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28 Cards in this Set
- Front
- Back
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Major functions of the pancreas
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-Major digestive and endocrine functions
-Major distinction are function of pancreas exocrine function: acinar cells secrete pancreatic enzymes and sodium bicarbonate and carbonic acid and other digestive molecules into pancreatic duct v. islet of langerhan cells. Endocrine pancreas that makes up rest of the pancreas here normal individual has 500- serveral million islets of langerhan scattered throughout the pancreas. These are the endocrine cells that contain insulin and glucagon as well as other regulatory hormones important for carbohydrate homeostasis and other functions associated with digestion and metabolism |
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Islet of Langerhan cells
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Islet of Langerhan is this ball of cells that has a geometry of not only cell types but also blood flow that is integrally related to hormones and their regulation
*Note that almost all these cell types are available on SURFACE *All of the islets have roles that extend beyond simple insulin/glucagon dual relationship Alpha cells -produce glucagon and co-contain ghrelin as opposed to epsilon cells which uniquely contain ghrelin -in general on outside Beta cells -contain insulin, proinsulin, C peptide, amylin -each has role in either pathologies of pancreas and diabetes or markers of secretion or as feeding, drinking and satiety -majority of cells in islet, produce insulin and other hormones -a little different in humans v. other animal cells, but they predominantly occupy the middle of islets (in mice it’s very segregated, middle are beta and other cell types are on edges. More mixed in humans) Delta cells -somatostatin general inhibitory role peptide Epsilon cells -contain ghrelin -stomach hormone, plays big role in appetite -orexigenic hormone : stimulates appetite -don’t reality understand grehlin in pancreas since it’s usually a stomach hormone -ghrelin increases significantly after bariatric surgery, contributes to weight loss following surgery and to adapting to surgery when patients are limited as to how much they can eat -what it does in the pancreas is less clear, some evidence suggests its an inhibitory hormone in the same manner that somatostatin is. F cells /PP cells -contain pancreatic polypeptide orexigenic hormone -stimulates appetite |
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Orexigenic hormones
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stimulates appetite
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DIRECTION OF BLOOD FLOW In the islets of langerhan
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As opposed to exocrine pancreas, these are endocrine organs, part of endocrine system, hormones go into the blood and act on distal sites.
Direction of blood flow important. Flows from center of islets to the periphery. It bathes all these cells and because there is paracrine action of these different hormones the implication would be is that the direction of blood flow would be assisting paracrine actions implying for example that insulin affects on glucagon secretion or somatostatin effects on other cells would be important. Also things like glucagon has positive inhibitory effect on insulin, yet its probably not that important from a paracrine standpoint because they probably don’t see that many beta cells because the blood flow is radiating out from the middle. Also close contacts and tight junctions between these cells and these may be more important than some of the blood flow and blood flow represents more endocrine function. |
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Blood flow to and from pancreas
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Blood flow to the pancreas:
-splenic artery and superior mesenteric artery Venous flow: -hormones carried here -splenic vein, inferior mesenteric vein, superior mesenteric vein that then join with the portal vein and go directly into the liver |
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Describe how the structure of the pancreas aids in its dual functions as an exocrine and endocrine pancreas.
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Close relationship with pancreas and liver plays important role of differential uptake by liver of insulin v. c peptide
These hormones see the liver first and then the rest of the body This is in big contrast to the exocrine pancreas. In this case we have the pancreatic duct that goes right down the middle of the pancreas into which these acinar cells and other ductal cells push all their product that joins with the bile duct into the duodenum whereas the Islets of langerhan are all associated with blood flow associated with the endocrine function. They are distinct yet somehow you’ll see somewhat related when it gets to other metabolic functions and appetite. |
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Run through the brief history of insulin / diabetes discovery
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INSULIN
-b cells -if born with type 1 diabetes, children would fail to live past first few years of life, or when they developed it would not live for more than a year. Painful death. -Experiments w/ dogs, looking at pancreatectomy and similarities between these children and difficulties in trying to develop extracts of pancreas that would mimic the functions of the pancreas was difficult. -Took a while to get extracts that would successfully work to lower blood sugar in pancreatectomized dogs; later tested on a young man with diabetes -very quickly thereafter these slaughterhouses around the country were devoted to extracts of bovine and pig pancreas to treat a population of people who were otherwise doomed. |
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What is more important, the overall amount of insulin present or the ratio of insulin to glucagon and other hormones?
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-Insulin contributes to glucose homeostasis along with glucagon and several other hormones
-Secretion is intimately tied to circulating levels of glucose -Insulin secretion responds to meal, esp carb meal -Ratio of insulin to glucagon goes up significantly with this meal -Notice that glucagon goes up also, but RATIO goes up 8 fold for mixed meal or much more for a carb meal -It is the RATIO that is important!!! Ratios important in biochemistry and endocrinology because it’s a way of exaggerating a physiological effect w/o having to increase secretion by tremendous amounts and that by subtle changes in ratio you can get big effects, similar to what we see with metabolic cycling in metabolism. This is also the reason why in the absence of insulin effects of glucagon become so dominant. These ratios become infintely large or small depending on what’s in the numerator in the absence of insulin. Even modest amounts of glucagon become very dominant. |
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Proinsulin – when is it secreted? What is its function? Where is it secreted from?
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-B cell function really important in regulating secretion of these hormones
-processing of insulin into biologically active insulin is part of this -Role of proinuslin interesting, probably is symptomatic or part of b-cell failure that occurs during diabetes. -Under normal circumstances list pro-insulin as one of the secreted products of the b-cell and it’s a minor product but a real product. It has modest effects on the insulin receptor it’s clearly secreted. Why it’s secreted isnt completely clear but probably has to do something with the fact that it’s processed in granules and secretory cells of beta cell and that processing is incomplete -Secretion of pro-insulin goes up a lot in type II diabetes, goes up significantly in progression to diabetes, may be diagnostic of stages towards diabetes -as you increase the rate of insulin secretion which is what happens as you go into type ii diabetes, the ability of the processing to keep up with secretion is not as successful, (easiest way of explaining why proinsulin secretion goes up) |
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C peptide
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-C peptide has similar role but not same functional role as proinsulin has right now.
-C peptide has no established biological function right now but it’s always been a useful marker for insulin secretion. -Useful marker because it’s largely untouched by same factors and organs that are significantly involved in insulin turnover and uptake 60% of insulin removed in portal blood as it passes through liver, but NONE of the c peptide is. -Levels of C peptide useful marker for total insulin secreted or in the face of injected insulin how much endogenous insulin is being secreted It can be easily measured in urine. This is the way it’s secreted. -This gives you an accurate molar estimate of how much insulin has been secreted over a period of time - Trying to identify enzymes involved in processing v. lysosomal degradation difficult, pose same difficulties now in trying to elucidate the functions of these hormones. |
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Glycemic index
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-Glycemic index, things that modulate rate at which glucose is taken up.
-Glycemic index is not a perfect index for several reasons. -Requires another level of analysis, like keeping track of calories, keeping track of GI, keeping track of what it contains, but also it isn’t particularly accurate because WE DON’T EAT SINGLE FOODS. -Therefore its hard to come up with an accurate estimate of all these things. Governed by how much food is cooked, how much oil is in food, -Hydrated starch easily digested – making pasta al dente, mixing it with cheese and mixing it with oil lowers that, decreases uptake |
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What is a very sensitive way of coordinating this without having to worry about neuronal or other inputs governing it
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-Have to regulate secretion of insulin and its relationship to ATP expression in B cells
- When you correlate levels of insulin secretion to amount of energy that cell is producing as a function of how much glucose is being taken up, this is a very sensitive way of coordinating this without having to worry about neuronal or other inputs governing it. -It is responding to actual blood levels. NOTE: 1. USES GLUT 2 -glut 2 is famous for having HIGH Km: therefore at levels of glucose significantly less than Km the transport of glucose through this carrier is linear: therefore, intracellular levels of glucose and rate through transporter is indicative of circulating plasma levels. 2. As we make ATP, close K channels, depolarization, calcium influx, insulin release *ATP levels become important, things that influence ATP levels are similarly important. -one thing that regulates ATP levels in many cells, including beta cells, are the uncoupling proteins: -B cells express lots of uncoupling protein 2 (UCP2) -not completely clear why -Hypothesis: 1. By uncoupling ETC with ATP expression that you might be modulating/moderating reactive oxygen species -brain, expresses a lot of UCP2 2. Observation that UCP2 levels go up during diabetes is part of overall question in its possible role either in response to or contributing to b-cell failure that occurs in diabetes. As UCP2 levels go up, ability to secrete insulin goes DOWN because you’re decreasing ATP levels and generating more heat. Difficult to dissociate between cause and response. uncoupling proteins -brown fat -uncouple electron transport from oxidative phosphorylation and release free energy in form of heat and protect many of our organs, especially after birth. also brown fat in adults |
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Genipin
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-compound isolated from gardenia fruit
-contains a compound that inhibits UCP2 -effective at augmenting insulin secretion from cells by inhibiting UCP2 function |
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in addition to ATP dependent insulin secretion, are there other things that modulate insulin secretion?
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-B-cells more complicated than that:
-->in addition to ATP dependent insulin secretion, there are other things that modulate insulin secretion which are important -complicated role of insulin during exercise and glucose homeostasis during exercise and trying to explain what is happening, and recommendations for diabetics -starts w fact that muscle cells are able to take up glucose in insulin dependent manner, this would be expected to lower blood glucose levels, increase glucagon levels, and stimulate glucose levels but insulin levels never really get that high during exercise. This is GOOD because you don’t want hypoglycemia in exercise. Part of that reason is because of these humoral and neural factors that are also important in regulating b cell function. cAMP and ultimately PKA levels are important in regulating insulin secretion. These levels are governed in part by input by inhibitory inputs by somatostatin, or by a-adrenergic agonists (norepinephrine, epinephrine). These stimulation INHIBIT insulin secretion whereas b-adrenergic stimulation will stimulate it. The a-adrenergic stiumlation goes up in exercise. |
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β-adrenergic stimulation augments _______.
α-adrenergic stimulation _____. |
β-adrenergic stimulation augments insulin secretion.
α-adrenergic (norepinephrine) stimulation inhibits it. |
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Islets richly innervated by sympathetic (_____) and parasympathic (_____) ANS.
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Islets are richly innervated by sympathetic (epinephrine) and parasympathic (acetylcholine) ANS.
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Amino acids, especially ____, and ___ weakly stimulate insulin.
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Amino acids, especially Arg and Leu, and ketohexoses (fructose) weakly stimulate insulin.
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Part of reason why insulin levels never really go up in exercise is in part because of:
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Part of reason why insulin levels never really go up in exercise is in part because of:
-a-adrenergic inhibition of cAMP levels and PKA. -This is a defense against hypoglycemia. *DON’T want insulin levels to go up and induce hypoglycemia.* -Muscles gonna be fine, don’t need inuslin to take up glucose. -Supplemental glucose during exercise is very EFFECTIVE because of this, save glycogen for end of race/run. -Also don’t want to induce insulin during exercise because you don’t want to inhibit flow of lipids and fats. |
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exercise-induced insulin would:
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1. increase muscle uptake of glucose;
2. inhibit lipolysis and FA release; 3. inhibit gluconeogenesis If you were to increase insulin in response to glucagon stimulated insulin release you would inhibit lipolysis and the amount of fat that you could burn during exercise. Would also inhibit gluconeogenesis. Never used to think of it as going up during exercise, but it does, moreso for endurance trained atheletes. |
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Why do you have a greater insulin response to oral glucose than intravenous glucose?
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INCRETINS
-name derived from fact that it increases the secretion of insulin under certain circumstances, such as oral glucose administration -insulin response to oral glucose is different/bigger than intravenous glucose dose -a lot of factors play into this, but the biggest factor is that gut hormones, like cholecystokinin, gastric inhibitory polypeptide (GIP), glucagon-like peptide 1 (GLP-1), that stimulate insulin secretion in response to a PERCEIVED intake of carbohydrate and that looking at good food or chewing food w/o swallowing it will increase insulin secretion in preparation for receiving those calories so that you can start handling those glucose or carbohydrate load immediately. -Important aspect of insulin homeostasis and carbohydrate homeostasis that can be difficult to mimic with just insulin administration -Also has interesting side effects – develops an appetite -->When you eat high glycemic index foods get big increase in glucose with a correspondingly fast response with insulin. That insulin drives very effective uptake of glucose. Not only do you drive level of glucose down but you get this undershoot where you become transiently hypoglycemic and you become hungry. -->When you eat toast and jelly for breakfast or doughnuts, you’re dying by 9:30-10 .. In part it drives appetite |
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What happens when you drink diet coke without eating anything?
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-->If body is expecting calories and you don’t get calories you get an insulin response that doesn’t have anything to do you so you become transiently hypoglycemic
**happens when you drink diet coke w/o eating anything!! Perception by body is that you’re eating something sweet, but there are no calories associated with it, so you develop appetite for sweets. People who drink diet coke alone tend to snack more than people who don’t because you’re seeking something to satisfy this craving that you’ve developed. Part of it is psychological – pavlovian. Part of it is behavior and learned response, also body responding to transient (mild hypoglycemic) and learned response to expecting something sweet. |
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What are the names of the gut hormones that stimulate insulin secretion in response to a perceived intake of carbohydrate?
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-the biggest factor is that gut hormones, like cholecystokinin, gastric inhibitory polypeptide (GIP), glucagon-like peptide 1 (GLP-1), that stimulate insulin secretion in response to a PERCEIVED intake of carbohydrate and that looking at good food or chewing food w/o swallowing it will increase insulin secretion in preparation for receiving those calories so that you can start handling those glucose or carbohydrate load immediately.
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Amylin
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Other part of b-cells is AMYLIN
-peptide: 37 aa derived from 67 aa precursor -Co-secreted with insulin with a ratio of 100 parts insulin : 1 part amylin -Has a role in glycemic regulation: 1. Slows gastric emptying 2. By slowing gastric emptying, you slow the absorption of glucose, don’t get as big a rise of glucose, thereby supporting satiety and preventing big spikes in blood glucose **Amylin secretion goes up during diabetes As insulin secretion goes up as you move towards diabetes, you increase the likelihood that this amylin is going to be improperly processed. |
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People who drink a lot of coffee are at significantly decreased risk of developing type II diabetes. WHY?
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Over-secretion of insulin & amylin with Type 2 diabetes can lean to inappropriate processing of amylin, leading to formation of amyloid deposits
__ Study: -caffeine intake and risk of diabetes -People who drink a lot of coffee are at significantly decreased risk of developing type II diabetes - >400 mg coffee per day (5-6 cups) have 17 – 30% decrease in risk of developing type II diabetes -coffee seems to help in so many regards: a. thermogenic b. performance enhancing c. decreases risk of type II diabetes d. cirrhosis e. liver cancers Coffee: -one of the causitive/contributing factors to b-cell failure is decreased secretion of amylin and that incorrect processing of amylin gives you these fibrils that lead to deposition of amyloid, the majority of which is b-cell amylin that then leads to b-cell apoptosis and death - this is reminiscent of degenerative diseases of central nervous system but now occurring in the PANCREAS. When it was discovered that components of coffee like caffeine, caffeic acid, and chlorogenic acid which are metabolic products of caffeine can block the formation of this amyloid and prevent plaques or deposits from forming in b-cells. Hypothesis: perhaps this is why heavy coffee drinkers decrease risk of type II diabetes. **have coffee that decreases risk of diabetes, contains polyphenols and caffeine metabolic products that down-regulate amyloid expression and prevent amyloid deposition in islets that then lower the risk of diabetes. ** |
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What components of coffee block the formation of amyloid and prevent plaques or deposits from forming in b-cells?
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Components of coffee like caffeine, caffeic acid, and chlorogenic acid are metabolic products of caffeine can block the formation of this amyloid and prevent plaques or deposits from forming in b-cells.
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Glucagon
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-B cells have a lot of functions to them that are very complicated and subtle
-Mix between appetite and gastric emptying and glycemic index and insulin response and apoptosis and all these sorts of things are interesting factors - Glucagon shares many of these complicating factors with a couple of really interesting twists. -This is the counter-regulatory hormone, the hormone that is involved in mobilizing rather than storing fuels and making fuels available to the body and breaking down glycogen and increasing gluconeogenesis. -And so, pancreatic cells respond to glucose levels as well, respond to protein levels as well. -Also contain incretin effects. Now incretin effects are opposite! Glucagon like peptide and pancreatic polypeptides will decrease glucagon expression in response to oral glucose as compared to IV glucose. Incretin effect is opposite and interesting. ___ Pancreatic α cells secrete glucagon in response to ingested protein Evidence for incretin effects for glucagon also Glucagon is a powerful insulin secretagogue; however, islet anatomy renders this less important |
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Summarize the paracrine effects between all the pacreatic hormones
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Summarizing paracrine effects
-difficult to know how important paracrine effects are - many studies done in vitro trying to mimic .. -Grehlin is inhibitory in the same way and in parallel with somatosatin -Insulin inhibits glucagon, glucagon activates insulin, glucagon activates somatostatin as a probable feedback regulator - Interesting, probably important, but hard to know where it fits in overall carbohydrate metabolism. |
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Future treatment for type 1 diabetes?
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-Working towards replacement for pancreatic transplants -Pancreatic transplants have become more successful 1 year post transplant 90% of patients are still alive and 80-90-95% of pancreas still functioning. - Difficult transplant, typically done in conjunction w/ kidneys -Hard to come up with good donors, so dealing w b cell transplantations or growing b-cells as a replacement for pancreatic transplants -Most calculation w/ b-cell transplants are 1 million to 2 million cells / kg bodyweight .. Tremendous number of cells hard to isolate from cadavers and if they could do it in cell culture and come up with viable explants or liver cohosting type relationships it would be a big advantage (functioning b-cell population living in liver would be great -Typically these transplants are done by keeping old pancreas in there, then if new transplant fails you aren’t left in a critical state -Currently identidying pathway for stem cells to make all the different types of cells.
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