Insulin Regulation of Blood Sugar and Diabetes - The Important Roles of Insulin and Glucagon: Diabetes and Hypoglycemia Normal Regulation of Blood Glucose The Important Roles of Insulin and Glucagon: Diabetes and Hypoglycemia Written by James Norman MD, FACS, FACE The human body wants blood glucose (blood sugar) maintained in a very narrow range. Insulin and glucagon are the hormones which make this happen. Both insulin and glucagon are secreted from the pancreas, and thus are referred to as pancreatic endocrine hormones. The picture on the left shows the intimate relationship both insulin and glucagon have to each other. Note that the pancreas serves as the central player in this scheme. It is the production of insulin and glucagon by the pancreas which ultimately determines if a patient has diabetes, hypoglycemia, or some other sugar problem. In this Article Insulin's Role in Blood Glucose Control Insulin Basics: How Insulin Helps Control Blood Glucose Levels Insulin and glucagon are hormones secreted by islet cells within the pancreas. They are both secreted in response to blood sugar levels, but in opposite fashion!

Insulin is normally secreted by the beta cells (a type of islet cell) of the pancreas. The stimulus for insulin secretion is a HIGH blood glucose...it's as simple as that! Although there is always a low level of insulin secreted by the pancreas, the amount secreted into the blood increases as the blood glucose rises. Similarly, as blood glucose falls, the amount of insulin secreted by the pancreatic islets goes down. As can be seen in the picture, insulin has an effect on a number of cells, including muscle, red blood cells, and fat cells. In response to insulin, these cells absorb glucose out of the blood, having the net effect of lowering the high blood glucose levels into the normal range. Glucagon is secreted by the alpha cells of the pancreatic islets in much the same manner as insulin...except in the opposite direction. If blood glucose is high, then no glucagon is secreted. When blood glucose goes LOW, however, (such as between meals, and during exercise) more and more glucagon is secreted. Like insulin, glucagon has an effect on many cells of the body, but most notably the liver.

The Role of Glucagon in Blood Glucose Control The effect of glucagon is to make the liver release the glucose it has stored in its cells into the bloodstream, with the net effect of increasing blood glucose. Glucagon also induces the liver (and some other cells such as muscle) to make glucose out of building blocks obtained from other nutrients found in the body (eg, protein). Our bodies desire blood glucose to be maintained between 70 mg/dl and 110 mg/dl (mg/dl means milligrams of glucose in 100 milliliters of blood). Below 70 is termed "hypoglycemia." Above 110 can be normal if you have eaten within 2 to 3 hours. That is why your doctor wants to measure your blood glucose while you are fasting...it should be between 70 and 110. Even after you have eaten, however, your glucose should be below 180. Above 180 is termed "hyperglycemia" (which translates to mean "too much glucose in the blood").

If your 2 two blood sugar measurements above 200 after drinking a sugar-water drink (glucose tolerance test), then you are diagnosed with diabetes. Updated on: 03/02/16 Blood Glucose and Insulin - How Diabetes Works | HowStuffWorks Blood Glucose and Insulin Prev Next The pancreas has many islets that contain insulin-producing beta cells and glucagon-producing alpha cells. Since diabetes is a disease that affects your body's ability to use glucose, let's start by looking at what glucose is and how your body controls it. Glucose is a simple sugar that provides energy to all of the cells in your body. The cells take in glucose from the blood and break it down for energy (some cells, like brain cells and red blood cells, rely solely on glucose for fuel). The glucose in the blood comes from the food that you eat. When you eat food, glucose gets absorbed from your intestines and distributed by the bloodstream to all of the cells in your body. Your body tries to keep a constant supply of glucose for your cells by maintaining a constant glucose concentration in your blood -- otherwise, your cells would have more than enough glucose right after a meal and starve in between meals and overnight.

So, when you have an oversupply of glucose, your body stores the excess in the liver and muscles by making glycogen, long chains of glucose. When glucose is in short supply, your body mobilizes glucose from stored glycogen and/or stimulates you to eat food. The key is to maintain a constant blood-glucose level. Up Next To maintain a constant blood-glucose level, your body relies on two hormones produced in the pancreas that have opposite actions: insulin and glucagon. Insulin and glucagon have opposite effects on liver and other tissues for controlling blood-glucose level Insulin is made and secreted by the beta cells of the pancreatic islets, small islands of endocrine cells in the pancreas. Insulin is a protein hormone that contains 51 amino acids . Insulin is required by almost all of the body's cells , but its major targets are liver cells, fat cells and muscle cells .

For these cells, insulin does the following: Stimulates liver and muscle cells to store glucose in glycogen Stimulates fat cells to form fats from fatty acids and glycerol Stimulates liver and muscle cells to make proteins from amino acids Inhibits the liver and kidney cells from making glucose from intermediate compounds of metabolic pathways (gluconeogenesis) As such, insulin stores nutrients right after a meal by reducing the concentrations of glucose, fatty acids and amino acids in the bloodstream. See the next page to learn about glucagon. You & Your Hormones | Hormones | Insulin You & Your Hormones Email article to a friend | Last updated: February 19, 2015 Insulin is an essential hormone produced by the pancreas. Its main role is to control glucose levels in our bodies. Diabetic person being injected with insulin to regulate their blood sugar levels. What is insulin? Insulin is a hormone made by an organ located behind the stomach called the pancreas . Here, insulin is released into the bloodstream by specialised cells called beta-cells found in areas of the pancreas called islets of Langerhans (the term insulin comes from the Latin insula meaning island).

Insulin can also be given as a medicine for patients with diabetes because they do not make enough of their own. It is usually given in the form of an injection. Insulin is released from the pancreas into the bloodstream. It is a hormone essential for us to live and has many effects on the whole body, mainly in controlling how the body uses carbohydrate and fat found in food. Insulin allows cells in the muscles, liver and fat ( adipose tissue ) to take up sugar (glucose) that has been absorbed into the bloodstream from food. This provides energy to the cells. This glucose can also be converted into fat to provide energy when glucose levels are too low. In addition, insulin has several other metabolic effects (such as stopping the breakdown of protein and fat). How is insulin controlled? When we eat food, glucose is absorbed from our gut into the bloodstream. This rise in blood glucose causes insulin to be released from the pancreas. Proteins in food and other hormones produced by the gut in response to food also stimulate insulin release. However, once the blood glucose levels return to normal, insulin release slows down. In addition, hormones released in times of acute stress, such as adrenaline , stop the release of insulin leading to higher blood glucose levels.

The release of insulin is tightly regulated in healthy people in order to balance food intake and the metabolic needs of the body. Insulin works in tandem with glucagon , another hormone produced by the pancreas. While insulin’s role is to lower blood sugar levels if needed, glucagon’s role is to raise blood sugar levels if they fall too low. Using this system, the body ensures that the blood glucose levels remain within set limits, which allows the body to function properly. What happens if I have too much insulin? Diabetic patients are given drugs including insulin treatment to lower their high glucose levels. However, if a person accidentally injects too much insulin, cells will take in too much glucose from the blood. This leads to abnormally low blood glucose levels (hypoglycaemia). The body reacts to hypoglycaemia by releasing stored glucose from the liver in an attempt to bring the levels back to normal. However, persistently low glucose levels in the blood can make a person feel ill. Unlike other cells in the body, nerve cells depend almost entirely on glucose as a source of energy. When the glucose level is too low, the majority of the symptoms result from these nerves not functioning properly. The brain is particularly affected by low glucose levels.

Symptoms include dizziness, confusion and even coma in severe cases. In addition, the body mounts a 'fight-back' response through a specialised set of nerves called the sympathetic nervous system. This causes palpitations, sweating, hunger, anxiety, tremor and a pale complexion. What happens if I have too little insulin? This is commonly seen in people with diabetes and is caused by different pathways in type 1 diabetics compared with type 2 diabetics. In some people, the pancreas is unable to make enough insulin, for example, in a condition called type 1 diabetes . This condition is caused when the beta cells that produce insulin have been destroyed. With too little insulin, the body can no longer move glucose from the blood into the cells, causing high blood glucose levels. If the glucose level is high enough, excess glucose spills into the urine. This drags extra water into the urine causing more frequent urination and thirst. This leads to dehydration which can cause confusion. In addition, with too little insulin, the cells cannot take in glucose for energy. Other sources of energy (such as fat and muscle) are needed to provide this energy. This makes the body tired and can cause weight loss.

If this continues, patients can become very ill. This is because the body attempts to make new energy from fat and causes acids to be produced as waste products. Ultimately, this can lead to coma and death if medical attention is not sought. Type 2 diabetes can be caused by two factors. Firstly, the patient’s beta cells may have an impaired ability to manufacture insulin. This means that while some insulin is produced, it is not enough for the body’s needs. Secondly, the insulin receptors, which allow insulin to exert its effects on individual cells, become insensitive and stop responding to the insulin in the bloodstream. A combination of these factors leads to similar symptoms as seen in type 1 diabetes. What is Insulin? What is Insulin? By Dr Ananya Mandal, MD Insulin is a hormone that is important for metabolism and utilization of energy from the ingested nutrients - especially glucose. Insulin chemistry and etymology Insulin is a protein chain or peptide hormone. There are 51 amino acids in an insulin molecule. It has a molecular weight of 5808 Da. Insulin is produced in the islets of Langerhans in the pancreas.

The name insulin comes from the Latin ''insula'' for "island" from the cells that produce the hormone in the pancreas. Insulin's structure varies slightly between species of animal. Both porcine (from pigs) and bovine (from cows) insulin are similar to human insulin but porcine insulin resembles human insulin more closely. What does insulin do? Insulin has several broad actions including: It causes the cells in the liver, muscle, and fat tissue to take up glucose from blood and convert it to glycogen that can be stored in the liver and muscles Insulin also prevents the utilization of fat as an energy source.

In absence of insulin or in conditions where insulin is low glucose is not taken up by body cells, and the body begins to use fat as an energy source Insulin also controls other body systems and regulates the amino acid uptake by body cells It has several other anabolic effects throughout the body as well Secretion of insulin Physiologic Effects of Insulin Glossary Physiologic Effects of Insulin Stand on a streetcorner and ask people if they know what insulin is, and many will reply, "Doesn't it have something to do with blood sugar?" Indeed, that is correct, but such a response is a bit like saying "Mozart? Wasn't he some kind of a musician?" Insulin is a key player in the control of intermediary metabolism, and the big picture is that it organizes the use of fuels for either storage or oxidation. Through these activities, insulin has profound effects on both carbohydrate and lipid metabolism, and significant influences on protein and mineral metabolism. Consequently, derangements in insulin signalling have widespread and devastating effects on many organs and tissues. The Insulin Receptor and Mechanism of Action Like the receptors for other protein hormones, the receptor for insulin is embedded in the plasma membrane.

The insulin receptor is composed of two alpha subunits and two beta subunits linked by disulfide bonds. The alpha chains are entirely extracellular and house insulin binding domains, while the linked beta chains penetrate through the plasma membrane. The insulin receptor is a tyrosine kinase. In other words, it functions as an enzyme that transfers phosphate groups from ATP to tyrosine residues on intracellular target proteins. Binding of insulin to the alpha subunits causes the beta subunits to phosphorylate themselves (autophosphorylation), thus activating the catalytic activity of the receptor. The activated receptor then phosphorylates a number of intracellular proteins, which in turn alters their activity, thereby generating a biological response. Several intracellular proteins have been identified as phosphorylation substrates for the insulin receptor, the best-studied of which is insulin receptor substrate 1 or IRS-1. When IRS-1 is activated by phosphorylation, a lot of things happen. Among other things, IRS-1 serves as a type of docking center for recruitment and activation of other enzymes that ultimately mediate insulin's effects. A more detailed look at these processes is presented in the section on Insulin Signal Transduction .

Insulin and Carbohydrate Metabolism Glucose is liberated from dietary carbohydrate such as starch or sucrose by hydrolysis within the small intestine , and is then absorbed into the blood. Elevated concentrations of glucose in blood stimulate release of insulin, and insulin acts on cells thoughout the body to stimulate uptake, utilization and storage of glucose. The effects of insulin on glucose metabolism vary depending on the target tissue. Two important effects are: 1. Insulin facilitates entry of glucose into muscle, adipose and several other tissues. The only mechanism by which cells can take up glucose is by facilitated diffusion through a family of hexose transporters . In many tissues - muscle being a prime example - the major transporter used for uptake of glucose (called GLUT4) is made available in the plasma membrane through the action of insulin. When insulin concentrations are low, GLUT4 glucose transporters are present in cytoplasmic< vesicles, where they are useless for transporting glucose. Binding of insulin to receptors on such cells leads rapidly to fusion of those vesicles with the plasma membrane and insertion of the glucose transporters, thereby giving the cell an ability to efficiently take up glucose.

When blood levels of insulin decrease and insulin receptors are no longer occupied, the glucose transporters are recycled back into the cytoplasm. The animation to the right depicts how insulin signalling leads to translocation of glucose transporters from the cytoplasm into the plasma membrane, allowing glucose (small blue balls) to enter the cell. Click on the "Add Glucose" button to start it. It should be noted here that there are some tissues that do not require insulin for efficient uptake of glucose: important examples are brain and the liver. This is because these cells don't use GLUT4 for importing glucose, but rather, another transporter that is not insulin-dependent. 2. Insulin stimulates the liver to store glucose in the form of glycogen. A large fraction of glucose absorbed from the small intestine is immediately taken up by hepatocytes, which convert it into the storage polymer glycogen. Insulin has several effects in liver which stimulate glycogen synthesis. First, it activates the enzyme hexokinase, which phosphorylates glucose, trapping it within the cell. Coincidently, insulin acts to inhibit the activity of glucose-6-phosphatase.

Insulin also activates several of the enzymes that are directly involved in glycogen synthesis, including phosphofructokinase and glycogen synthase. The net effect is clear: when the supply of glucose is abundant, insulin "tells" the liver to bank as much of it as possible for use later. A well-known effect of insulin is to decrease the concentration of glucose in blood, which should make sense considering the mechanisms described above. Another important consideration is that, as blood glucose concentrations fall, insulin secretion ceases. In the absense of insulin, a bulk of the cells in the body become unable to take up glucose, and begin a switch to using alternative fuels like fatty acids for energy. Neurons, however, require a constant supply of glucose, which in the short term, is provided from glycogen reserves. When insulin levels in blood fall, glycogen synthesis in the liver diminishes and enzymes responsible for breakdown of glycogen become active. Glycogen breakdown is stimulated not only by the absense of insulin but by the presence of glucagon , which is secreted when blood glucose levels fall below the normal range. Insulin and Lipid Metabolism The metabolic pathways for utilization of fats and carbohydrates are deeply and intricately intertwined.

Considering insulin's profound effects on carbohydrate metabolism, it stands to reason that insulin also has important effects on lipid metabolism, including the following: Insulin promotes synthesis of fatty acids in the liver. As discussed above, insulin is stimulatory to synthesis of glycogen in the liver. However, as glycogen accumulates to high levels (roughly 5% of liver mass), further synthesis is strongly suppressed. When the liver is saturated with glycogen, any additional glucose taken up by hepatocytes is shunted into pathways leading to synthesis of fatty acids, which are exported from the liver as lipoproteins. The lipoproteins are ripped apart in the circulation, providing free fatty acids for use in other tissues, including adipocytes, which use them to synthesize triglyceride. Insulin inhibits breakdown of fat in adipose tissue by inhibiting the intracellular lipase that hydrolyzes triglycerides to release fatty acids. Insulin facilitates entry of glucose into adipocytes, and within those cells, glucose can be used to synthesize glycerol. This glycerol, along with the fatty acids delivered from the liver, are used to synthesize triglyceride within the adipocyte.

By these mechanisms, insulin is involved in further accumulation of triglyceride in fat cells. From a whole body perspective, insulin has a fat-sparing effect. Not only does it drive most cells to preferentially oxidize carbohydrates instead of fatty acids for energy, insulin indirectly stimulates accumulation of fat in adipose tissue. Other Notable Effects of Insulin In addition to insulin's effect on entry of glucose into cells, it also stimulates the uptake of amino acids, again contributing to its overall anabolic effect. When insulin levels are low, as in the fasting state, the balance is pushed toward intracellular protein degradation. Insulin also increases the permiability of many cells to potassium, magnesium and phosphate ions. The effect on potassium is clinically important. Insulin activates sodium-potassium ATPases in many cells, causing a flux of potassium into cells. Under certain circumstances, injection of insulin can kill patients because of its ability to acutely suppress plasma potassium concentrations. Insulin Deficiency and Excess Diseases Diabetes mellitus, arguably the most important metabolic disease of man, is an insulin deficiency state. It also is a significant cause of disease in dogs and cats.

Two principal forms of this disease are recognized: Type I or insulin-dependent diabetes mellitus is the result of a frank deficiency of insulin. The onset of this disease typically is in childhood. It is due to destruction pancreatic beta cells, most likely the result of autoimmunity to one or more components of those cells. Many of the acute effects of this disease can be controlled by insulin replacement therapy. Maintaining tight control of blood glucose concentrations by monitoring, treatment with insulin and dietary management will minimize the long-term adverse effects of this disorder on blood vessels, nerves and other organ systems, allowing a healthy life. Type II or non-insulin-dependent diabetes mellitus begins as a syndrome of insulin resistance. That is, target tissues fail to respond appropriately to insulin. Typically, the onset of this disease is in adulthood. Despite monumental research efforts, the precise nature of the defects leading to type II diabetes have been difficult to ascertain, and the pathogenesis of this condition is plainly multifactorial. Obesity is clearly a major risk factor, but in some cases of extreme obesity in humans and animals, insulin sensitivity is normal. Because there is not, at least initially, an inability to secrete adequate amounts of insulin, insulin injections are not useful for therapy.

Rather the disease is controlled through dietary therapy and hypoglycemic agents. Hyperinsulinemia or excessive insulin secretion is most commonly a consequence of insulin resistance, associated with type 2 diabetes or the metabolic syndrome. More rarely, hyperinsulinemia results from an insulin-secreting tumor (insulinoma) in the pancreas. Hyperinsulinemia due to accidental or deliberate injection of excessive insulin is dangerous and can be acutely life-threatening because blood levels of glucose drop rapidly and the brain becomes starved for energy (insulin shock). Lecture 23: Endocrine system Endocrine System A. Hormones = chemical messengers carried by blood to non-adjacent "target" cells. 1. Overview of hormone functions - Regulation of growth and development. - Homestatic control (regulation of internal environment; parameters maintained w/in relatively narrow limits) - Control of reproductive system processes (ovulation, mestruation, maintanence of pregnancy) - Effects on Behavior (modification, modulation, initiation of specific patterns) 2. Endocrine glands, endocrine cells and some neurons secrete hormones into tissue fluid from which they diffuse into capillaries. Sources of hormones in humans = the endocrine system [Fig.

37.2] 3. Target cells = cells with receptors for a given chemical messenger that can alter their activities in response to messenger. - Hormones are transported throughout the body by the blood, but they only elicit responses in target cells. - Receptors may be on cell surface (non-steroid hormones) or internal to cell in cytoplasm or nucleus (steroid hormones) [cf. Figs. 37.3 and 37.4] B. Types of Hormones [Table 37.1] There are two main classes (chemical groups) into which hormones fall: 1. steriods (in vertebrates sythesized from cholesterol by adrenal cortex, testis, ovary and placenta) [examples: cortisol, estradiol] C. How hormones work in target tissues. 1. Steriod hormones and thyroid hormones (gene activation) [Fig. 37.3]: a. Relatively small, lipid soluble. Therefore, diffuse freely into and out of cells. b. Affect target cells that have receptor proteins in their cytoplasm (or nucleus) c. Hormone-receptor complex moves into nucleus (if not already there).

(Current evidence is that this is an active tranport process and that only target cells have transport mechanism) d. Complex binds to DNA and stimulates transcription of specific genes (synth. of mRNA) --> protein synthesis. e. Full effect of hormone manifested over minutes to days. 2. Peptide/protein hormones (second messenger mechanism) [Fig. 37.4]: a. Do not diffuse into cells. b. Target cells have specific receptor for hormone on cell surface. c. Hormone binds to receptor and causes a second messenger to be released within the cell. d. Second messenger can be - cyclic nucleotide: c-AMP (rx. inside cell catalyzed by adenylate cyclase) --> many c-AMP molecules - Ca ion; binding of hormone causes Ca channels in cell membrane to open --> influx of many Ca ions. Ca ions bind to protein = calmodulin. e. c-AMP molecules or Ca-calmodulin complexes activate many enzymes (= cascade of reactions) --> rapid response to hormone (seconds to minutes). D. Examples of hormone control 1. Secretion of ADH (antidiuretic hormone) by pitutitary. [Fig.

37.5] - dehydration (low blood pressure) --> secretion of ADH --> increased retention of water (more water reabsorbed by kidneys). - cell bodies in region of brain called hypothalamus synthesize ADH. ADH moves down axons to posterior pitutitary; accumulates in axon terminals; released by action potentials. ADH enters bloodstream. = Neurohormone [What are the target cells for ADH?] - What stops secretion of ADH by posterior pituitary? [As more water is retained by body, blood pressure rises and production of ADH falls off. = Negative feedback] 2. Stimulation of Cortisol Secretion by Adrenal Cortex [Fig. 37.10] Low blood sugar --> Hypothalamus secretes CRH (corticotropin-releasing hormone) --> Anterior pituitary cells (certain cells only) secrete ACTH (adrenocorticotropic hormone) --> Adrenal cortex secretes cortisol (and other glucocorticoids) [cortisol prevents sugar uptake by muscle cells] - Negative Feedback control pathways: - cortisol inhibits ACTH secretion by adrenal cortex - cortisol also inhibits CRH secretion by hypothal. 3.

Role of Pancreatic Islets [Fig. 37.9]: - Islets of Langerhans = clusters of endocrine-secreting cells disbursed throughout pancreas. Alpha cells secrete glucagon; beta cells secrete insulin a. Insulin lowers blood glucose level by stimulating cells (esp. skeletal muscle and fat cells as well as liver cells) to take up glucose; stimulates muscles and liver to store glucose as glycogen. b. Glucagon raises blood glucose level by stimulating liver to convert glycogen to glucose and by stimulating the conversion of fatty acids and amino acids to glucose. c. Secretion of insulin and glucagon is controlled directly by the concentration of glucose in the blood. [Normal "fasting level" = 90mg/100ml blood] d. Insulin-glucagon system is fast-acting for keeping blood glucose level tightly regulated. (Brain cells cannot utilize other nutrients as fuel.) e. Diabetes mellitus: - Type II = maturity onset: Insulin receptors cannot bind hormone. - Type I = juvenile onset = insulin-dependent: Decrease in the number of beta cells --> insulin deficiency. Requires daily injections of insulin. 4.

Role of Adrenal Medulla - Medulla is central portion of adrenal gland which produces epinephrine and norepinephrine [cortex produces cortisol (discussed earlier) along with mineralocorticoids and androgen] a. Medulla develops from neural tissue and its secretion is controlled by sympathetic nerves. b. Trigger for increased output is perception of a "threatening" situation resulting in fear or anger. Brain integrates information and stimulates output of medulla directly via sympathetic nerves (ACh stimulates output of epinephrine and norepi.) c. Effects of epineph., norepineph. -vasodilation of vessels to brain, muscles, heart -vasoconstriction of vessels to kidney, skin (paling) -heart rate speeds up E. Human Endocrine System (similar in most vertebrates) 1. Principal organs (Fig. 37.2): -Hypothalamus, Pituitary gland (two lobes), Pineal gland, Thyroid gland, Parathyroid glands (4), Thymus gland, Adrenal glands, Pancreas (islets of Langerhans), Ovaries or Testes. 2. Role of Hypothalamus and Pituitary.

- Hypothalamus links nervous and endocrine systems. - Hypothalamic neurons secrete hormones that regulate the release of hormones from the anterior lobe of the pituitary gland. Pituitary hormones, in turn, control activity of other endocrine glands. [note: An endocrine gland can be a target organ for hormones secreted by other endocrine glands] - The pituitary gland has two lobes: a. Posterior Lobe [Fig. 37.5] contains endings of neurosecretory cells whose cell bodies are located in the hypothalamus. - peptide hormones secreted = oxytocin and ADH. (These hypothalamic hormones are released directly into the systemic circulation where they act on the kidneys (ADH) or on mammary glands and the uterus (oxytocin)). b. Anterior Lobe [Fig. 37.6]lu contains endocrine cells that secrete prolactin, growth hormone, and several trophic hormones that stimulate other endocrine glands (see Table 37.2). -Hypothalamus secretes releasing and release-inhibiting hormones that control the anterior lobe of the pituitary.

- cells of anterior lobe are targets for specific releasing and/or release-inhibiting hormones. - special portal system: capillaries in hypothalamus pick up hypothalamic hormones ("brain hormones") and carry them to a second capillary bed in the anterior lobe. Structural Biochemistry/Protein function/Insulin - Wikibooks, open books for an open world Structural Biochemistry/Protein function/Insulin Overview[ edit ] Insulin is a hormone secreted by the pancreas that regulates glucose levels in the blood. Without insulin, cells cannot use the energy from glucose to carry out functions within the body. Insulin was first discovered in 1921 by Frederick Grant Banting and Charles Best from extracted substances from the pancreas of dogs in their laboratory. The material was then used to keep diabetic dogs alive, and then used in 1922 on a 14 year old diabetic boy. The FDA approved insulin in 1939. In 1966 insulin was synthesized by Michael Katsoyannis in his laboratory, which marked the first complete hormone to be successfully synthesized.

Synthetic insulin is used as a drug to treat diabetes, and the current forms on the market include insulin from bovine and porcine pancreases, but the most widely used is a form made from recombinant human insulin. Primary Structure of Human Insulin Function[ edit ] Insulin is made in the pancreas by beta cells. After the body takes in food, these beta cells release insulin, which enables cells in the liver, muscles and fat tissues to take up glucose and either store it as glycogen or allow blood to transfer it to organs in the body for use as an energy source. This process stops the use of fat as a source of energy. When glucose levels are elevated in the blood, insulin is produced at higher rates by the pancreas in order to maintain normal sugar concentrations in the blood. Without insulin, the body cannot process glucose effectively and glucose begins to build up in the blood stream instead of being transported to different cells . In contrast with elevated levels of glucose in the blood, when there is a deficit of glucose available to the body, alpha cells in the pancreas release glucagon , a hormone that causes the liver to convert stored glycogen into usable glucose which is then released into the bloodstream.

Some of the effects of the insulin on the metabolism include: 1. Controlling cell intake of substances like glucose in many organs like muscles and adipose tissues. 2. Controlling amino acid uptake, thus increasing DNA replication and protein synthesis 3. Altering the activity of enzymatic cells Other Cellular effects of insulin include: 1. Increasing synthesis of glycogen. Glycogen is a type of storage for glucose and is stored in the liver. Levels of blood glucose determine whether glucose is stored as glycogen or is excreted. Low levels of glucose cause the liver to excrete glucose, while higher levels of glucose allows glucose to be stored as glycogen. 2. Increasing the synthesis and esterification of fatty acids. This is caused by the insulin causing fat cells to convert blood lipids to triglycerides. Esterification is caused when the insulin causes the adipose tissue to convert fats from fatty acid esters. 3. Increasing the esterification of fatty 4. Decreasing protein breakdown (proteolysis) 5. Reducing lipolysis 6. Increasing uptake of substances like amino acid and potassium 7. Relaxing wall of arteries of muscles, which vasodilation 8.

Increasing secretion of HCl into the stomach Structure[ edit ] Insulin is a hormone consisting of 2 polypeptide chains. Each chain is composed of a specific sequence of amino acid residues connected by peptide bonds . In humans, chain A has 21 amino acids, and chain B has 30. Post translational modifications result in the connection of these two chains by disulfide bridges . Cysteine residues on A7 and B7, as well as A20 to B19 are covalently connected by disulfide bridges. Chain A also has an internal disulfide bridge connecting A6 to A11. The 3D structure of insulin is composed of 3 helices and the three disulfide bridges. Hydrophobic amino acid residues are clustered on the inside of the molecule while the polar amino acids residues are located on the outer surface. This arrangement of amino acid residues lends stability to the overall molecule. A single molecule of insulin can form a dimer with another insulin molecule, but the most active form is a single unit. The chemical formula for the insulin monomer is: C256H381N65O79S6.

Add caption here Synthesis[ edit ] Insulin Synthesis Using Recombinant DNA Technology. Insulin production takes place in the pancreas, however diabetics lack the capability to produce insulin, so insulin derived by synthetic means is required to maintain normal blood glucose levels. Bovine and porcine insulin is similar to human insulin, however insulin synthesized from these sources can have adverse affects when used to treat diabetic patients due to possible long term effects from the continual injection of a foreign substance into the body. As a result of these possible adverse effects, in 1977, researches at the Genentech corporation developed means to reproduce insulin derived from humans through recombinant DNA technology. The steps involved in cloning human insulin begin with extracting proinsulin mRNA from the pancreas of a human with a functioning pancreas. Next, the enzyme reverse transcriptase is used to synthesize a strand of DNA that is complementary to the proinsulin mRNA . This DNA complement is called cDNA. The cDNA and RNA strands form a double helix hybrid. Next, the RNA is hydrolyzed off by raising the pH, and the DNA strand complementary to the original cDNA strand is formed with the help of an enzyme called terminal transferase .

Restriction enzymes can be used to cut the gene and isolate just the sequence that encodes for the insulin protein. Next, circular units of DNA, called plasmids , are extracted from E. coli bacteria cells and cut with the same restriction enzyme that was used to cut the human chromosome. Using the same restriction enzymes creates complementary ends on the plasmid and the insulin gene. Next, the insulin gene is inserted into the plasmid at the proper location and the enzyme DNA ligase is used to form the phosphodiester bonds between the insulin gene and the plasmid. This step essentially “glues” the insulin gene into the E. coli plasmid vector. A certain type of plasmid called an “expression vector” is used in this process, which contains a bacterial promoter that facilitates the formation mRNA. Once the insulin genes are ligated into the vector, the vector is inserted into a bacterial cell. The bacterial cell acts as a host for the translation process of mRNA to protein. These host cells are harvested and allowed to reproduce, which creates a colony of insulin producing bacterial cells. The insulin can then be purified and packaged.

Alternative Synthesis[ edit ] Another possible method to synthesize insulin was recently proposed by a pharmaceutical company SynBioSys in 2006 which used safflower to produce insulin rather than bacteria. Their goal ultimately was to reduce economic costs by exceeding its target and achieving accumulation levels of 1.2 percent of total seed protein. The company claims that this breakthrough in plant-produced insulin have the potential to "fundamentally transform the economics and scale of insulin production." The company announces safflower produced insulin can be up to 60% less expensive than insulin manufactured through bacterial cells. The clinical testing trials were promising: SBS-1000 was bioequivalent to most common brand name insulin medications. SBS-1000 in humans showed no difference in metabolizing bacteria based insulin rather than through safflower. SBS-1000 was well tolerated at pharmacologically active dosages. Release[ edit ] Insulin is released in the body by the Beta cells in the islets of Langerhans. This is done in two phases, which includes a response in a change in blood glucose level and another type of release which is slower and is independent of sugar.

Insulin released by a change in blood glucose level starts when glucose enters glycolysis and the respiratory cycle. During this cycle, ATP is produced by oxidation, and thus the level of ATP produced is representative of the blood glucose level. When the amount of ATP produced gets to a certain point, potassium channels that are activated by ATP close, depolarizing the cell membrane, leading to a change in other voltage activated channels, such as the calcium channels. Due to the depolarization, voltage gated calcium channels open, allowing an influx of calcium ions into the cell. The increased level of calcium in the cell activates phospholipase C. Phospholipase C cleaves the membrane phospholipid phosphatidyl inositol 4,5-bisphosphate, which in turn becomes inositol 1,4,5-triphosphate and diacylglycerol. The newly formed inositol 1,4,5-triphosphate (also known as IP3) binds to receptors on IP3 gated channels embedded on the membrane of the endoplasmic reticulum. The IP3 gated channels allow an influx of calcium ions in the cell, repolarizing the cell.

Insulin, which was synthesized prior to this reaction, is stored in secretory vesicles, and is waiting to be released. The increased levels of calcium due to the binding of IP3 causes the release of the insulin from these vesicles. The beta cells of the islets of Langerhan regulates the glucose level by this reaction. When the blood glucose level is physiologically normal, the beta cells cease to secrete any more insulin. This is done by the sympathetic nervous system, by the release of the hormon norepinephrine. When blood glucose level drops, hyperglycemic hormones (glucagon) are released by the alpha cells of the Islets of Langerhans. This causes glucose to be released into the blood from storage within the body, and most mainly comes from the liver. The glucose is stored as glycogen within the liver. Degradation[ edit ] Insulin has two routes of degradation after it has attached to the receptor site on the cell membrane. (1) It may be released into the extracellular environment or (2) it may be degraded by the cell. If insulin is to be degraded by the cell, the insulin-receptor complex is brought into the intracellular area via endocytosis.

Subsequently, insulin-degrading enzymes break down the molecule. Insulin is degraded primarily in the liver and the kidneys. The liver is responsible for degrading insulin that is in the bloodstream for the first time; the kidneys are responsible for degrading insulin that is in normal circulation. Natural, endogenously produced insulin is estimated to be degraded within one hour after its initial release into circulation by the pancreatic beta cells. The half life of insulin is approximated to be 4-6 minutes. Diabetes[ edit ] Diabetes is a condition which the body either cannot produce insulin or does not respond properly to insulin. There are two types of diabetes. Type 1 diabetes is when insulin is not produced by the body. This is due to an autoimmune condition, in which body attacks the Beta cells of the Islets of Langerhans. This can be treated by insulin injections. Type 2 diabetes is when there is a resistance to insulin, reduction in production of insulin, or both. Insulin is used to maintain a balance of glucose levels in a body’s bloodstream. After a meal, digestion of the carbohydrates occurs and enters the blood as glucose to provide the body with energy.

To maintain a body’s blood sugar level, excess sugar is stored in the liver and is released once the blood sugar level starts to become low. This is where diabetes occurs; when the glucose is unable to enter the cells from the pancreas when the sugar levels are too low. If this disease is left untreated, complications, such as blindness and damage to the kidneys can occur. Non Diabetic Uses of Insulin[ edit ] 1) Intravenous feeding solutions: One of the active ingredients in IV solutions used for feeding the body in hospital patients is insulin. The presence of insulin in the boyd helps improve the adsorption of nutrients and when combined with growth hormones, can help reverse negative protien balance. 2) Intravenous GIK solution: Glucose, insulin and potassium solutions have been used to reduce the mortality rate of acute mycoradial infractions, or otherwise known as heart attacks, along with postoperative cardiac failure. By addition of GIK infusions, it is a quick way to infuse potassium into all the cells of the heart even when circulation has ceased completely to readily restore action potential in cardial muscle to induce contraction.

3) Dialysis shock recovery: A bit insulin can be added to an electrolyte solution that can help patients absorb electrolytes quickly to recover from a dialysis shock. 4) Sports Drinks and Oral Rehydration Solutions: The sugars found in these drinks, such as gatorade, allow for increased secretion of insulin in the body which speeds up absorption of water and electrolytes into all the cells of the body.

Question: What human hormone causes certain body cells to take up glucose from the blood and store it as glycogen?
Answer: Insulin