
4. amino acids, decreased bloods sugar, CCK, VIP, catecholamines.
5. insulin/glucose, somatostatin.
6. by inhibiting both alpha and beta cell secretion of glucagon and insulin secretion.

7. hypoglycemia.
8. sympathetic stimulation, cortisol, growth hormone.
9. anxiety, tremors, sweating are caused by sympathetic action and hunger is caused by hypothalamus.
10. low blood sugar levels after a meal that results from excess release of insulin triggered by high content of high glycemic index carbohydrates (or insufficient protein).

11. to store metabolic fuels.
12. by binding to receptors which translocate glucose transporter proteins into the cell membrane.
13. GLUT1- ubiquitous, placenta, GLUT2- beta cell, liver, kidney, intestine, GLUT3- ubiquitous, GLUT4- muscle,adipose, GLUT5-jejunum.
14. GLUT4.
15. causes uptake of amino acids and sugar (and therefore promotes glycogen storage).
16. glycogen synthesis, fatty acid synthesis.
17. uptake of glucose and converion into fatty acids and glycerols, triglyceride synthesis, and uptake of fatty acids from blood lipoproteins.
18. high glucose levels, amino acids, parasympathetic stimulation (cephalic phase of pancreatic secretion), growth hormone, cortisol, GI hormones such as gastrin, secretin, CCK, GIP.
19. somatostatin, catecholamines.

20. insulin and glucagon inhibit each other's release from islet cells via paracrine actions.
21. the basin of attraction is the set of homeostatic variables which the body settles into over time; long term changes in hormone levels or autonomic activity can shift this basin of attraction to a new equilibrium point.

22. autoimmune destruction of pancreatic beta cells which results in low levels of insulin, and thus a shift from glucose metabolism to ketone body metabolism.
23. polyuria (excess urine volume), polydipsia (excess thirst), polyphagia (excess hunger)
24. type II diabetes is an insulin resistance that is caused by excess fatty acids, cortisol, or testosterone, which blocks insulin's anti-lipolytic effect on adipose tissue. can not be compensated by excess insulin secretion.

immunology: class notes 3/2-3/3- autoimmunity

autoimmunity is the phenomenon of the immune system attacking host cells, including immune system cells. it arises either from "spontaneous" factors, or from infection, or from various environmental triggers. autoimmunity can be viewed in the same framework as the four types of hypersensitivity in that the mechanisms are the same. the exception is type I hypersensitivity, which involves a class switch to IgE- this mechanism is not seen in autoimmunity. type II autoimmunity involves a class switch to IgG, which binds to different self-antigens.

the first example of type II autoimmunity is autoimmune hemolytic anemia, in which b cells specific for red blood cells start proliferating and producing antibodies, which bind to red blood cells. in this case, the b cells can proliferate using a "antibody crosslinking" mechanism, bypassing the need for IFN-gamma. the antibodies opsinize red blood cells and leave them primed for phagocytosis and destruction by macrophages and natural killer cells. myesthenia gravis is another example of type II autoimmunity, in which antibodies bind to acetylcholine receptors at the neuromuscular junction and thus prevent neural conduction. grave's disease is the third example, where antibody binds to thyroid stimulating hormone receptors, this time stimulating the receptor, resulting in hyperthyroidism.

type III autoimmunity involves a class switch to IgA. this often induces formation of antibody/antigen complexes which block blood vessels or nephritic tubules and cause macrophages to come and secrete reactive oxygen species and damage surrounding tissue. lupus is an example of type III autoimmunity- where the self antigens are all contained within the nucleus of cells: histones, nucleosomes, spliceosomes, transcription factors. these self antigens are thus attacked only in places of high cell turnover or division; such as the skin and joints.

type IV autoimmunity involves a t cell mediated response against self antigens. the first main example is type I diabetes, where pancreatic beta cells are attacked by CD8 t cells specific for insulin, which are activated by dendritic cells which express co-stimulatory molecules by means of a simulaneous infection (or other "spontaneous" means). in multiple sclerosis, the self antigen is the myelin basic protein which coats neurons-- in this case CD4 t cells are activated to produce antibody which opsinize the myelin sheath and cause macrophages to attack. at this point the myelin sheath can be regenerated from oligodendrocytes, but eventually CD8 t cells are activated to attack the oligodendrocytes as well. finally, rheumatoid arthritis is an autoimmune disease in which the antigen is not clearly defined; either collagen or heat shock proteins, which end up with macrophages being recruited to joints and causing damage by reactive oxygen species, etc. rheumatoid factor is also present in the disease, which acts as an antibody to antibodies and can form antibody complexes which can exacerbate disease by damage by macrophages.

questions
1. what is autoimmunity?
2. how does autoimmunity arise?
3. what are some factors involved in development of autoimmune disease?
4. what percentage of monozygotic twins and dizygotic twins show autoimmune disease concordance?
5. what disease occurs when an autoimmune response to myelin basic protein is mounted?
6. what disease occurs when an autoimmune response to insulin is mounted?

7. what is type I hypersensitivity and how is it related to autoimmunity?
8. what is type II hypersensitivity and how is it related to autoimmunity?
9. what are the two ways in which IgM normally class switches to IgG?
10. describe the mechanism of autoimmune hemolytic anemia.
11. describe the mechanism of myesthenia gravis.
12. describe the mechanism of grave's disease.
13. how would one test for the presence of an autoimmune disease in which host cells are being killed (as in question 10)?
14. how would one test for the presence of an autoimmune disease in which host cell receptors are being blocked? (question 11)?
15. how would one test for the presence of an autoimmune disease in which host cell receptors are being overstimulated (as in question 12)?

16. what is the class switching that occurs in type III autoimmunity?
17. how is damage caused by self-specific IgA in type III autoimmunity?
18. what are the self antigens in lupus?
19. why does lupus cause joint pain and skin problems?
20. what is the difference in the autoimmune response to apoptosis vs. necrosis?

21. what is type IV autoimmunity? what are some examples?
22. why does type I diabetes result in hyperglycemia?
23. what is the hereditary component to type I diabetes?
24. which immune system cells "escape tolerance" in type I diabetes?
25. describe the mechanism of autoimmunity in type I diabetes.
26. how are CD8 t cells activated in type I diabetes?
27. what is glutamine acid decarboxylase and how is it related to type I diabetes?

28. what is MS?
29. what is the relative prevalance of MS in males compared to females?
30. what is the average age of onset in MS?
31. what are some epidemiological trends of MS?
32. what is the mechanism to the autoimmune response in MS?
33. what is the role of oligodendricytes in MS?

34. what is rheumatoid arthritis?
35. what is the relative prevalance of rheumatoid arhritis in women vs. men? why?
36. what is the self antigen in rheumatoid arthritis?
37. what are heat shock proteins and what do they do?
38. what are gamma delta t cells and how might they be involved in rheumatoid arthritis?
39. how are joints damaged in rheumatoid arthiritis?
40. what is it that recruits macrophages and neutrophils to the joint areas?
41. what is rheumatoid factor? how does it exacerbate disease?


answers
1. an immune response to self-tissue.
2. either by spontaneous/unknown causes, or in response to extreme childhood stress or trauma, or by infection.
3. environmental (including nutrition), hereditary, the tissues involved, the mechanism of the autoimmune response.
4. mono: 20%, di: 5%
5. multiple sclerosis.
6. diabetes.

7. an allergic response which involves a class switch to IgE. this type of mechanism is not found in autoimmunity.
8. a cytotoxic/antibody dependent response which involves a class switch to IgG. this type of mechanism is the main response used against self tissues in autoimmunity.
9. via IFN-gamma or CD40/CD40L.
10. b cells which are specific to host blood cells are not destroyed during development as they should be and begin proliferating and class switching to IgG (subverting the normal mechanism in question 9 by "cross linking antibodies"). IgG binds to red blood cells and are either opsinized by macrophages or destroyed by NK cells.
11. b cells secrete antibodies which are specific for the host's nicotinic acetylcholine receptors- which blocks acetyl choline binding and results in muscle weakness.
12. b cells secrete antibodies which are specific for thyroid stimulating hormone receptors- which stimulate the receptors, resulting in hyperthyroidism and a downregulation of the TSH receptors on the affected cells.
13. in the case of autoimmune hemolytic anemia, one could look for an abnormally low red blood cell count or an abnormally high b/t cell count in a blood sample.
14. one could test for elevated amounts of the ligand which can no longer bind to the receptor.
15. one could test for elevated levels of the product of the stimulation of the particular host cell, or test for presence of phosphorylated proteins (indicating that the receptor has been bound to and endocytosed).

16. a class switching of IgG or IgM to IgA.
17. IgA can form large complexes with self antigen in vessels or nephritic tubules and block them. additionally, macrophages will bind to the antibodies using Fc receptors and produce reactive oxygen species, which will damage nearby tissues.
18. histone, nucleosome, spliceosome, transcription factors: Ro, La.
19. the self antigens are contained in the nucleus of cells; thus they are primarily exposed to the autoimmune response at places of high apoptosis and necrosis, which would expose nuclear contents during degradation. the joints and skin are two such places.
20. apoptosis is considered "silent" compared to necrosis because only necrosis initiates the inflammatory response.

21. t-cell mediated autoimmunity: multiple sclerosis, type I diabetes, rheumatoid arthritis.
22. because the insulin producing beta-islet cells in the pancreas are destroyed and thus cells can not take in glucose from the blood.
23. the passing down of HLA molecules which are predisposed for diabetes: HLA DR3, DR4, DQ, DQB1*0302.
24. CD8 t cells, CD4 t cells, b cells.
25. a dendritic cell phagocytoses and presents insulin on its surface in both MHC classes. normally, this does not provoke a response from the immune system; however, if this occurs simultaneously with an infection, co-stimulatory molecules will be expressed and t cells specific to insulin will be stimulated to destroy pancreatic beta cells.
26. APC's will stimulate CD4 t cells, which will differentiate into Th1 cells, which will produce IFN-gamma, which will activate CD8 t cells.
27. another antigen that can invoke a similar autoimmune response against the pancreas.

28. an autoimmune disorder which results in multiple sites of demyelination in the brain, spinal cord without axonal degeneration.
29. 7:1 more common in females.
30. 25-35
31. high prevalence in far northern and far southern locales: might be vitamin D related. also very dependent on residence during the first 15 years of life. higher prevalance in high socioeconomic groups and among caucasians.
32. dendritic cells ingest and present myelin basic protein in both MHC classes, causing CD4 t cells to differentiate into Th1 cells, which secrete IFN-gamma, which cause a class switch in MBP specific b cells to produce IgG. IgG binds to myelin and opsinizes, priming myelin for opsinization by macrophages (by way of Fc receptors).
33. oligodendrocytes produce MBP and as such can counter the effects of MS-- until the CD8 t cells are stimulated to attack the oligodendrocytes.

34. an autoimmune disease that leads to destruction of cartilage, bone, and joint deformities.
35. 3:1 prevalence in women as compared to men-- estrogen triggers higher TNF-production via macrophages.
36. unknown; possibly collagen, or heat shock
37. bind to denatured proteins and prevent them from being degraded; activated by excess heat or cold.
38. a special type of t cell that makes high levels of IFN-gamma, causing a class switch to IgG, and also is involved in the production of RF factor.
39. by macrophages which produce reactive oxygen species, IL-1, TNF-alpha.
40. Th17 cells, cytokines such as IL-1, TNF-alpha, IL-6, IL-17.
41. antibody for antibodies which can bind to all antibodies within one isotype. they exacerbate disease when forming antibody "complexes", the accumulation of antibody and RF factor, which blocks vessels and causes macrophages to come and produce ROS, etc.