Pancreas 1.docx

Pancreas: General Info The pancreas is glandular organ located in the abdominal cavity. It has 2 lobes. 1 lobe is behind the stomach and the other is apposition to the proximal duodenum. Exocrine Pancreas Contain acinar cells (produce digestive enzymes) and duct cells Digestive enzymes are secreted...

Pancreas: General Info The pancreas is glandular organ located in the abdominal cavity. It has 2 lobes. 1 lobe is behind the stomach and the other is apposition to the proximal duodenum. Exocrine Pancreas Contain acinar cells (produce digestive enzymes) and duct cells Digestive enzymes are secreted here into the lumen of the duodenum Endocrine Pancreas Has 4 types of cells (that are all polypeptides) organized into islets (AKA: Islets of Langerhans) 4 cells: alpha (20%), beta (70%), delta (5%), f-cells (<5%) All 4 of the above cells are involved in glucose metabolism and regulation of blood glucose levels Secretes hormones into the blood Involved in endocrine function (such as glucose metabolism) Makes up 2-3% of the pancreas Islets of Langerhans is made up of: Acini: exocrine function (acini surrounds the external part of the Islets of Langerhans) Alpha cells: secrete glucagon Beta cells: secrete insulin in response to hyperglycemia Delta cells: secrete somatostatin F-cells: secrete pancreatic peptide Peptide Hormones All pancreatic hormones are polypeptides Hormone examples: somatostatin, pancreatic peptides, glucagon, insulin Pancreatic hormones circulate unbound in blood because they are hydrophilic. They have a short half-life of less than or equal to 30 minutes. They will also bind to cell surface receptors. Insulin Synthesis Active insulin is made of 2 peptide chains, alpha and beta, which are held together via disulfide bridges Step 1: In the rER, (rough endoplasmic reticulum) pre-proinsulin is synthesized Step 2: In the ER, the “signal” sequence is removed to form proinsulin Step 3: Proinsulin goes to the golgi apparatus and is packaged into vesicles Step 4: The C-peptide (AKA: mature vesicle) is cleaved C-peptide Test This test measures the amount of C-peptide within the blood or urine, thus determining whether or not the pancreas is synthesizing insulin. This test is used to differentiate between type 1 and type 2 diabetes. It also helps evaluate the efficiency of treatment. Insulin: General Info Each species has a slightly different amino acid sequence for insulin. However, canines and porcine have the exact same type of insulin. Insulin release is dependent on nutritional, endocrine, exocrine, and neural variables. Secretagogue is a substance that stimulates the secretion of another substance. Secretagogue importance is based on nutritional status and natural diet of the species. Examples include: Glucose being important for omnivores Amino acids and fatty acids being important to carnivores Fatty acids being important for the stimulation of insulin release in humans Sulfonylureas (AKA: glipizide) is a hypoglycemic treatment. It specifically works by closing the potassium channels of the pancreatic beta cell to trigger insulin production, and therefor decrease glucose levels. Insulin Secretion from beta cells Beta cells use GLUT-2 insulin dependent (glucose) transporters at the cell surface. This allows for glucose to diffuse towards the concentration gradient within the cell. Extracellular fluid glucose directly impacts intracellular glucose levels within beta cells. Step 1: Glucose enters the pancreatic beta cell using the GLUT-2 transporter. Step 2: Glucose is used to create ATP. Step 3: High ATP concentration triggers the closure of potassium channels to close. Step 4: Due to high levels of potassium in the cell, the inside of the cell has an increased positive charge, triggering depolarization to occur. Step 5: Depolarization triggers the opening of voltage gated calcium channels. Step 6: The calcium entering from these channels triggers cellular response. This cellular response is the activation of insulin gene expression via CREB (calcium responsive element binding protein) which will increase insulin production. Step 7: After secretion, insulin binds to RTK (receptor tyrosine kinase). Insulin Releasing Pattern Insulin secretion follows biphasic kinetics: Acute phase: pre-synthesized insulin is secreted. Resulting in quick spike of insulin release (shown on a graph). In this phase, insulin is used from stored vesicles= quick response to glucose stimulation. The acute phase is typically triggered by hypoglycemia. Chronic phase: Requires the synthesis and secretion of insulin. Therefore, because insulin has to be made, this is a delayed response time to glucose stimulation. However, there would be a longer, prolonged spike of insulin release (shown on a graph). The chronic phase is typically triggered by diet. Insulin Sensitive Tissues Insulin will facilitate glucose entry into the cells by increasing the amount of specific glucose transporters (GLUT-4) in the cell membrane. GLUT-4 is the only GLUT transporter that is sensitive to insulin. Muscle and adipose tissue REQUIRE insulin to take glucose inside of their cells. Resistance exercise (used to build muscle), can stimulate translocation of GLUT-4 transporters to muscle membrane, increasing glucose uptake within the cell. Insulin: Net Effect Net effect is to: decrease blood concentration of glucose, fatty acids, and amino acids. By facilitating glucose entry into cells, insulin helps promote intracellular conversion of these compounds to their storage forms. This means that insulin has a catabolic effect. Examples include: Glucose converted into glycogen (stored in liver and skeletal muscle) Amino acid converted into protein Fatty acid converted to triglycerides (TAGs- stored in adipose tissue) Insulin: Action on Muscles (smooth, cardiac, striated) Insulin will stimulate glycogen synthesis enzymes. Insulin will stimulate glucose conversion to glycogen for storage. AKA: promote glycogenesis. Insulin will promote using glucose as an energy source. This is implemented by insulin reducing fatty acid oxidation. In the absence of insulin, muscles will use fatty acids as their energy source. Insulin will promote amino acid usage (not storage) to promote muscle growth. Insulin: Action on Adipose Tissue Insulin will increase glucose uptake in the adipocytes by: Stimulating the DHAP (Dihydroxyacetone phosphate) pathway, which will synthesize glycerol. Stimulating glycolysis which will increase pyruvate formation. Then, more acetyl-CoA is formed which can be used for fatty acid synthesis. Those fatty acids are combined with glycerol to form TAGs (triacylglycerol). The TAG’s are stored in adipocytes, which increases lipogenesis. Insulin will inhibit lipolysis, which is the process of breaking down TAG’s into fatty acid and glycerol. Insulin: Action on the Liver Glucose will only enter the liver using a GLUT-2 transporter and does not require insulin for the uptake of glucose. However, the liver does require the actions of insulin. Insulin will promote fatty acid synthesis within the hepatocytes. This stimulates the fatty acids and TAG’s into lipoprotein-bound vesicles (like VLDL), so that they can be transported into adipocytes. Insulin will stimulate glycogenosis (to make more glycogen), and glycolysis (to make more ATP). Because insulin wants to decrease glucose levels, it will also decrease gluconeogenesis, ketone body synthesis, and glycogenolysis. Gluconeogenesis is the creation of glucose from non carbohydrate sources. Glycogenolysis is the break down of glycogen into glucose. Insulin: Metabolism Insulin is mainly metabolized in the liver but is excreted via the kidneys. In the liver, specific enzymes will decrease the disulfide bonds, causing the alpha and beta chains to inactivate. Because active insulin is made of alpha and beta chains, this inactivates the insulin. These chains are further subjected to protease activity which will break them apart further (or reduce them) into amino acids and peptides. Protease is an enzyme that breaks apart proteins. Insulin clearance half life is 10 minutes.