OSUCOM Week 4 - 1

• 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)

• 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 cell^α: 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.

• 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

in skeletal and cardiac muscles, sER (now called Sarcoplasmic Reticulum (SR)) sequesters Ca2+ for the contractile process.

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.

• Decreased insulin sensitivity
• Decreased insulin release
• Hypersecretion of glucagon
• Impaired incretin effect
• Accelerated gastric emptying.

A hormone that causes insulin release before blood glucose levels increase.

Glucagon-Like-Peptide is a major incretin that is created in cells in the jejunum and ileum. It is created from proglucagon.

Glucose-dependent Insulinotropic Polypeptide. It is created in K cells in the mucosa of the duodenum and jejunum.

• 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.

• 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.

• 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

• 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)

• 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

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.

Monomers (active form) -> Dimers -> hexamer (with a Zn2+ center) (storage form)

• -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.

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

• Oxidation
• Reduction
• Hydrolysis
• Cytochrome p450 enzymes

Conjugation (addition of glutathione, acetyl, methyl, sulfate, etc)

• 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.

• 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.

VKORC1 and CYP2C9