Insulin, Receptor Tyrosine Kinases Flashcards
What are the four different types of cells found in the pancreas?
- Alpha cells: secrete glucagon
- Beta cells: secrete insulin.
- Delta cells: secrete somatostatin
- PP cells: secrete pancreatic polypeptide.
Pancreas
Pancreas, together with the gallbladder and the liver, are involved in processing of nutrients. Pancreas is both
an exocrine gland and an endocrine gland, which is unusual. Acinar cells of the pancreas are exocrine and are involved in the secretion of digestive enzyme things like chymotrypsin, amylase, and lipase are secreted by the acinar cells. Embedded in the acinar cell regions are islets which contain the endocrine tissue whichs excrete and synthesis peptide hormones insulin and glucagon. Some also secrete somatostatin and pancreatic polypeptide.
What are the 3 major energy sources of the body?
Glycogen, triglycerides, protein.
Glycogen
Polymer of glucose that has alpha 1,4 and alpha 1,6 linkages. Storage supply of carbohydrates (glucose) that can easily be broken down to obtain glucose.
Triglycerides
Energy storage molecule composed of glycerol head and 3 fatty acid tails.
What is the relative distribution of glycogen in the body. Does the muscle share glycogen? Why?
about 80% of the glycogen is in the muscle. Muscle wont share its glycogen with anyone else. So glycogen broken down in the muscle
is only used for the muscle and no one else. This is because the glycogen is not broken down in a way that could cross the plasma membrane.
Glycogen is broken down by phosphorylase into glucose-1-phosphate and further enzymatically changed to glucose-6-phosphate. In other cells, such as the liver cells, it can be changed to glucose. Once its in the form of just glucose it can be transported across the plasma membrane.
Where does blood glucose come from?
The muscle has most of the glycogen but can’t share it. The rest of the glycogen has to come from the liver where it can be broken down into glucose and transported to the rest of the body. Glycogen in the liver can be broken down very fast during exercise.
During fasting the glycogen is broken down slower and able to be
replenished by liver glucose.
What is gluconeogenesis?
The process of making glucose from non-carb sources such as fat and protein.
What do acinar cells do?
Secrete digestive enzymes.
What do alpha cells do?
Secrete glucagon in response to low blood glucose (hypoglycemia). Glucagon stimulates glycogenolysis. Also stimulates gluconeogenesis. Net result is an increase in blood glucose. Alpha cells mainly stimulate catabolic reactions by secreting glucagon. Starving state stimulates glucagon release.
What do beta cells secrete?
Insulin in response to elevated blood glucose (hyperglycemia). Insulin inhibits glycogenolysis and gluconeogenesis. This leads to decreased blood glucose levels. Fed state stimulates insulin release.
Outline the process of hormone release and effects after a carb rich meal.
In response to increased blood glucose levels, insulin is secreted so it can start metabolizing blood glucose and making glycogen, fats, and proteins. After insulin secretion, blood glucose levels start to fall. Glucagon levels go down after being fed to prevent the degradation of fats and proteins. Happens over a couple of hours.
Outline the process of hormone release and effects during fasting.
In response to fall of blood glucose, alpha cells secrete glucagon and insulin secretion by beta cells falls. This stabilizes the fall of blood glucose. Glucogenolysis increases to raise blood glucose levels. Happens over a period of days.
What do insulin and glucagon work towards?
The rise and fall of both hormones serves to stabilize the levels of glucose to normal levels.
What happens to glucose in the blood that is taken up into the liver after a meal.
Glucose is converted to glucose-6-phosphate which can be used as fuel or stored as glycogen as well as used in the synthesis of fatty acids which can then be moved to adipose tissue.
What happens in the liver when glucagon is released?
Glycogen is broken down to glucose-6-phosphate which is converted to glucose and sent into the blood. Fatty acids from adipose tissue are brought to the liver and used as fuel. So glucagon stimulates catabolic reactions, stimulating the breakdown of glycogen, protein, and triglycerides for the production of glucose. Epinephrine and norepinephrine also stimulate these effects.
Even though there isn’t much therapeutic use for glucagon, what is one thing it can be used for?
There’s not much therapeutic use of glucagon, but it is used in some cases of hypoglycemia
due to too much insulin. So for instance if a diabetic individual takes too much insulin
glucagon can help to correct. Glucagon works through the Gs pathway and protein
kinase A. PKA can then phosphorylate 2 important substrates: 1. Phosphorylase kinase,
which is involved in breaking down glycogen.So phosphorylation increases its activity. Phosphorylase is then going to breakdown glycogen to glucose-1-phosphate. 2. Phosphorylation
of glycogen synthase, which is going to inhibit its activity and so glycogen synthesis is inhibited. Basically the same pathway that epinephrine and norepinephrine use to raise blood
glucose levels.
Describe the structure of insulin and the conversion to insulin from the preproinsulin form.
Insulin is a small protein. MW is 6 kDa. Has two separate chains on it: A chain and B chain. The chains are connected by disulfide groups. There is a signal sequence on the N-terminus that gets cleaved off in the pre stage. The C chain gets cleaved off in the pro stage,so there’s 2 cleavages that take place. Insulin is stored in vessicles inside cells and is often complexed with zinc to yield multimers of insulin which makes it more stable. Many of the therapeutically prepared solutions of insulin are also complexed with zinc to make it longer lasting and more stable. Insulin is released from the cells by calcium mediated vessicle secretion just like neurotransmiter release. But the cells that they are secreted from are not neurons.
Is insulin stored for a long time? Is it free in the plasma?
About 20% of insulin is secreted daily, so it had to be resynthesized and is not stored for a long time. It’s a protein, so it doesn’t require a binding protein and is free in the plasma when traveling through the blood. Only circulates for about 10 min.
How is insulin released from the beta cells?
Pancreatic beta cells are electrically excitable cells (like neurons, muscle). 1. Blood glucose rises. 2. Glucose is taken up by cell via a GLUT2 glucose transporter. 3. Intracellular ATP/ADP ratio increases as ATP increases and ADP decreases. 4. ATP dependent potassium channels close. 5. Membrane depolarizes, giving increased action potentials. 6. Voltage gated calcium channels open. 7. Calcium causes insulin secretion. 8. Insulin lowers blood glucose.
Why does closing the ATP-dependent potassium channels lead to depolarization?
The channels are inhibited by high levels of ATP or low levels of ADP. The channel would normally hold te membrane potential stable and negative by allowing potassium ions to flow out of the cell. So by inhibiting the stabilization of the membrane potential, it depolarizes the membrane and action potentials can fire. This activates calcium voltage gated channels letting calcium come in. Calcium is involved in vesicle secretion and allows for insulin to be secreted.
What is different about the insulin receptor compared to other receptor tyrosine kinases?
Insulin receptor looks different than the
other receptors. The other receptors are single pass transmembrane
proteins with an extracellular domain
that binds the ligand and an intracellular catalytic domain that has
tyrosine kinase activity. Insulin looks
like its already been dimerized (the other receptors work through dimerization as well but start out as monomers until they bind ligand). Since its pre-dimerized, it doesnt require dimerization after ligand
binding. Insulin receptor has a couple of different subunits in it while the other receptors are singly polypeptide chains. When the insulin receptor is made in cells, it starts off as one
long polypeptide and is proteolytically cleaved so that theres the extracellualr subunit and the intracellular subunit. So developmentally, the receptor starts out as a single pass TM protein
and is then cleaved into two parts followed by dimerization by disulfide bridges. It’s an alpha2beta2 heterodimer.
What are receptor tyrosine kinases involved in?
Cell proliferation, growth, differentiation or migration. They work by dimerization and then cross-auto phosphorylation of the catalytic domains which phosphorylate tyrosine residues on the cytoplasmic region.
How are typical RTKs activated?
Signal molecule binds to undimerized receptor. Dimerization occurs, transautophosphorylation (cross-phosphorylation) of receptor occurs on tyrosine residues on the cytoplasmic C terminus. Phosphorylated tyrosines serve as docking sites to activate other proteins.
