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101 Cards in this Set
- Front
- Back
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T/F : the Pancreas contains both endocrine and exocrine tissue
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True.
Exocrine tissue is 99% of the pancreatic weight. The Exocrine tissue secretes bicarbonate and digestive enzymes. |
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Islets of Langerhans (endocrine portion of pancreas) secretes what important hormones? (2)
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Insulin and Glucagon. The islets are small portion of the pancreas.
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What are the 4 major cell types of the Islets of Langerhans
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1. α cells release glucagon
2. β cells release insulin 3. δ cells release somatostatin and gastrin 4. PP cells release pancreatic polypeptide |
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Where is insulin produced in the Islets?
Where is Glucagon and Somatostatin produced? |
Cells at center of islet make insulin.
Cells at periphery make glucagon and somatostatin which contradict insulin |
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What are the functions of Glucagon and Somatostatin in relation to Insulin??
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Glucagon and Somatostatin contradict Insulin
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Where does the pancreas secrete its Endocrine products? it's Exocrine products?
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Endocrine pancreas secretes into rich
capillary beds Exocrine pancreas secretes into ducts |
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What do we know about Type A (alpha cells) of the Islets?
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● Tend to be around the B (β) cells toward the islet
periphery ● Secrete glucagon, proglucagon, glucagon-like peptides (GLP-1 and GLP-2) |
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Where are the Type B (beta cells) of the islets and what do they secrete?
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● Tend to be concentrated in the center of the islet
● Secrete insulin, amylin, proinsulin, C-peptide, GABA |
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T/F: Type B (beta cells) of the islets secrete Insulin, Amylin, Glucagon, C-peptide, and GABA?
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FALSE.
Beta Cells secrete -Insulin -Amylin -Proinsulin -C-peptide -GABA |
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Where are the Type D (delta cells) of the islets and what do they secrete?
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Type D (δ) cells
● Tend to be around the B (β) cells toward the islet periphery ● Secrete somatostatin |
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Where the the Type PP (F) cells of the islets and what do they secrete?
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Type PP (F) cells
● Tend to be around the B (β) cells toward the islet periphery ● Secrete pancreatic polypeptide (PP) |
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T/F : Islets are NOT richly vascularized.
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FALSE.
The islets are richly vascularized. There is 5 to 10x more blood flow to the islets than to a comparable portion of the exocrine mass. |
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T/F : Islets make up about 1% of the pancreas mass but have about 10 - 15% of the blood flow in the pancreas
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True.
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T/F : Beta Cells secrete insulin from the islet center.
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True.
Blood flows from the islet center to the periphery, carrying insulin outward. |
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T/F : Insulin does NOT inhibit A cell Glucagon secretion.
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FALSE.
Insulin DOES inhibit alpha (A cell) Glucagon secretion. |
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T/F : Insulin inhibits D cell somatostatin secretion.
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True.
Insulin inhibits D cell somatostatin secretion |
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Hyperglycemia and it's Acuity
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Hyperglycemia : high levels of glucose in the blood.
-NOT an acute threat but long term hyperglycemia is dangerous can lead to DM/DKA |
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Hypoglycemia and it's Acuity
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Hypoglycemia : low levels of glucose in the blood.
-dangerous, VERY SERIOUS ISSUE - Brain depends on a constant supply of glucose - Toxic to many cells and tissues |
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What are the functions of insulin and glucagon in the body regarding energy homeostatis?
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Insulin and glucagon are the primary hormones
- Controls uptake, utilization, storage, and release |
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Actions of Insulin
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-Promotes the uptake and storage of glucose
-Promotes the uptake of other small, energy-containing molecules |
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Counter-regulatory Hormones (of insulin)
-Glucagon -Catecholamines -Glutacorticoids -Growth Hormones |
-Promote the release of nutrients
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INSULIN
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Insulin is a 51-amino acid protein composed of two
peptide chains that are linked by two disulfide bridges Human pancreas contains approximately 8 mg of insulin ● 0.5 to 1.0 mg is secreted daily Insulin is initially synthesized in pancreatic β cells as preproinsulin ● Cleaved to proinsulin and packaged into vesicles ● Processed to insulin and free connecting (C) peptide in vesicles --Remains in the vesicles until physiologic conditions render it's expulsion |
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Insulin Secretion - How it happens
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● Preformed insulin stored in secretory vesicles
- Low basal rate of insulin secretion - Increased upon exposure to glucose ● Glucose metabolism - Increases the intracellular ATP/ADP ratio |
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What happens to the ATP/ADP ratio as more glucose is present?
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It Increases
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T/F: GLUT2 is an important constituent present on beta cells always.
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True.
Glucose enters the beta cells via GLUT2 transporters. |
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Intracellular glucose
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- Phosphorylated to glucose-6-phosphate by HEXOKINASE
- Processed in the glycolytic pathway and the citric acid cycle - ATP is generated increasing the ATP/ADP ratio in the β cell |
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The cascade that leads to Insulin Secretion
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With high glucose the high ATP/ADP ratio
● Closes the ATP-sensitive K+ channel (K+/ATP channel) ● Depolarization of the cell activates voltage-gated Ca2+ channels - Leads to an influx of extracellular Ca2+ - Increased intracellular [Ca2+] stimulates exocytosis of the vesicles storing insulin |
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Secondary Mechanism for Insulin Secretion
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cyclic AMP : Generated at the plasma membrane from ATP
● Potentiates glucose-stimulated insulin secretion ● Cyclic AMP-dependent pathways appears to be important in the exocytotic machinery ● Leads to the release of Ca2+ from intracellular stores --Leads to further secretion |
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T/F: In beta cells the primary GLUT transport is GLUT4 whereas in liver and muscle cells, the primary GLUT transport is GLUT2.
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FALSE.
In beta cells, the primary transporter is GLUT2, that is always present on the cells. In muscle and liver cells, the primary transporter is GLUT4. |
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When blood glucose is high it is transported into the beta cells via GLUT 2
When glucose is metabolized, leads to high ratio of ATP/ADP in beta cell, shuts down K/ATP channel Leads to depolarization and influx of Ca into the beta cells, leading to an increase secretion of insulin via vesicles, leading to fusion of the beta |
How the insulin secretion happens
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This channel is an important target for T2 DM
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K+/ATP channels
● Octameric structure - 4 subunits of Kir6.2 ◦ Tetramer forms the pore of the K+/ATP channel ◦ Binds ATP directly - 4 subunits of SUR1 ◦ Regulate the channel's sensitivity to ADP and pharmacologic agents ◦ Confers sensitivity of the channel to ADP and to drugs ◦ Mg2+-ADP binding to SUR1 activates the channel |
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The K+/ATP Channel Features
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● Octameric structure
- 4 subunits of Kir6.2 ◦ Tetramer forms the pore of the K+/ATP channel ◦ Binds ATP directly - 4 subunits of SUR1 ◦ Regulate the channel's sensitivity to ADP and pharmacologic agents ◦ Confers sensitivity of the channel to ADP and to drugs ◦ Mg2+-ADP binding to SUR1 activates the channel |
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K+/ATP Channels is Pancreatic Beta Cells
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Composed of Kir6.2 and SUR1 subunits
- Mutations in Kir6.2 or SUR1 can result in hyperinsulinemic hypoglycemia |
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K+/ATP Channels in Cardiac and Smooth Muscle
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Composed of Kir6.2 and SUR2 isoform
-Unlike beta cells which express SUR1 isoform!! |
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K+/ATP Channels in some other Smooth Muscle
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Express Kir6.1 and SUR2 isoform
Different than other smooth muscle and cardiac muscle...where Kir6.2 is the isoform. |
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Nutrient Activators of Insulin Secretion
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-Nonglucose sugars,
-Amino acids -Fatty acids These promote insulin transcription, translation, processing and packaging into vesicles. |
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Insulin action at target tissue (Muscle, Liver, Adipose)
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Binds to receptors on surface of target cells
-All tissues express insulin receptors -MUCH higher level of insulin receptors are expressed on "ENERGY STORING TISSUES" : Muscle, Liver, Adipose |
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What is Insulinase? Where is it produced? What is it's Half life?
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-degrades insulin RAPIDLY (therefore insulin must be secreted regularly by beta cells)
-Produced in the: --Liver --Kidney T1/2 is 6 Minutes! |
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Binding of the insulin to the extracellular portion of the receptor does what?
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- Activates the intracellular tyrosine kinase
- Autophosphorylates tyrosine on the nearby β subunit - Phosphorylates the insulin receptor substrateproteins (IRS-proteins) ◦ Recruit second messenger proteins with src homology 2 (SH2) domains ◦ Type IA phosphatidylinositol 3′-kinase (PI3-kinase) is an important one ***PI3-kinase is an important second messenger |
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T/F: Liver and Muscle have the LOWEST expression of insulin receptors.
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FALSE.
Highest expression |
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What are the Metabolic Effects of Insulin Receptor Activation?
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Regulates multiple pathways related: glucose
utilization, distribution, and storage ● The effects vary in different tissues due to the presence or absence of particular enzymes |
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Net Effect of Insulin
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-remove glucose from the
blood, -utilize glucose for cellular energy, -store excess glucose as glycogen and fat deposits Absence of insulin or presence of counter-regulatory hormones produces opposite effects |
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T/F: Insulin favors glycogenolysis.
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FALSE.
Insulin favors Glycogenesis (the production of glycogen for storage of glucose) |
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What are the 2 main pathways of Energy Homeostatis?
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1. Glycogen Metabolism (short-term, finite stores)
● Glycogen is the major carbohydrate in humans (esp. in the liver and muscle) ● Muscle glycogen - Source of glucose for muscle itself ● Liver glycogen - Maintains blood glucose 2. Lipid Synthesis (long-term stores, infinite capacity) |
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T/F: Glycogenesis and glycogenolysis are different
pathways (not two directions on the same pathway) ? |
TRUE!
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Cyclic AMP regulates glycogenesis and glycogenolysis
● Glycogen phosphorylase ● Glycogen synthase ● Both regulated through phosphorylation through cAMP pathway |
true
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T/F: GLUT2 transporters are regulated by insulin?
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FALSE.
They are always present on beta cells and are constituents of those cells in the pancreas. Always secreting. |
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Insulin vs. Glucagon
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Insulin: inhibits cAMP production, promotes glucose storage
Glucagon: activates cAMP production, promotes glucose release |
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T/F : Insulin favors glycogenesis while starvation and counter-regulatory hormones favor glycogenolysis.
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True.
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What is the point of Glucose-6-Phosphatase? Where is it? Where is it not? What is the ramification?
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Glucose-6-Phosphatase helps with glucose EXPORT from tissues that it is liberated from.
-The Liver and Kidney have G-6-Pts and thus can transport glucose to other parts of the body. -MUSCLE cells do not have G-6-Pts therefore when glucose is liberated from the muscle it cannot be transported elsewhere, it stays in the muscle. |
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Glucose Import vs. Glucose Export, including the enzymes that regulate this
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Glucokinase: when glucose enters the cell it needs to be phosphorylated. Glucokinase is most associted with Glucose Import. Helps in glucose uptake
Glucose-6-phosphatase: is most closely related to Glucose export. Phosphate must be cleaved for Glucose-6-phosphate must be cleaved. Liver and Kidney only have this enzyme and the only organs that can export glucose into the blood in a starvation state. |
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Glucose Import Enzyme
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Glucokinase
Hexokinase is most closely associated with GLUCOSE IMPORT. Another enzyme that turns glucose into Glucose-6-Phosphate. |
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Glucose Export Enzyme
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Glucose - 6 - Phosphatase
-Only present in Liver and Kidney, not muscle. |
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So Glycolysis ...
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Glycolysis (stimulated by insulin)
● Enzymes of glycolysis are found in the cytosol ● Availability of glucose controlled by transport into the cell - Controlled by insulin - Exception: liver and pancreatic β-islet cells ● Hexokinase has a high affinity (low Km) for glucose - Saturated under normal conditions in the liver - Acts at a constant rate to provide glucose 6-phosphate |
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T/F : the liver contains and isozyme for hexokinase called glucokinase.
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True.
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What is the function of Glucokinase?
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◦ Km very much higher than the normal intracellular
concentration of glucose ◦ Functions to remove glucose from the blood following a meal |
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Three enzymatic steps can be considered
physiologically irreversible (regulatory sites) : |
1. Hexokinase (Glucokinase)
2. Phosphofructokinase 3. Pyruvate Kinase |
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T/F: Gluconeogenesis and Glucose export into the bloodstream is antagonized by insulin
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True
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T/F: Lipid Synthesis is antagonized by insulin.
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FALSE.
Lipid synthesis is stimulated by insulin. STORAGE! |
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Type II DM
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Insufficiency of insulin production in the face of insulin resistance
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Type I DM
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Absolute lack of insulin
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What happens in TIDM?
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Insulin Responsive Tissues
-Fail to take up glucose, amino acids, and lipids Unopposed action of counter-regulatory hormones -Induces STARVATION like state |
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Type 1 effects in the Liver
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-Favors Gluconeogenesis and Glycogenolysis
-Converts Fatty Acids to Ketone bodies to the brain Ketones equilibrate into -β-hydroxybutyrate and -Acetoacetate ● Excessively high concentrations of these acids can deplete serum bicarbonate and cause metabolic acidosis ◦ Diabetic ketoacidosis (DKA) ◦ Serious, potentially life-threatening medical emergency |
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Type 1 effects in the Muscle
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- Breaks down protein and releases amino acids
- Provides a fuel source for liver gluconeogenesis |
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Type 1 effects in the Kidney
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- Blood glucose levels exceed the kidney's capacity
to reabsorb glucose - Glucose in the urine produces an osmotic diuresis and causes polyuria and polydipsia |
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Type 1 effects in the Adipose
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- Triglycerides are broken down and released
- Liver breaks down these fatty acids for gluconeogenesis and ketone body production |
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Administering Insulin for what effects?
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● Reverses the metabolic starvation due to
counter-regulatory hormones - Reverse amino acid breakdown in muscle - Reverse ketogenesis in the liver |
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Insulin Preps
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see table in notes.
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What is insulin and how is it administered?
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Insulin is a protein
● Rapidly degraded in the GI tract ● Not effective as an oral agent (new drugs in clinical trials) Insulin is administered parenterally ● Typically subcutaneous injection ● Creates a small depot of insulin at the site of injection |
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What affects the rate of absorption for insulin?
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-Solubility of the insulin preparation
-Local circulation -Site-to-site variability can greatly affect absorption -Person-to-person variability can greatly affect absorption |
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Result of Faster Absorption of Insulin?
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-Faster onset of action
-Shorter duration of action |
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Regular Insulin
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Short-acting preparation
Structurally identical to endogenous insulin ● Zinc ions are added for stability ● Clear solution and at neutral pH Regular insulin aggregates into hexamers ● Dissociation of the hexamers to monomers is the rate-limiting step for absorption Administration ● Subcutaneously ● Intravenously (only form given by this route) - Diabetic ketoacidosis - During postoperative management of diabetic patients |
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Insulin lispro
insulin aspart insulin glulisine |
ULTRA-RAPID acting insulin
Designed to keep the molecule in a monomeric form to speed absorption Structurally similar to regular insulin |
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Differences : Insulin Lispro
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- B28 proline and B29 lysine are changed to
produce B28 lysine and B29 proline |
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Differences : Insulin Aspart
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- The B28 proline is replaced and becomes
B28 aspartate |
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Differences : Insulin Glulisine
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- The B3 asparagine is changed to B3 lysine
- The B29 lysine is changed to B29 glutamic acid |
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Ultra-Rapid Insulin Forms (Lispro, Aspart, Glulisine)
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● Can be injected minutes before a meal
● Administered subcutaneously ● Dispensed as clear solutions at neutral pH and contain small amounts of zinc |
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NPH (neutral protamine Hagedorn) Insulin
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Intermediate-acting preparation
w Insulin is combined with protamine ● Protein isolated from rainbow trout sperm - Added in a zinc suspension at neutral pH - Cloudy solution ● Prolongs the time required for absorption of insulin - Complexes with insulin - Proteolytic enzymes cleave the protamine from the insulin |
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Insulin Glargine and Insulin Detemir
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Long Acting forms of Insulin
Long-acting preparations ● Steady release (24 hours) without a peak ● Mimics the basal insulin secretion Structurally similar to regular insulin ● Insulin glargine: the A21 asparagine to A21 glycine and two arginines are added to the C terminus (B31and B32 arginine) ● Insulin detemir: the B30 threonine is deleted and a 14-C fatty chain is attached to B29 lysine Modifications increase the presence of the hexamer form ● Insuline glargine modifications raise the isoelectric point from 5.4 to near neutral ● Insulin glargine is less soluble when injected |
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Insulin Glargine and Insulin Detemir
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Modifications increase the presence of the hexamer form
● Insulin detemir fatty acid chain leads to slow dissociation from the hexamer form ● Molecule is more lipophilic ● Zinc is added to further stabilize the hexamer ● Following dissociation the monomer binds serum albumin and is released slowly |
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Preparations of Insulin Glargine and Insulin Detemir
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Preparations
- Both dispensed as clear solutions - Insulin glargine at acidic pH - Insulin detemir at neutral pH |
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Type II Diabetics and Insulin Therapy
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Type II diabetic patients
● Insulin resistance is typically more severe in muscle and liver than in fat cells ● Insulin causes more glucose uptake in adipose tissue often resulting in weight gain |
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Care and Monitoring for TI and TII
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Assessment of intensive therapy to maintain continuous normoglycemia
- Critical to assess accurately the level of control achieved with therapy - Continuous normoglycemia greatly reduces longterm complications of diabetes |
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HbA1C
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Glucose in the blood nonenzymatically glycosylates
blood proteins - Nonenzymatic glycosylation of hemoglobin in red blood cells generates HbA1c Normal = 4 to 5.6% Diabetes = 6.5%< |
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Nonenzymatic Glycosylation of HbA1C
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Occurs at a rate proportional to the level of glucose in the blood
◦ Based on the lifespan of a red blood cell being approximately 120 days ◦ HbA1c level yields an estimate of the average blood glucose level over time |
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Hyperinsulinemia Causes
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- Exogenous insulin overdose for Type I or Type II
diabetes - Main challenge in therapy of diabetes - Most common cause of hypoglycemia |
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Levothyroixine
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L-isomer of T4
Most thyroid hormone in the blood is in the form of T4 ● Reservoir of “prodrug” (T4) may be an effective buffer Table 12 Pharmacology of the Thyroid Gland Pharm 623 24 of 33 ● Normalizes metabolic rates over a wide range of conditions The half-life of T4 is 6 days, as compared to the 1-day half-life of T3 ● Allows a patient to take just one thyroid hormone replacement pill per day ● Exception: myxedema coma ● Faster onset of T3 enhances recovery from life-threatening hypothyroidism |
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Levothyroxine (2) & Liothyronine (T3) Adverse Effects and CI
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Hyperthyroidism,
osteopenia, pseudotumor cerebri, seizure, myocardial infarction Acute myocardial infarction Uncorrected adrenal cortical insufficiency Untreated thyrotoxicosis |
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Levothyroxine and Liothyronine Indications and Therapeutic Considerations
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These are THYROID HORMONE REPLACEMENTS
Mechanism—Replace missing endogenous thyroid hormone with exogenous thyroid hormone Cholestyramine and sodium polystyrene sulfonate decrease absorption of synthetic thyroid hormone Rifampin and phenytoin increase metabolism of synthetic thyroid hormone Because of its longer elimination half-life, T4 is usually preferred for the treatment of hypothyroidism T3 may be preferred in myxedema coma due to its faster onset of action |
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Perchlorate
Thiocyanate Pertechnetate |
These are IODIDE UPTAKE INHIBITORS
Mechanism—Compete with iodide for uptake into the thyroid gland follicular cells via sodium-iodide symporter, thereby decreasing intrathyroidal supply of iodide available for thyroid hormone synthesis |
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Perchlorate
Thiocyanate Pertechnetate Indications, Adverse Effects and CI |
Hyperthyroidism
Radiocontrast agents Aplastic anemia GI irritation No major contraindications Clinical use in hyperthyroidism is limited due to the risk of developing aplastic anemia Frequently used as radiocontrast agents |
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Radioactive Iodide
Iodide in high concentrations Propylthiouracil Methimazole |
These are INHIBITORS OF ORGANIFICATION AND THYROID HORMONE RELEASE
Mechanism—Radioactive iodide strongly emits beta-particles that are toxic to thyroid follicular cells. High-concentration iodide inhibits iodide uptake and organification via Wolff-Chaikoff effect. Propylthiouracil inhibits thyroid peroxidase and conversion of T4 to T3. Methimazole inhibits thyroid peroxidase. |
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Radioactive Iodide
Iodide in high concentrations Propylthiouracil Indication |
Hyperthyroidism
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Radioactive Iodide
AE, CI, and Therapeutic Considerations |
May worsen ophthalmopathy
in Graves' disease, hypothyroidism Do not use in Pregnancy Alternative to surgery in the treatment of hyperthyroidism Excess radiation can destroy thyroid, thereby causing hypothyroidism |
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Iodide in High Concentrations
AE, CI, and Therapeutic Considerations |
ed for temporary suppression of thyroid gland
function Also used before thyroid gland surgery to allow technically easier excision |
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Propylthiouracil & Methimazole
AE, CI, and Therapeutic Considerations |
Agranulocytosis,
hepatotoxicity, vasculitis, hypoprothrombinemia (PTU) Rash, arthralgias Pregnancy and breastfeeding (methimazole) Methimazole is generally preferred in the treatment of hyperthyroidism due to lower incidence of serious adverse effects PTU is the preferred agent in thyroid storm due to additional peripheral inhibition of T4-to-T3 conversion |
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Propranolol
Esmolol Amiodarone |
These are INHIBITORS OF PERIPHERAL THYROID HORMONE METABOLISM
Mechanism—Block 5′-deiodinase, thereby inhbiting T4 to T3 conversion |
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Propranolol
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Hypertension
Angina Heart failure Pheochromocytoma Bronchospasm, atrioventricular block, bradyarrhythmia Sedation, decreased libido, mask symptoms of hypoglycemia, depression, dyspnea, wheezing CI: Bronchial asthma or chronic obstructive pulmonary disease Cardiogenic shock Uncompensated cardiac failure Second- and third-degree AV block Severe sinus bradycardia Propranolol blocks β1- and β2-receptors equally Propranolol is extremely lipophilic; its CNS concentration is sufficiently high that sedation and decreased libido may result The sympatholytic effect of beta-blockers is more important in treating the symptoms of hyperthyroidism than the minor effect of these drugs on 5′-deiodinase |
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Esmolol
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Thyroid storm
Bronchospasm, atrioventricular block, bradyarrhythmia Sedation, decreased libido, mask symptoms of hypoglycemia, depression, dyspnea, wheezing Bronchial asthma or chronic obstructive pulmonary disease Cardiogenic shock Uncompensated cardiac failure Second- and third-degree AV block Severe sinus bradycardia Esmolol is a β1-selective adrenergic antagonists Esmolol has an extremely short half-life (3–4 min) and thus is used for emergency β blockade, as in thyroid storm Esmolol is a preferred β-adrenergic antagonist for treatment of thyroid storm because of its rapid onset of action and rapid elimination half life |
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Amiodarone
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Recurrent
ventricular fibrillation, unstable ventricular tachycardia Atrial fibrillation Supraventricular arrhythmias Arrhythmias, asystole, bradycardia, heart block, heart failure, hypotention, sinus arrest, neutropenia, pancytopenia, hepatic failure, severe pulmonary toxicity (pneumonitis, alveolitis, fibrosis), thyroid dysfunction Fatigue, corneal microdeposits, blue-gray skin pigmentation, photosensitivity Patients receiving ritonavir Severe SA-node disease Second- or third-degree AV block Bradycardia with syncope IV formulation (Cordarone®) contains benzyl alcohol, which has caused gasping respiration and cardiovascular collapse (“gasping syndrome”) in neonates Inhibits type 1 5'-deiodinase (not a clinical use) Metabolism of amiodarone releases iodine as iodide resulting in increased plasma concentrations of iodide Can cause hypothyroidism by the Wolff– Chaikoff effect Can also cause hyperthyroidism since the excess iodide load can lead to increased thyroid hormone synthesis and release Can induce an autoimmune thyroiditis that leads to release of excess thyroid hormone |
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Dexamethazone
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This is GLUCOCORTICOIDS
Mechanism—Inhibit hormone secretion and peripheral conversion of T4 to T3 Inflammatory conditions in many different organs Autoimmune diseases Patients with severe accelerating thyrotoxicosis (thyroid storm) Exophthalmos Immunosuppression, cataracts, hyperglycemia, hypercortisolism, depression, euphoria, osteoporosis, growth retardation in children, muscle atrophy Impaired wound healing, hypertension, fluid retention Inhaled glucocorticoids may also cause oropharyngeal candidiasis and dysphonia Topical glucocorticoids may also cause skin atrophy Systemic fungal infection Chronic glucocorticoid treatment should be tapered slowly; abrupt withdrawal of systemic glucocorticoids can lead to acute adrenal insufficiency Inhibits the glandular secretion of hormone Inhibits the peripheral conversion of T4 to T3 Additive to that of propylthiouracil suggesting a different mechanism of action Concurrent administration of propylthiouracil, SSKI, and dexamethasone for thyroid storm causes a rapid reduction in serum T3 concentration within the normal range in 24 to 48 hours |
