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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)
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.
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
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.
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.
What are the major effects of type II diabetes?
- Decreased insulin sensitivity
- Decreased insulin release
- Hypersecretion of glucagon
- Impaired incretin effect
- Accelerated gastric emptying.
What is an incretin?
A hormone that causes insulin release before blood glucose levels increase.
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.
What is GIP?
Glucose-dependent Insulinotropic Polypeptide. It is created in K cells in the mucosa of the duodenum and jejunum.
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.
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.
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
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)
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
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.
Describe how insulin is stored in pancreatic beta cells
Monomers (active form) -> Dimers -> hexamer (with a Zn2+ center) (storage form)
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.
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.
- How a drug is processed / What a body does to the drug.
- Think ADME:Absorption, Distribution, Metabolism, Excretion
What are the parts of phase I metabolism?
- Cytochrome p450 enzymes
What is phase II metabolism?
Conjugation (addition of glutathione, acetyl, methyl, sulfate, etc)
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.
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.
What genes affect warfarin, and should be checked before administering?
VKORC1 and CYP2C9