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78 Cards in this Set
- Front
- Back
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What is insulin's effecto n glycogen?
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Stimulates storage of glycogen in liver and muscle
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What is insulin's effect on fats?
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Synthesis of fatty acids and triacylglycerols and their storage in adipose tissue.
The carbs that cannot be stored as glycogen are converted into fats. |
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What is insulin's effect on proteins?
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Synthesis in various tissues >50 proteins.
Direct effect in promoting amino acid uptake by cells and conversion of these amino acids into protein. Inhibits breakdown of protein already in the cells. |
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What are the paracrine effects of insulin?
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It suppresses glucagon release from the alpha-cells in the islets.
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What other hormones does the pancreas secrete?
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Amylin, somatostatin, pancreatic polypeptide
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What is the organization of the pancreas?
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1-2 million islets of Langerhans (.3mm diameter)
60% beta cells lie in the middle of each islet and secrete insulin and amylin 25% alpha cells secrete glucagon 10% somatostatin PP cell - secretes pancreatic polypeptide |
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What is the function of amylin?
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Inhibits insulin secretion
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How is insulin made?
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Preproinsulin (MW 11,500)
Cleaved in ER to => proinsulin (MW 9000) Cleaved in golgi => insulin + c-peptide => vesicles 5-10% of final secreted product is still proinsulin |
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What is the function of C-peptide?
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Binds to a membrane structure, G protein and initiates activation of two enzyme systems:
1) Sodium-potassium ATPase 2) Endothelial nitric oxide synthase |
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What is measuring C-peptide levels useful for?
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To determine how much endogenous insulin a diabetic patient is still making on their own.
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What is the half life of insulin?
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6 minutes.
Circulates in unbound form so it is cleared within 10-15 min Unbound insulin is degraded by enzyme INSULINASE in the liver > kidneys & muscles > other tissues |
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What is the composition of the insulin receptor?
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4 subunits held together by disulfide linkages
2 alpha that are outside the cell membrane 2 beta that penetrate through the membrane => become autophosphorylated => activates a local tyrosine kinase => phosphorylation of enzymes (insulin-receptor substrates IRS) |
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What are the end effects of insulin stimulation?
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1) Seconds => translocation of vesicles to membranes with glucose transport proteins => 80% of body cells increase uptake of glucose (muscles and adipose) => glucose immediately phosphorylated (3-5 min)
2) Membranes become permeable to amino acids, K ions, and phosphate ions 3) Changed states of phosphorylation of enzymes changes the activity levels (10-15 min) 4) Transcription of DNA => Translation of mRNA => new proteins => new enzymes |
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Muscle depends on what for fuel during its resting state?
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Fatty acids.
Resting membrane is slightly permeable to glucose when not stimulated by insulin. Between meals the amount of insulin secreted is too small to promote entry. |
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What two conditions do muscles use large amounts of glucose?
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1) Moderate/heavy exercise. Muscle fibers become more permeable to glucose even without insulin because of the contractile process.
2) First few hours after a meal, large quantities of insulin are secreted. Rapid transport into muscle cells, and during this time glucose is burned instead of fats. |
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What happens if the muscles are not exercising but glucose is transported into them?
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Most of the glucose is stored as muscle glycogen.
2-3% concentration. Useful for short periods of extreme energy use, and to provide spurts of anaerobic energy for a few mins at a time. (glycolysis producing lactic acid) |
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How much can insulin increase the rate of transport of glucose?
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15 fold
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What are the steps by which insulin causes glucose uptake and storage in the liver?
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1) Inactivates liver phosphorylase (glycogen => glucose)
2)Increased uptake of glucose => Increased glucokinase activity => phos of glucose in cells => trapped glucose 3) Increased enzymes that promote glycogen synthesis (glycogen synthase => polymerization of monosaccharide units to form glycogen) |
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How much can the glycogen in the liver increase under the influence of insulin?
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Total of 5-6 %
Almost 100 grams |
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What occurs when blood glucose levels begin to fall between meals?
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1) Pancreas stops insulin secretion
2) All actions of insluin are stopped 3) Glucagon released => phophorylase activated => glycogen splits to glucose phosphate 4) Glucose phosphatase activated => dephosphorylates glucose => glucose released into blood |
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How much of the glucose taken up by the liver is recycled inbetween meals?
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60% is stored and then returned.
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What happens to the fatty acids that are made from glucose?
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Packaged as triglycerides => VLDL => adipose tissue => deposited as fat
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In what two ways does insulin inhibit gluconeogenesis?
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1) inactivating enzymes
2) inhibiting release of amino acids keeping them from becoming precursors for gluconeogenesis. |
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What effect does insulin have on the brain?
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Almost none. the brain cells are permeable to glucose and can use glucose without the intermediation of insulin.
Normally only use glucose for energy. |
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When do symptoms of hypoglycemic shock develop?
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20-50 mg/100 mL of glucose.
Nervous irritability = fainting, seizures, coma |
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Why is glucose transported into adipose cells?
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To form glycerol portion of the fat molecule. Insulin promotes fat deposition.
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What are the different factors that lead to increased fatty acid synthesis in the liver?
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1) Insulin increases transport of glucose into liver cells. After 5-6% all additional glucose becomes fat. Glucose => pyruvate => acetyl co A => fatty acids.
2) Excess citrate and isocitrate fromed by TCA activate acetyl-CoA carboxylase (acetyl-CoA => malonyl CoA) 3) Insulin activates lipoprotein lipase in capillary walls of adipose tissue => splits TG's into FA's => absorbed into adipose cells => reconverted to TG's |
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What other effects does insulin have on fat storage in adipose cells?
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1) Inhibits the action of Hormone Sensitive Lipase => hydrolyzes TG's stored => release into blood (stopped)
2) Promotes glucose transport through the cell membrane into fat cells. Glucose => alpha-glycerol phosphate => glycerol + FA => TG's (stored) |
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What does insulin deficiency cause?
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1) Lipolysis of stored fat. Hormone sensitive lipase is strongly activated => hydrolysis of TG's => FA's and glycerol released into blood
2) Release of FA's into blood. FFA's in blood rises within minutes => becomes major source of energy for all tissues (except brain) 3) Increase in plasma cholesterol (too many FA's) 4) Increase in plasma phospholipids (too many FA's) 5) Excessive acetoacetic acid formed in liver 6) Depression of the utilization of acetoacetic acid in peripheral tissues 7) Formation of ketone bodies 8) Increased catabolism of proteins, plasma amino acid concentration rises => gluconeogenesis => increased urea excretion (protein wasting in DB) |
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Why is excessive acetoacetic acid formed in the liver when insulin is deficient?
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Excess FA => activation of carnitine transport mechanism (into mitochondria) => beta oxidation of FA => acetyl-CoA release (excess) => condensed to acetoacetic acid => blood
Peripheral cells convert acetoacetic acid into acetyl-CoA and used for energy. |
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What concentration of acetoacetic acid denotes severe state acidosis of body fluids?
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10 mEq/L
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How does the formation of ketone bodies occur?
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Acetoacetic acid => B-hydroxybutyric acid + Acetone
Presence in large quantities is called Ketosis |
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How does insulin promote protein synthesis and storage?
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1) Stimulates transport of AA into cells.
2) Increases translation of mRNA => new proteins 3) Increases the rate of transcription of DNA sequences => enzymes 4) Inhibits the catabolism of proteins 5) Depresses gluconeogenesis in liver => decreases activity of enzymes |
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What amino acids are strongly transported into cells by insulin?
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Valine, leucine, isoleucine, tyrosine, phenylalanine.
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How do insulin and growth hormone work together?
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Promote growth dramatically.
Synergistic function => cellular uptake of a different selection of amino acids => growth achieved |
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What type of glucose transporter do the B cells have?
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GLUT 2, permit a rate of glucose influx proportional to blood concentration.
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What is the rate limiting step for glucose metabolism in the beta cell?
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Glucose => Glucose-6-phosphate via glucokinase.
Major mechanism for glucose sensing and adjustment of insulin to glucose levels. |
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How does glucose stimulate insulin release in the pancrease?
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Glucose-6-phosphate => oxidized to ATP => closes the K+ chnnels in the cell => depolarizes membrane => opens voltage-gated Ca channels => Ca influx => fusion of docked insulin-containing vesicles => excocytosis
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Can the beta cells metabolize other substrates?
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Yes:
Certain amino acids can stimulate insulin secretion, when combined with glucose they potentialte the glucose stimulus for insulin secretion. Arginine and lysine |
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What other hormones help the pancreas secrete insulin?
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Glucagon, Glucose dependant insulinotropic peptide (gastric inhibitory peptide), acetylcholine => increase Ca levels => enhance the effect of glucose
Gastrin, CCK, secretin, GIP, GH B-adrenergic receptors Vagus nerve |
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What other hormones inhibit release of insulin?
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Somatostatin, norepinephrine (A-adrenergic receptors)
Leptin |
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What is the release of insulin at the fasting levels of blood glucose?
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80-100 mg/100mL = 25
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What happens if glucose concentration is suddenly increased to a level 2-3x normal?
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1) Insulin concentration increases 10-fold (3-5) min => immediate dumping of preformed insulin. Then decreases halfway back to normal (in 5-10 min)
2) Second insulin rise @ 15min. Plateau in 2-3hrs. Additional preformed insulin release, and synthesis of new insulin. |
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When is the peak for insulin reached?
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10-25 times the basal level
Blood glucose 400-600 mg/100mL |
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What GI hormones cause an increase in insulin? Which is the most potent?
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Gastrin
Secretin CCK Glucose-dependent insulinotropic peptide = most potent Cause an "anticipatory" increase in blood insulin in preparation for absorption. Increase the sensitivity of the insulin response, doubling the rate of insulin secretion as glucose rises. |
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What other hormones increase insulin and potentiate the glucose stimulus ?
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Glucagon
Growth hormone Cortisol Progesterone & Estrogen Any one of them can lead to exhaustion of beta cells. |
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What other hormones play roles in carb vs. fat burning?
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GH (hypoglycemia, promote fat burn)
Cortisol (hypoglycemia, promote fat burn) Epinephrine (hypoglycemia in stress, increases FA concentration in blood) Glucagon |
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What are the reasons for an increase in plasma FA concentration with epinephrine?
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1) Potent effect on causing glycogenolysis in liver => glucose release into blood
2) Direct lipolytic effect on adipose cells => hormone sensitive lipase activated => increase blood FFA's Enhancement of FA's is greater than enhancement of blood glucose. Exercise, circulatory shock, anxiety. |
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Summary of insulin actions:
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Increase:
Muscle glucose uptake Glucose use Protein synthesis Glycogenesis Fat synthesis (adipose) Decrease: Glucose output Ketogenesis Liver gluconeogenesis Glycogenolysis Tissue lipolysis |
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Where else is glucagon released?
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L-Cells of the intestine
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What are the contents of proglucagon?
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Several peptides linked in tandem:
Glicentin-related peptide Glucagon Glucagon-like peptide 1 (GLP-1) Glucagon-like peptide 2 (GLP-2) When cleaved, glucagon is 30-40% of what is released from proglucagon. |
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What is the half life of glucagon?
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3-6 minutes
Removed by liver and kidney. Can reach concentrations of 500pg/mL in portal vein. |
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What is the pattern of blood flow in the islet cells of the pancreas?
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Bathe the B-cells first then the A-cells. B-cells may influence A-cell function by an endocrine mechanism.
A-cell on B-cell is paracrine. |
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Summary of the effects of glucagon:
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Increase:
Glucose output Ketogenesis Liver gluconeogenesis Glyogenolysis Tissue lipolysis (large doses) Decrease: Glycogenesis |
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What is glucagon composed of?
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29 amino acids (MW 3485)
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How potent is glucagon?
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Only 1ug/kg can elevate concentration of glucose 20mg/100mL blood (25%) in 20 mins.
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How does glucagon increase glycogenolysis in the liver?
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1) Activation of adenylyl cyclase in hepatic cell membrane
2) Formation of cAMP 3) Activation of PK regulator protein 4) Activation of PK 5) Activation of Phosphorylase B kinase 6) Conversion of Phosphorylase B => A 7) Glycogen => Glucose-1-phosphate 8) Glucose-1-phosphate => glucose-6-phosphate => glucose Each succeeding product is produced in greater quantity than the preceding product. (amplifying mechanism) |
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What occurs if someone is infused with glucagon for 4 hours?
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All liver stores of glycogen become depleted.
Continued infusion will cause hyperglycemia from increasing the rate of AA uptake by liver cells and conversion of them to glucose via gluconeogenesis. |
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What is the rate limiting step in gluconeogenesis?
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Pyruvate => PEP
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What are other effects of glucagon?
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Activation of adipose cell lipase => release of FA
Inhibits the storage of TG's in liver => liver cannot remove FA's from blood Enhances the strength of the heart Incresases blood flow in tissues (kidneys) Enhances bile secretion Inhibits gastric acid secretion |
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What is the most important regulator of glucagon secretion?
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Blood glucose concentration.
Increasing blood glucose, decreases glucagon. |
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What else stimulates glucagon secretion?
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Amino acids (alanine, arginine)
Exercise => increases glucagon concentration 4-5 fold (increased AA circulating from contraction may cause increase) B-adrenergic stimulation |
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What inhibits glucagon secretion?
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Somatostatin (14 AA, 3min half life)
Hyperglycemia |
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What causes somatostatin secretion?
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1) increased blood glucose
2) Increased amino acids (arginine, leucine) 3) Increased FA 4) Increased concentrations of GI hormones from upper GI tract released in response to food (VIP, CCK) 5) Glucagon |
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What are the inhibitory effects of somatostatin?
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1) depresses secretion of insulin and glucagon
2) Decreases motility of: stomach, duodenum, gallbladder (decreases visceral blood flow) 3) Decreases secretion and absorption in GI tract, prologues gastric emptying time (decrease in the secretion of gastrin so acid is not prevented) 4) Decreases pancreatic exocrine secretions |
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What is the principle role of SST?
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Extend the period of time over which the food nutrients are assimilated into the blood.
Also: decreases the utilization of absorbed nutrients, prevents rapid exhaustion of the food => makes food available over a longer period of time. Also keeps the pituitary from secreting GH |
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What is the composition of somatostatin?
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Preprosomatostatin = 116 AA peptide coded by chromosome 3
Somatostatin = 14 cyclic peptide (MW 1600) produced from C-terminus of prepro molecule. Relased from teh hypothalamus (CNS, pancreas specific) Somatostatin (GI) = 28 AA that makes up 70-75% of the immunoreactivity. 7-10 times more potent in inhibiting GH and insulin. Secreted from gastric and duodenal mucosal cells. |
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How many SST receptors are there?
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5, all coupled to G-proteins
4 of them accept both 14 and 28 forms of SST. |
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What are the receptor pathways for SST?
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1) Gi-complex protein => inactivation of adenylate cyclase => reduced cAMP => inactivation of PKA
2) Regulation of phosphotyrosine phosphatases 3) MAP kinase 4) Alterations in Ca and K ion concentrations |
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What does inactivation of adenylate cyclase lead to (SST binding)?
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Suppresses secretion of GH and TSH from the anterior pituitary gland.
Suppresses secretion of insulin and glucagon from pancreas. |
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What do sulfonylurea drugs do? What specific one also increases secretion of pancreatic SST?
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Increase insulin secretion by closing K+ channels in B cells.
Tolbutamide: also increases SST secretion |
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What is an analog of SST that has a longer half life?
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Octreotide, an octapeptide variant of somatostatin with a half life of 110 min
Used to treat tumors. |
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How much of the glucose absorbed from the gut is immediately stored in the liver as glycogen?
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2/3
Liver functions as a glucose buffer system |
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How much does the liver affect fluctuations in blood glucose?
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Keeps the blood glucose within 1/3 of what it would otherwise be.
Liver disease = huge fluctuations in blood glucose |
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What effect does low blood glucose have on the brain?
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Low blood glucose on the hypothalamus stimulates the sympathetic NS.
Adrenal glands secrete epinephrine => release of glucose to blood |
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What happens if hypoglycemia is prolonged?
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If stretched out hours/days:
Release of GH, and Cortisol => decrease rate of glucose utilization Increase fat utilization |
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What tissues can ONLY use glucose?
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Brain, retina, germinal epithelium of hte gonads
Most of the glucose between meals is used for brain metabolism. |
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Why is it important that blood glucose not rise too high?
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1)Glucose exerts osmotic pressure in the extracellular fluid, and can cause cells to secrete water and dehydrate them
2) Loss of glucose in urine 3) Osmotic diuresis by kidneys from loss of glucose in urine = loss of fluids and electrolytes 4) Damage to blood vessels |
