Pancreas Pt 2.docx

Glucagon: General Info It is produced by the pancreatic alpha cells (which make up 70% of the Islet of Langerhans). Glucagon has an antagonistic relationship with insulin, meaning that it does the opposite of it. Glucagon synthesis: pre-prohormone converting to prohormone and then converting to horm...

Glucagon: General Info It is produced by the pancreatic alpha cells (which make up 70% of the Islet of Langerhans). Glucagon has an antagonistic relationship with insulin, meaning that it does the opposite of it. Glucagon synthesis: pre-prohormone converting to prohormone and then converting to hormone. Glucagon synthesis is stimulated when glucose levels drop below threshold in the blood plasma (AKA: hypoglycemia). These threshold levels vary per species. Glucagon Clearance half-life: 5-7 minutes (endogenous) Glucagon has a similar function/structure amongst various species. Glucagon: Secretion Step 1: Glucose will enter the cell using GLUT-1 transporters. Step 2: Glucose is used to make ATP. When there is a low concentration of glucose, there would therefore be a low concentration of ATP intracellularly. Step 3: Low ATP levels stimulate the closure of ATP sensitive potassium channels. PLEASE NOTE: This is the opposite of what happens with insulin due to insulin and glucagon having opposite relationships. In insulin secretion, HIGH ATP levels will cause the CLOSURE of the ATP sensitive potassium channels, which then stimulates insulin release because there is too much ATP and insulin wants to LOWER glucose levels. While, in glucagon secretion, LOW ATP levels will cause the CLOSURE of the ATP sensitive potassium channels because low levels stimulate glucagon secretion to increase glucose levels. Step 4: The efflux of potassium is therefore decreased. However, the potassium that did enter the cell prior to the closing of this channel, did make the inside of the cell more positive and caused cell membrane changes (depolarization). Step 5: The cell membrane channels will cause the opening of the voltage gated calcium channels. Step 6: Influx of calcium will trigger the exocytosis of glucagon. Glucagon: Mechanism of Action Step 1: Glucagon will bind to liver cell GPCR cell membrane receptors. Step 2: Binding will activate the G-protein. Step 3: Adenylyl Cyclase will convert ATP into cAMP (cyclic AMP). Step 4: cAMP will activate PKA (protein kinase A). Step 5: PKA will phosphorylate multiple enzymes. Glucagon: Actions Glucagon’s effects are MAINLY within the liver and adipose tissue, with goals of enhancing glucose availability to the other organs of the body. With glucose metabolism, glucagon will: Increase glycogenolysis Increase gluconeogenesis Decrease glycolysis With lipid metabolism, glucagon will: Increase lipolysis which is the breaking down of TAG’s into FFA (free fatty acids) and glycerol. This is relevant because the FFA can go to beta oxidation reaction, and the glycerol can be used in gluconeogenesis reactions. Increase ketogenesis With protein metabolism, glucagon will: Increase ureagenesis Increase hepatic amino acid uptake Glucose Homeostasis Step 1: Carbohydrates, fats, and proteins are ingested. Step 2: If the levels of glucose are greater than 110mg/dL, the insulin is stimulated for release. Step 3: Insulin will cause carbohydrates to be the main energy source for all the cells. Anything left in excess will be stored as fat and glycogen. Step 4: Once glucose levels are below 60mg/dL, glucagon and epinephrine will be stimulated for release. Step 5: The release of glucagon and epinephrine will result in hepatic glycogenolysis for approximately 24hours. Step 6: This results in cortisol and GH release. Step 7: Gluconeogenesis of glycerol, amino acids, and lactate take place. Step 8: Once glucose intake/ingestion is reduced, the fatty acids go back to being the main source of energy for all cells, except for the brain which relies on ketones. Insulin Counterregulatory Hormones These are all hormones that counter the actions of insulin to prevent hypoglycemia. They are typically used during episodes of fasting. These hormones include: Hormones used for acute response: Glucagon Epinephrine/Norepinephrine Hormones used for chronic response: Cortisol GH (growth hormone) Insulin deficiency Lack of deficiency of insulin produces a syndrome called “diabetes mellitus” Diabetes= “siphon: to pass through” in Greek Mellitus= “sweet” in Latin Type 1 diabetes: There is absence of insulin, resulting in absolute insulin deficiency. Type 2 diabetes: There is insulin resistance, resulting in relative insulin deficiency. Beta cell dysfunction MUST be present for diabetes to develop. Healthy beta cells can adapt to obesity and insulin resistance by increasing insulin production. Diabetes mellitus: Type 1 This is characterized by permanent hypoinsulinemia, as there is absolute deficiency of insulin. There is no increase in endogenous insulin after stimulation. The patient is insulin dependent to prevent ketoacidosis, maintain glycemia, and increase chance of survival. Most common in dogs (in 95% of cases) Risk factors: auto-immune disorders, genetics, obesity, pancreatitis Lack of insulin will result in increased blood glucose levels. For insulin sensitive tissues, the GLUT-4 transporters will be compromised (won’t work as efficiently). This will lead to weight loss because glucose is not able to be transported into skeletal muscle or fat cells- however, the energy stored in there will simultaneously be getting broken down and used. Therefore, energy is being used in these locations but can’t be replenished, causing weight loss symptoms. This will also trigger polyphagia, because the body will constantly be in a state of hunger, causing the patient to eat more food. (glucose is not entering the satiety center) Hyperglycemic state: Pathway of Symptom Development Being in a hyperglycemic state will result in the “PPP” symptoms of polyurea, polydipsia, and polyphagia. Step 1: Insulin deficiency is present. Step 2: Hyperglycemia (increase in blood glucose levels) will take place due to insulin deficiency. Step 3: Due to exceeding renal tubular threshold, glycosuria will take place. This means that because the blood glucose levels are so high, the body will attempt to excrete the excess glucose via urine. Step 4: This will result in osmotic diuresis and polyurea. During this stage, the body will be excreting lots of water with the urine, causing the urine to be very dilute. Water has an osmotic relationship with glucose, so as the body attempts to excrete the excess glucose via urine, the glucose in the urine will be pulling water with it during excretion. Step 5: The body will try to be compensatory by attempting to replenish the water that is leaving the body, by increasing thirst (AKA: polydipsia)- increasing water consumption. Diabetes mellitus: Causing Weight Loss Due to the body removing the excess glucose at a rapid rate, the body is not able to use any glucose as an energy source because it is being excreted before it can be used. Because of this, there is an increase in glucagon release and the body will implement hepatic gluconeogenesis to try to get energy from other sources within the body. Therefore, weight loss happens because the body is taking energy from where it is stored, while also utilizing little to none of the glucose obtained from the diet (from carbohydrates). This will result in increased lipolysis, which can cause hyperlipidemia because lipolysis will also cause a large amount of FFA and glycerol to enter the blood stream. Because there is an increase in lipolysis, the enzyme HSL (hormone sensitive lipase) will be strongly activated. The FFA will be used as the primary energy source with the absence of glucose. Except for in the brain which relies on ketones, there will also be an increase in ketone synthesis. Increased ketone production, if in excess, will cause the ketone body to dissociate. This dissociation will cause the blood pH to lower (become more acidic). This results in an illness called “diabetes ketoacidosis”. In the liver, excess FFA will be converted into cholesterol and phospholipids. TAG will also be formed here, leading to non-alcoholic fatty liver disease within patients. The body will also increase the catabolism of proteins, despite the synthesis of proteins declining. Diabetes mellitus: Cataracts Cataracts are the most common long-term complication of this illness, specifically in dogs. Step 1: Aldose Reductase will reduce the glucose in the eye lens and will produce alcohols: sorbitol and galactitol. Step 2: Because alcohols are hydrophilic agents, they will have an osmotic relationship with water, and will pull water with it, resulting in water influx into the lens. Step 3: This will eventually result in the swelling and rupture of the eye lens, which is what causes opacity within the eye. Diabetes mellitus: Type 2 Type 2 Diabetes mellitus is characterized by the resistance to the metabolic effects of insulin. It is most common in cats (in 80% of cases) Risk factors: islet amyloidosis, obesity (metabolic syndrome)- increasing risk by 3.9 times Option 1: Obesity can lead to insulin resistance. This will cause a decline in the effects of insulin on liver, fat tissue, and muscles. Ultimately, this results in relative deficiency. Option 2: Relative deficiency and absolute deficiency can lead to beta cell failure. This will decrease insulin production and can result in glucotoxicity or amyloidosis. Glucotoxicity is the progressive impairment in insulin secretion resulting from chronic high glucose level exposure. Islets of Langerhans Amyloidosis Amylin (Islet amyloid polypeptide- AKA: IAPP) This is a polypeptide that is secreted by the beta cells with insulin secretion. So, if insulin secretion is increased, so is the secretion of amylin. Amylin works by increasing satiety (feeling of fullness after eating), reducing gastric emptying, and reducing glucagon production. As amylin aggregates, it will form amyloid. Amyloidosis is the amyloid deposition within the pancreatic islets. This deposition is toxic to beta cells and can lead to beta cell dysfunction- meaning that the beta cells can start having difficulty producing insulin and may stop production. Amyloidosis will cause irreversible damage. While, glucotoxicity will cause reversible damage, and is most commonly found in pre-diabetics. Diabetes Neuropathy This is one of the most common chronic complication, where hyperglycemia causes nerve injury in the Schwann cells and axons of myelinated fibers. It can also cause microvascular abnormalities. Pathogenicity is not well understood but this condition can happen in dogs and cats. There have been very few studies of this condition within cats. Pancreatic Somatostatin (produced by delta cells) Somatostatin will: decrease motility and secretary activity in the GI tract Inhibit secretion of all endocrine cell types in the Islets of Langerhans which affects glucagon more than insulin. Pancreatic Polypeptide (produced by F or PP cells) Secretion of pancreatic polypeptide is stimulated by vagal stimulation, protein ingestion, or GI hormones. Secretion is inhibited by somatostatins. Pancreatic polypeptides will impact the GI tract by: Decreasing gastric emptying Decreasing gut motility Inhibit gallbladder contraction Inhibit pancreatic digestive enzyme secretion