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What are the major cells in the pancreatic islets, and what do they do?
- Alpha cells (15%-20%, smallest in size): produce glucagon which increases blood glucose levels. Glucagon (linear polypeptide) weighs 3,500 daltons.
- Beta cells (60%-70%): Produce insulin when blood glucose is greater than 70 mg/100 ml, which decreases blood glucose levels. Insulin (2 protein chains) weighs 5,700 - 6,000 daltons
- Delta cells (5%-10%, biggest in size): Produce somatostatin which regulates growth hormone. Somatostatin weighs 1638 daltons (cyclical structure)
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What are the minor cells in the pancreatic islets, and what do they do?
- PP cell (F cell)α: secrete pancreatic polypeptide (stimulates gastric chief cells, inhibits: bile secretion, intestinal mobility, pancreatic enzyme/HCO3 secretion).
- D 1 cell: Secrets Vasoactive Intestinal Peptide (VIP) (similar to glucagon, but it also stimulates pancreatic exocrine secretion).
- EC cellα: Secretes secretin, motilin, and substance P. Secretin stimulates secretion of pancreatic enzymes/HCO3-. Motilin increases gastric and intestinal motility. Substance P has neurotransmitter properties.
- Epsilon cell: Secretes Ghrelin, which stimulates appetite.
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What cells tend to have abundant sER
- Cells that...
- -Function in lipid metabolism
- -Synthesize and secrete steroids
- -Detoxify enzymes related to cytochrome p450
- -Modify and detoxify hydrophobic compounds such as pesticides and carcinogens
- -Metabolize glycogen
- -Form and recycle membranes
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What does sER do in skeletal and cardiac muscles?
in skeletal and cardiac muscles, sER (now called Sarcoplasmic Reticulum (SR)) sequesters Ca2+ for the contractile process.
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What is the role of sER in drug metabolism?
Many cells in the liver show increased sER when toxins are present. Toxins and carcinogens can be converted to water-soluble conjugated products that can be eliminated from the body. A lipophilic drug challenge will increase the amount of sER in hepatocytes.
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What are the major effects of type II diabetes?
- Decreased insulin sensitivity
- Decreased insulin release
- Hypersecretion of glucagon
- Impaired incretin effect
- Accelerated gastric emptying.
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What is an incretin?
A hormone that causes insulin release before blood glucose levels increase.
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What is GLP-1?
Glucagon-Like-Peptide is a major incretin that is created in cells in the jejunum and ileum. It is created from proglucagon.
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What is GIP?
Glucose-dependent Insulinotropic Polypeptide. It is created in K cells in the mucosa of the duodenum and jejunum.
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How can incretins be used in therapy?
- GLP-1 is effective in therapy for type II diabetes, but is degraded quickly by DPP-4.
- GIP is not effective and is present in normal levels during type II diabetes.
- Therefore, GLP-1 + DDP-4 inhibitors, or long lasting incretin mimetics must be used.
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Describe the effects of counterregulatory hormones in health and diabetes
- Counterregulatory hormones work against the action of insulin.
- The major CRH are glucagon, epinephrine, cortisol, growth hormone. These promote glycogen breakdown, ketogenesis, and gluconeogenesis.
- Type I diabetics have an impaired CRH response, increasing their odds of hypoglycemia. Glucagon response is lost, and epinephrine becomes the main CRH.
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Describe the pathophysiology of diabetic ketoacidosis (DKA).
- Insulin deficiency ->
- intracellular starvation ->
- excessive counterregulatory hormones released ->
- increased fatty acetyl-CoA entry into hepatic mitochondria to produce glucose and ketones (acetoacetic acid and beta hydroxybutyric acid) ->
- hyperglycemia and ketonemia.
- This can lead to acetone breath, vomiting, ketonuria, tachypnea, shock, impaired consciousness, and coma
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Define the three major classes of general hormone signaling
- 1) Endocrine (ductless, released into circulation to affect distant cells)
- 2) Exocrine (released to a surface or organ lumen, ie digestive enzymes, sweat)
- 3) Paracrine (released into interstitial space to affect neighboring cells)
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Using insulin as an example, describe the synthesis and processing of the protein into its mature form
- 1) Transcription of gene
- 2) Signal sequence is translated, causing binding to rER
- 3) Preproinsulin is synthesized and then processed to proinsulin in rER (loses the signal sequence)
- 4) Proinsulin is processed to insulin in golgi (loses the C chain, which was required for folding and creating interchain bonds)
- 5) Packed and stored in secretory vessel
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Describe the structural features of the insulin protein
Has an A chain and a B chain, connected by two disulfide bonds. A C chain was previously removed after allowing for the proper folding and bond forming.
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Describe how insulin is stored in pancreatic beta cells
Monomers (active form) -> Dimers -> hexamer (with a Zn2+ center) (storage form)
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Describe the method by which insulin secretion is triggered
- -Glucose enters the ß cell, becomes glucose-6-phosphate, and enters glycolysis, producing ATP.
- -Increased ATP inhibits K+ channels, causing membrane depolarization
- -Voltage sensitive Ca2+ channels open.
- -An influx of Ca2+ causes exocytosis of insulin
note: Insulin release is biphasic, with a large initial peak followed by another longer release period.
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Contrast the structure of insulin with that of glucagon
Glucagon is also a peptide hormone that begins as a prohormone. It consists of a single amino acid sequence (29 amino acids long) that forms a single alpha helical structure.
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Define pharmacokinetics:
- How a drug is processed / What a body does to the drug.
- Think ADME:Absorption, Distribution, Metabolism, Excretion
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What are the parts of phase I metabolism?
- Oxidation
- Reduction
- Hydrolysis
- Cytochrome p450 enzymes
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What is phase II metabolism?
Conjugation (addition of glutathione, acetyl, methyl, sulfate, etc)
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What are CYP genes?
- CYP genes, ie CYP2C19*1, produce cytochrome p450 enzymes.
- *1 = wild type. *2, *3, etc = less common variations or mutations.
- In this example, 2 is the family,
- C is the subfamily,
- 19 is the enzyme.)
- CYP genes are found in the liver and small intestines and metabolize products.
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What are some of the most important CYP genes?
- CYP3A is the biggest subfamily.
- CYP2C9 metabolizes 19% of clinical drugs, including warfarin, an oral anticoagulant.
- CYP2D6 metabolizes about 25% of clinical drugs including many antidepressants, but is inhibited by cocaine, protease inhibitors, and other drugs.
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What genes affect warfarin, and should be checked before administering?
VKORC1 and CYP2C9
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