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74 Cards in this Set
- Front
- Back
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What does the B-cell primarily respond to?
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Glucose in the bloodstream.
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What is the relationship between glucose concentration and insulin release?
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Sigmoidal relationship.
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What is the threshold potential for glucose?
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4Mm or 90 mg/dL
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What does euglycemia mean?
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Euglycemia means normal concentration of glucose in blood.
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What is euglycemia?
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4Mm or 90 mg/dL
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What is ED50?
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The minimal dose required to produce the desired effect.
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What is the ED50 for glucose?
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8 mM
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After eating a large meal, how is insulin released?
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Insulin is released in 2 phases.
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When does the first phase of insulin release occur?
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In response to glucose.
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How does the first phase of insulin release occur?
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By pre-docked granules (so cell can quickly respond to glucose.
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How is the first phase of insulin release regulated?
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Ionically regulated.
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How is the second phase of of insulin released?
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Granules are NOT already on plasma membrane and have to migrate and fuse so that they can release insulin.
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How is the second phase of insulin release regulated?
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Regulated by slow acting mediator, (possibly a lipid)
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Beta cells can adapt to glucose. If the beta cells sees glucose, glucose is taken away. If the beta cells see glucose again, then they will have a rapid effect against glucose, producing insulin. What is this effect called?
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Priming effect
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If glucose is around too long, what phase does the B-cell enter?
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Desensitization phase.
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Where is GLUT2 found?
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Beta cells, liver, and maybe the hypothalamus.
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What brings glucose inside the cell?
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GLUT2
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What is the Km of the glucose transporter?
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50mM
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If we eat a large meal, will we exceed the ability of the transporter to transport?
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NO, glucose concentration outside of the cell will be equal to the glucose concentration inside of the cell.
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Down regulation of GLUT2 may cause what?
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B-cell dysfuntion in TypeIIDM
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Once glucose enters the cell, what happens next?
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Phosphorylation by glucokinase to G6P.
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What is considered to be the "glucose-sensor" in the cell?
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Glucokinase.
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What enzyme catalyzes the rate limiting step in beta cell and liver?
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Glucokinase.
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What point regulates the flux of glucose into beta cell and is probably what regulates insulin release over a fairly significant range?
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Km of glucokinase for glucose is the same as ED50 for glucose-induced insulin release.
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What is made from glycolysis inside the Beta-cell?
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Trioses and pyruvate.
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Once pyruvate is made, what does it do?
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Pyruvate then enters the mitochondria where it is metabolized to produce reducing equivalents and increases in ATP.
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As ATP increases, what happens?
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Ratio of ATP:ADP increases, this change in ratio leads to closure of the K+ATP channel.
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Closure of the K+ATP channel leads to what?
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Depolarization of plasma membrane-->opens voltage-gated Calcium channels (specifically the L-type)
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What can the voltage-gated Ca channels be closed by?
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These calcium channels are closed by dihydrophyridines such as verampil.
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Once Ca enters the cell, what happens?
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Causes mobilization of granules by activation of kinases.
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Where are sulfonylurea receptors located?
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K+ATP channel
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What is sulfonylurea used for?
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Drugs used in the treatment of TIIDM.
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What do sulfonylurea channels do?
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Cause CLOSURE of the K+ATP channel and, therefore, an influx of calcium and insulin release!
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What is the disadvantage with sulfonylureas?
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Stimulate the release of insulin independent glucose concentration-->hypoglycemia
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How does Diazoxide work in the treatment of TIIDM?
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Diazoxide binds to receptor and OPENS the K+ATP channel. However, this drug prevents glucose induced insulin-release in response to sulfonylureas.
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What else will cause insulin release?
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All metabolized sugars, certain amino acis such as Arginine
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What amino acids can cause insulin release?
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Arginine, Leucine, Lysine
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What neuronal activity occurs, after you eat a large meal?
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Vagal response-->Ach-CoA stimulates beta cell in presence of glucose.
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What turns off the beta cell?
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NE, and somatostatin
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What are gastrointestinal peptide hormones also known as?
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Incretins!
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What are the 2 types of incretins?
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Glucagon-like-peptide 1 & Gastrointestinal peptide
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Where does GLP1 come from?
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Intestinal tract in response to an intake of a meal.
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What is the BIG advantage of GLP1 over sulfonylureas?
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Potentiates glucose-induced insulin release and does not work well in absence of glucose. Big advantage over sulfonylureas b/c will NOT cause hypoglycemia.
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What hormone causes beta cell neogenesis?
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GLP1
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A problem in Type 1 and Type 2 Diabetes is insufficient beta cell mass. What could potentially solve this problem?
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GLP1 causes beta cell neogenesis and could possibly increase mass!
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How does GLP1 affect the beta cell's phenotype?
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Increases transcription for GLUT2 and insulin gene.
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What are the 2 major disadvantages of GLP1?
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1.Requires injection (it's a peptide)
2.Quick turnover in blood (seconds) |
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What drug binds and activates GLP1 receptor and has a much longer half-life?
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Exendine-4
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How does glucose regulate insulin biosynthesis?
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1.Increases mRNA stability and translation.
2.Increases insulin promoter activity via transcription factors |
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What transcription factors, responsible for increasing insulin promoter activity, are regulated by glucose concentrations?
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Pdx-1, beta2 and MAPA
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In diabetes, what happens to the pathways responsible for glucose induced insulin biosynthesis?
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1.Could be defective
2.Tend to be downregulated in cells exposed to chronic hyperglycemia |
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What heterogenous, monogentic form (one gene) disorder is responsible for 2-5% of type 2 diabetes?
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MODY
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How is MODY inherited?
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Autosomal dominant
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How many genes are defective in typical TIIDM?
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Polygenic
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What are the characteristics of an individual with MODY?
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1.young, 25 yrs. or younger @ time of onset
2.lean 3.fragile beta cells that are easily damaged-->have primarily one defect in insulin secretion |
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Defects in what gene could cause MODY?
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1.HNF4alpha gene
2.glucokinase gene 3.HNF1alpha gene 4.Pdx-1 gene 5.HNF4beta gene 6.BETA 2 gene |
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What is the leading theory for beta-cell decomposition?
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1.Glucose causing the cell to be defective
2.Obese people have increased FFA and this is lipotoxic to cell 3.Combination of BOTH! |
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Chronic hyperglycemia and/or hyperlipidemia cause what?
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An increase in sensitivity of the beta cell to glucose.
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Why does chronic hyperglycemia and/or hyperlipidemia cause an increase in sensitivity of the beta cell to glucose?
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This response is probably trying to overcome the insulin resistance.
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What does chronic hyperglycemia and/or hyperlipidemia do to the Islets of Langerhans?
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Islets of Langerhans increase their size-->hypersecretion of insulin-->depletes stores and eventually get loss of glucose-stimulated insulin release.
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Initially, in response to beta cell decomposition, what is the response of the B-cell to glucose, arginine, and sulfonylureas?
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B-cell does not respond to glucose, but does respond to arginine and sulfonylureas.
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Eventually, what happens to the beta-cell response to glucose, arginine, and sulonfylureas during beta cell decomposition?
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Eventually it will not respond and will see beta cell destruction via apoptosis, if the blood glucose levels are not corrected.
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What are 2 causes of TIIDM?
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1.TIIDM runs in families
2.Environment is important |
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What is the only way to mimic beta cell action?
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Beta cell transplantation.
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What is the normal anatomical romance of the pancreas?
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The majority of the pancreas secretes exocrine enzymes, which drain into duodenum then to the bladder and are excreted in urine.
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What is the vasculature of the pancreas hooked up to?
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Islets of Langerhans
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When are pancreas transplants typically done?
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When the patient is on dialysis so you can do kidney and pancreas transplant at the same time.
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How can one check to see if a pancreas transplant worked?
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The results can be indicated by HgbA1c.
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How does HgbA1c give a long-term snapshot of overall glycemic control?
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B/c RBC's last for 120 days. HgbA1 is glycosylated hemoglobin.
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Does pancreas transplantation work?
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Yes, the results were much closer to normal after the transplant was given.
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What are some problems with pancreas transplantation?
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Requires immunosuppression, beta cells are sensitive to immunosuppressants.
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How is Islet of Langerhans transplantation done?
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Isolate islets of Langerhans, gain access to portal vein, put there and they can go to liver and lodge there. Most function for a short time but then die.
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What were the results of the Edmonton trial?
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Showed that one can get success when change immunosuppression (lowered glucocorticoid levels and F5A6-immunosuppressant)
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What is the problem with trying to use embryonic stem cells and adult stem cells to make beta cells?
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Beta cells come from the endoderm and embryonic and adult stem cells love to make mesoderm. Mesoderm makes muscle and fat, it is extremely difficult to get mesoderm cells to differentiate into endoderm cells.
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