Analysis of Insulin Related Paper

Paper: Reduction of Low-Molecular-Weight Protein Tyrosine Phosphatase Expression Improves Hyperglycemia and Insulin Sensitivity in Obese Mice

Summary:

The purpose of this experiment was to investigate the role of Low-Molecular-Weight Protein Tyrosine Phosphatase (LMW-PTP) in glucose metabolism and insulin action. More specifically, the researchers were attempting to determine if reducing the expression of LMW-PTP in vitro and in vivo would enhance insulin signaling activity and reduce glucose levels. The basis for this experiment was built around the findings of recent studies which suggest that LMW-PTP may have a role as a negative regulator of insulin-mediated mitogenic and metabolic signaling. For instance, LMW-PTP also known as acid phosphatase locus 1 (ACP1) is an 18 kDa cytosolic enzyme with catalytically active isoforms (A and B). It is widely expressed in various tissues in mammals, however, it is most highly expressed in the liver and brain and least expressed in skeletal muscle tissue. In any event, LMW-PTP dephosphorylates tyrosine phosphorylated proteins which is how it is thought to affect the insulin pathway.

For example, insulin initiates a physiological response by binding to its membrane bound receptor which causes autophosphorylation of the beta subunit and in turn activates the receptor. This results in the phophorylation of the receptors two major downstream substrates, IRS-1 and IRS-2. These substrates then phophorylate a number of other enzymes within the target cell which induce the appropriate biological response such as the phophorylation and inactivation of glycogen synthase kinase. The inactivation of this enzyme results in the activation of glycogen synthase which increases the utilization of glucose for glycogen synthesis. Thus, the end result is the reduction of blood glucose levels in the bloodstream.

The way in which LMW-PTP actually affects this pathway is it dephosphorylates the tyrosine residues on the beta subunit of the insulin receptor. This decreases the receptors ability to respond to insulin as the activation of the receptor depends on the phosphorylation of these tyrosine residues. In this way, LMW-PTP reduces insulin sensitivity which makes it a possible contributor to both hyperglycemia and diabetes. In fact, recent studies have shown that LMW-PTP is associated with dyslipidemia and hyperglycemia in human subjects, but its exact role in regulating insulin levels in vivo is still unknown. In any event, in knowing how LMW-PTP operates itself, the researchers of this experiment investigated the effects of reducing its expression in vitro and in vivo to see how it affects the actions of insulin. Their hypothesis for the experiment was that reducing the expression of LMW-PTP should increase insulin sensitivity.

To perform this experiment, they used a specific antisense oligonucleotide (ASO) to suppress the expression of LMW-PTP in cultured mouse hepatocytes as well as the liver and fat of diet-induced obese (DIO) and leptin-deficient obese (ob/ob) mice. They did this by selecting and isolating a LMW-PTP ASO. They then isolated mouse hepatocytes and transfected them with the LMW-PTP ASO. At the same time, they also transfected the DIO and ob/ob mice with the same LMW-PTP ASO. After weeks of treatment (varying lengths of time for each), the cells for all three trials were analyzed using a variety of tests to determine the effects that the ASO treatment had on insulin sensitivity and plasma glucose levels. In doing so, it was discovered that the reduction of LMW-PTP expression with ASO in all three cell types (isolated hepatocytes, DIO mice, and ob/ob mice) resulted in increased phosphorylation and activity of key insulin signaling intermediates including the insulin receptor (beta subunit), P13-kinase, and Akt in response to insulin stimulation. In this way, the ASO-treated DIO and ob/ob mice both showed enhanced insulin sensitivity as the plasma insulin and glucose levels were lowered in both animals. Similarly, there was improved glucose and insulin tolerance observed in the DIO mice, however, the treatment did not decrease body weight or increase metabolic rate. Therefore, it was concluded that LMW-PTP is a key negative regulator of insulin action and that reducing its expression improves insulin sensitivity. In turn, the action of this enzyme holds potential as a novel target for the treatment of insulin resistance and type 2 diabetes.

Overall the authors show that:

1) The reduction of LMW-PTP expression with ASO in all three cell types (isolated hepatocytes, DIO mice, and ob/ob mice) results in increased phosphorylation and activity of key insulin signaling intermediates including the insulin receptor (beta subunit), P13-kinase, and Akt in response to insulin stimulation.
2) LMW-PTP is a key negative regulator of insulin action.
3) The reduction of LMW-PTP expression enhances insulin signaling in mouse hepatocytes.
4) The reduction of LMW-PTP expression improves insulin sensitivity in DIO mice with no change in body weight.
5) The reduction of LMW-PTP expression improves insulin sensitivity in ob/ob mice with no change in body weight.
6) The reduction of LMW-PTP expression improves insulin action in both liver and fat cells of both mice.
7) The plasma insulin and glucose levels were lowered in both types of mice.
8) There was improved glucose and insulin tolerance observed in the DIO mice.

Critique of the paper:

- The paper is very well written, however, it seemed to be dragged out and there was a lot of repetition.
- The figures were clear and appropriate, however, I did not like their layout. They were all jumbled together at the end of the paper and the captions for each figure were not on the same page as the figure itself which was inconvenient when analyzing the figures.
- The paper itself was also very clear and easy to understand and the key points were presented in an appropriate order.
- I found the experimental methods section to be a bit exhaustive and it got confusing at times. For example, it mentions that C57BL/6J-Lep mice were purchased for this experiment which made no sense to me. As far as I could gather, I believe they were the ob/ob mice. I think a small explanation of what these mice were would have been appropriate.
- It was also unclear how the antisense oligonucleotide reduced the expression of the LMW-PTP gene. I feel that they could have explained that a bit better.
- Other than that, all of the conclusions seemed to support the results and the researchers of the experiment accomplished what they set out to do which was to determine the role of LMW-PTP in insulin signaling and glucose metabolism.
- The data was presented in a very organized manner and the explanations of the results were very detailed.
- The results also followed their expectations very closely and they successfully accomplished the goal of the experiment which was to prove that reducing LMW-PTP expression in vivo and in vitro would increase insulin sensitivity.
- Overall the paper was very good and I enjoyed learning about this topic.

Possible future experiments:

1) Question: Does treating normal mice (mice that have normal blood glucose levels) with LMW-PTP ASO injections reduce their plasma blood glucose concentrations to unhealthy levels?

Methods: Treat normal mice with daily injections of a LMW-PTP ASO as performed in this experiment to suppress LMW-PTP expression. The blood glucose concentrations of the mice will then have to be monitored for several weeks to determine if they are lowered below normal levels. One will also have to check for any negative impacts that this treatment may be having on the mice.

Results: If the blood glucose levels are lowered significantly in the mice, causing negative impacts such as kidney problems or death then it can be concluded that LMW-PTP ASO injections can reduce blood glucose concentrations to unhealthy levels. Therefore, this would have to be taken into account when considering LMW-PTP ASO injections as a possible treatment for type 2 diabetes.

2) Question: Can suppressing LMW-PTP expression be used as a valid treatment for type 2 diabetes?

Methods: Treat mice that have type 2 diabetes with daily injections of a LMW-PTP ASO as performed in this experiment to suppress LMW-PTP expression. One can then monitor glucose levels in the mice over a long-term period to determine if blood glucose concentrations return to normal levels in response to the injections. The mice will also have to be analyzed for any significant side effects of the treatment that would negatively impact the mice in anyway. Similarly, such an experiment would also have to be performed numerous times with consistent results in order to be considered valid.

Results: If reducing LMW-PTP expression in the diabetic mice reduces glucose to normal levels without any side effects then this technique will be considered a successful means for treating type 2 diabetes in mice. Thus, this treatment can then be considered to treat type 2 diabetes in humans.

Function and Pathologies of Insulin

Insulin Tissue Localization:

Insulin acts on the majority of tissues throughout the human body. However, the target tissues on which it has its most significant effects are fat tissue, skeletal muscle tissue, and liver tissue (1).

Receptors and their localization:

There has only been one type of receptor identified for insulin. The insulin receptor is a transmembrane protein that is embedded in the plasma membrane of its target cells. It does not matter if the receptor is located in the muscle, liver, or fat, it still has the same structure and operates in the same manner. This receptor is composed of two alpha subunits and two beta subunits which are linked together by disulfide bonds. The alpha chains are completely extracellular and possess insulin binding domains which make them the portion of the receptor that actively binds insulin molecules. Meanwhile, the beta domains penetrate through the plasma membrane and into the cell where it is able to interact with other molecules within the cell (4).

For instance, the beta subunits have tyrosine kinase activity. This means that the insulin receptor is able to function as an enzyme and phosphorylate itself as well as other target proteins. In order for this to occur, the receptor must first be activated by an insulin molecule. This activation starts with the alpha subunits which recognize and bind the insulin molecule. In turn, this causes the beta subunits to phosphorylate themselves which activates the catalytic activity of the receptor. Once activated, the insulin receptor is able to phosphorylate a number of intracellular proteins which in turn initiate the appropriate biological response within the specific target cell. In this case, the main function of the response is to reduce the amount of glucose in the blood when the concentrations are too high (4).

Function:

The primary function of insulin is to regulate blood glucose levels within the body to ensure that they are maintained at a relatively constant and stable level. Thus, like the majority of hormones, the purpose of insulin is to maintain some form of homeostasis within the body. In this case, it is blood glucose levels. As already mentioned, insulin’s specific role in mediating glucose concentrations in the blood is to ensure that they do not get too high (2).

For example, glucose is usually consumed by the body in its carbohydrate form such as starch or sucrose. These carbohydrates travel through the digestive tract to the small intestine where they are hydrolyzed into individual glucose molecules. This glucose is then absorbed into the blood and transported throughout the body. This results in elevated concentrations of glucose in the blood which stimulates the release of insulin (2).

The way in which the beta cells (body) are able to recognize these high blood sugar levels is that the plasma membranes of beta cells have special channels that serve as glucose detectors. When these “detectors” recognize that blood sugar levels are higher than normal, they signal the beta cells to release insulin into the blood stream. Once in the blood stream, insulin is able to return blood glucose to normal levels by initiating its various target tissues which reduce the amount of glucose in the blood stream. They are able to do this through a variety of mechanisms which initiate the uptake, storage, and utilization of glucose. In most cases, this is accomplished by converting soluble nutrients absorbed by the small intestine into their storable forms which are usually insoluble energy-rich products such as glycogen, protein, and fat (4).

Effects on Skeletal Muscle Tissue:

One of insulin’s many target tissues are skeletal muscle fibers. Here, it can either stimulate glucose uptake by activating glycogen synthesis. This involves converting glucose into glycogen through the glycogen synthase enzyme. Or, it can stimulate the uptake of amino acids and convert them into protein. Both actions result in the removal of glucose from the blood stream (2).

Effects on Liver Tissue:

Insulin also acts on liver cells where it triggers a variety of responses to remove glucose from the blood. Firstly, it can stimulate glycogen synthesis which causes the liver cells to uptake glucose and convert it into glycogen. Secondly, it can inhibit the production of the enzymes in liver cells which are involved in glycogen breakdown (glycogenolysis). Lastly, it is can inhibit gluconeogenesis which is responsible for converting fats and proteins into glucose. All of these actions result in less free glucose in the bloodstream (1).

Effects on Adipose Tissue:

Insulin also has a direct effect on adipose (fat) cells as it stimulates lipogenolysis. This results in the uptake of glucose from the blood in order to synthesize fat. At the same time, it also inhibits lipolysis which is the breakdown of triglycerides into fatty acids and glycerol which ultimately results in the production of glucose. Thus, both of these actions once again cause glucose to be removed from the bloodstream (2).

Effects on Hypothalamus:

Another one of the tissues that insulin acts on is the hypothalamus. Here, it reduces appetite which reduces the amount of glucose being ingested by the body (1).

Pathologies:

Type I (insulin-dependent) diabetes mellitus – This is a disease caused by a deficiency of insulin in the body. In turn, people with this disease suffer from severe hyperglycemia which simply refers to high levels of glucose in the blood stream. This form of diabetes is due to the destruction of pancreatic beta cells within the body. The cause of this is usually due to the body having autoimmunity to one or more of the components of these cells. The onset of this disease generally occurs in childhood and it can be treated or controlled by insulin replacement therapy. This simply involves continuously injecting the individual with an alternate source of insulin. Some of the primary symptoms or side effects of this disease include a failure of the kidney to reclaim glucose so that glucose spills over into the urine causing it to smell and taste sweet. Similarly, there is also an increase in the volume of urine because of the osmotic effect of this glucose which reduces the return of water to the blood. In addition, if this disease is left untreated, it could even result in death. However, if tight control of blood glucose concentrations is maintained by monitoring, treatment with insulin and dietary management, it will minimize the long-term adverse effects of this disorder on blood vessels, nerves and other organ systems. Ultimately, this will allow the individual to live a healthy life (1).

Type II (non-insulin-dependent) diabetes mellitus – This form of the diabetes disease is a result of insulin resistance, instead of a lack of insulin. In these patients, there is no initial deficiency in the amount of insulin in the body. The problem seems to lie in the target tissues inability to respond appropriately to insulin. In contrast to type I diabetes, the onset of this disease generally occurs in adulthood. The exact cause of the disease is unknown at this point, but recent research has shown that it may be due to an abnormality in the insulin receptor or defect in insulin signaling. In any event, the resistance to insulin that is observed in this disease also causes the individual to suffer from hyperglycemia. Thus, the side effects that are observed in this disease are very similar to those found in type I diabetes. Unfortunately, insulin injections do not work as a medication for this disease as there is no initial deficiency in insulin levels. Instead, drugs that contain hypoglycemic agents are administered through dietary therapy in order to treat this disease (1).

Hyperinsulinemia (excessive insulin secretion) – This disease is actually the opposite of diabetes mellitus as it is a result of an over-secretion of insulin. It is typically caused by an insulin-secreting tumor which secretes insulin in concentrations much higher than normal. This results in high levels of insulin in the blood which causes an increase in the amount of glucose being removed from the blood through the insulin mediated pathways. In turn, there is a significant drop in blood glucose levels and the individual suffers from hypoglycemia. This causes the brain to become starved for energy and the body goes into what is known as “insulin shock”. Some of the symptoms and side effects of this are impaired functioning of the central nervous system which may include dizziness, speech problems, and even loss of consciousness. If left untreated this disease could be potentially life-threatening. Fortunately though, this condition is much less common than diabetes mellitus (4).

References:

1) http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/P/Pancreas.html
2)
http://en.wikipedia.org/wiki/Insulin
3)
http://www.endocrineweb.com/diabetes/2insulin.html
4) http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/pancreas/insulin_phys.html
5)
http://www.fda.gov/diabetes/insulin.html

Structure

Insulin is a small, 6000 dalton protein (polypeptide) consisting of an alpha and beta chain. The alpha chain has 21 amino acids, while the beta chains has 30 amino acids. These two chains are connected by two disulfide bridges which yield a protein with a total of 51 amino acids. The final product is a protein that has a 3D conformation which is highly conserved among vertebrate species (1).

However, the insulin hormone is not a protein that is directly synthesized through translation. It is actually derived from a polypeptide known as preproinsulin which has to undergo a series of alterations and modifications in order to obtain the insulin molecule. For example, in the beta cells of the pancreas, insulin mRNA is originally translated and produced as preproinsulin which is composed of 110 amino acids. This polypeptide is then passed on to the endoplasmic reticulum where the signal peptide consisting of 24 amino acids is cleaved by enzymatic activity during insertion into the organelle. The resulting peptide is known as proinsulin which consists of an amino-terminal B chain, a carboxy-terminal A chain, and a C peptide. This polypeptide is then passed onto the golgi apparatus where the middle section consisting of 33 amino acids (C peptide) is cleaved by endopeptidases. After this cleavage we are left with “mature insulin” consisting of an A and B chain and the C peptide molecule. Both of these peptides are then packaged into vesicles within the Golgi which bud off the Golgi body and accumulate in the cytoplasm. Here, the “mature insulin” molecule is modified to its active form by enzymes within the vesicles. These vesicles which contain active insulin are stored in the cytoplasm until the beta cell is stimulated causing the release of both insulin and the C peptide into the blood via exocytosis (7).

The primary structure of the protein consists of the two separate alpha and beta chains which both have a relatively linear conformation. The amino acids of both of these chains are connected by peptide bonds with an amino group (N-terminal) on one end of each chain and a carboxylic acid group (C-terminal) on the other end of each chain (2).

In the secondary structure of the hormone, hydrogen bonds form between the peptide bonds of the two chains. This causes the amino acids of the joined chains to coil to form short sections of alpha helix. The alpha chain of the secondary structure is fairly compact and contains two sections of alpha helix which are separated by a flat ribbon section. This formation allows the two helices to lay along side one another which brings the side chains of the helices in close proximity so that they can interact through Van der Waals forces. This also helps to stabilize the secondary structure of the hormone. Meanwhile, the beta chain consists of a single, larger section of alpha helix which appears to wrap around the alpha chain. It also has smaller glycine residues which allow it to fold into a V shape. This brings the C-terminal residues in Van der Waals conatact with the residues of the alpha helix portion of the beta chain which also helps to stabilize the structure. Overall, the secondary structure of insulin is mainly stabilized by hydrogen bonds which form a relatively compact and simple three-dimensional configuration (2).

In the tertiary structure of insulin, this three-dimensional configuration is further stabilized by disulphide bridges which form between the thiol (SH) groups on the cysteine residues. Due to the fact that there are only six cysteines present in this protein, only three disulfide bridges are able to form in the tertiary structure. Two of these bridges form between the alpha and beta chains of the hormone, while one bridge forms within the alpha chain itself. In any event, these three bridges are the primary means of stabilizing the tertiary structure and are a very effective means of keeping the protein intact. Meanwhile, there are also weaker bonds such as salt bridges and Van der Waal’s forces which also aid in stabilizing the tertiary structure of the hormone. Once bound together by these forces, the tertiary structure of insulin has a compact three-dimensional dimmer with several alpha helical domains. The exterior of this molecule is mainly polar, while the interior is mainly non-polar (2).

Finally, the insulin molecule can also take on a quaternary structure as a dimer or hexamer. For instance, in solution, insulin molecules have a tendency to form dimers as hydrophobic bonds can also occur between the residues of two insulin monomers (3). However, insulin is only active as a single unit or monomer so the dimer is unable to initiate a biological response. In the meantime, in the presence of zinc ions, insulin can also form into granules consisting of hexamers. These hexamers (granules) are formed by interactions between the hydrophobic surfaces of six insulin molecules which creates a very strong and stable structure. These hexamers can be very useful when it comes to storing insulin as the toroidal form of these hexamers is the form in which insulin is stored in beta cells before it is released into the blood stream (2).

In any event, even though the insulin molecule can form primary, secondary, tertiary, and quaternary structures, it is only active in one specific form. This is the monomer version of its tertiary structure. The reason for this is that the insulin receptor only recognizes insulin as a single molecule or monomer. Thus, it is not active as a dimer or hexamer (quaternary structures) which are actually the storage forms of the molecule. Similarly, it is also not active in its primary and secondary structures as the insulin receptor is also unable to recognize the insulin molecules in these forms. For instance, the protein has to be folded and compacted in the correct conformation before it can be recognized by the receptor. Consequently, the primary and secondary structures of the molecule do not yet have the correct conformation and are too unstable to be recognized by the insulin receptor (5).

Now that we know that the monomer form of insulin's tertiary structure is the only version of the molecule that is biologically active, we can also look at what portion of the molecule is acutally involved in the activation of the recpetor. In the case of insulin it has several surface residues including Ser-A12, Leu-A13, Glu-A17, His-B10, Glu-B13, and Leu-B17 which are all responsible for binding the hormone to the receptor. Together, these residues are collectively known as the "primary binding surface" and are most important to the function and biological activity of the insulin hormone. The reason for this is that this is the portion of the molecule that actually interacts with and binds to the receptor. Thus, it is through these residues that insulin is able to interact with the cells and initiate the appropriate biochemical response. In this way, without this "primary binding surface", insulin would not be a biologically active molecule (5).

At the same time, we also know that there is an active insulin receptor for the insulin hormone. This receptor is a transmembrane protein with tyrosine kinase activity. It has two alpha and two beta subunits which are linked together by disulfide bonds. The alpha chains are completely extracellular and house the insulin binding domains. In other words, this is the part of the receptor that recognizes and binds the insulin hormone. Meanwhile, the beta chains pass through the membrane and the intracellular portion has tyrosine kinase activity. Through these tyrosine kinase domains, the beta subunits of the receptor are able to phosphorylate themselves (autophosphorylation) after the hormone binds to the alpha subunits of the receptor. This activates the receptor and initiates the corresponding biochemical response to the hormone within the cell. For instance, once active, the insulin receptor begins to phosphorylate a number of other proteins and enzymes within the cell through action of the tyrosine kinase. This alters the activity of these enzymes causing them to activate specific biochemical pathways which generates the desired response to the hormone (4).

Gene coding sequence for preproinsulin in humans:

1 agccctccag gacaggctgc atcagaagag gccatcaagc agatcactgt ccttctgcca
61 tggccctgtg gatgcgcctc ctgcccctgc tggcgctgct ggccctctgg ggacctgacc
121 cagccgcagc ctttgtgaac caacacctgt gcggctcaca cctggtggaa gctctctacc
181 tagtgtgcgg ggaacgaggc ttcttctaca cacccaagac ccgccgggag gcagaggacc
241 tgcaggtggg gcaggtggag ctgggcgggg gccctggtgc aggcagcctg cagcccttgg
301 ccctggaggg gtccctgcag aagcgtggca ttgtggaaca atgctgtacc agcatctgct
361 ccctctacca gctggagaac tactgcaact agacgcagcc cgcaggcagc cccacacccg
421 ccgcctcctg caccgagaga gatggaataa agcccttgaa ccagcaaaa

Comparative analysis of the protein sequences of preproinsulin in homo sapiens (humans), rattus losea (rats), and felis catus (cats):

*From this analysis one can see that the amino acid sequences for insulin is highly conserved among vertebrate species.


References:

1) http://en.wikipedia.org/wiki/Insulin
2) http://www.biotopics.co.uk/as/insulinproteinstructure.html
3) http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/pancreas/insulin_struct.html
4) http://en.wikipedia.org/wiki/Insulin_receptor
5) http://images.google.ca/imgres?imgurl=http://www.betacell.org/images/CMS/structure-insulin-panel3-th.jpg&imgrefurl=http://www.betacell.org/content/articles/print.php%3Faid%3D8&h=536&w=500&sz=50&hl=en&start=2&tbnid=Na2M8_NNQxwKDM:&tbnh=132&tbnw=123&prev=/images%3Fq%3Dinsulin%2Breceptor%26svnum%3D10%26hl%3Den
6) http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/pancreas/insulin.html
7) http://www.betacell.org/content/articles/print.php?aid=1

Insulin

In the early 1920’s Frederick Banting with the help of Charles Best was able to both discover and isolate a pure form of the hormone insulin. In fact, by the late 1920’s insulin was recognized as the first hormone ever discovered which earned Banting a Nobel Prize. Since then, many other hormones have been discovered which have all been determined to have their own specific roles in regulating different components of the human body. When combined, these hormones all work together to keep the body in homeostasis by responding to changes that may occur within the body or the surrounding environment. Upon recognizing a change (stimulus), the body is capable of releasing various hormones which initiate the appropriate response necessary to correct the change and bring the conditions within the body back to normal levels.

Insulin is one of many endocrine hormones found throughout the human body. An endocrine hormone is a chemical or protein (peptide) that is secreted by an endocrine tissue directly into the blood stream. Once it has entered the blood, the hormone is then carried by both blood and tissue fluids to the specific target cells that it acts upon. The specific endocrine tissues that secrete insulin are the bundles of cells found within the pancreas known as the islets of Langerhans. Even though the pancreas is mainly an exocrine gland, it contains millions of these islets which actually have an endocrine function. The islets of Langerhans are composed of four different types of cells including beta cells, alpha cells, delta cells, and gamma cells. However, it is only the beta cells that are capable of both synthesizing and secreting insulin.

It is within the beta cells that insulin is synthesized from its precursor molecule, proinsulin. The way in which this is accomplished is that inside a beta cell, proinsulin can be converted to insulin through the action of the proteolytic enzymes PC1 and PC2 (prohormone convertases) and the exoprotease, carboxypeptidase E. For instance, in the formation of insulin, the PC1 and PC2 enzymes remove the center portion (C-peptide) of the proinsulin molecule by cleaving it from the carboxyl and amino terminals of the polypeptide. The two remaining polypeptide chains, the alpha and beta chains are then bound together by disulfide bonds through the work of the carboxypeptidase E enzyme. The resulting molecule is the hormone known as insulin which can readily be secreted by the beta cells when it is needed by the body. In its final form, the insulin hormone that is secreted into the blood stream is a small protein (polypeptide) consisting of an alpha (21 amino acids) and beta (30 amino acids) chain. These two chains are connected by two disulfide bridges which yield a protein with a total of 51 amino acids.

The main function of insulin is to regulate carbohydrate metabolism within the body. More specifically, it regulates the levels of glucose in the blood as all sugars are converted to some form of glucose upon entering the body. Insulin’s role in regulating blood glucose levels is to ensure that they do not get too high. Thus, insulin is secreted by the beta cells in a normal person when the body recognizes that there are high levels of glucose in the blood. The way in which the beta cells (body) is able to recognize high blood sugar levels is that the plasma membrane of beta cells have special channels that serve as glucose detectors. When these “detectors” recognize that blood sugar levels are higher than normal, they signal the beta cells to release insulin into the blood stream. Once in the blood stream, insulin is able to return blood glucose to normal levels by initiating several responses in the body which aid in removing glucose from the blood. It does this by acting on many of the bodies organs which all remove glucose from the blood in a similar fashion.

For instance, one of insulin’s many target tissues are skeletal muscle fibers. Here, it can either stimulate the uptake of glucose and convert it into glycogen or stimulate the uptake of amino acids and convert them into protein. Both actions result in the removal of glucose form the blood stream. At the same time, insulin also acts on liver cells where it triggers a variety of responses to remove glucose from the blood. Firstly, it can stimulate the liver cells to uptake glucose and convert it into glycogen. Secondly, it can inhibit the production of the enzymes in liver cells which are involved in glycogen breakdown (glycogenolysis). Lastly, it is can inhibit gluconeogenesis which is responsible for converting fats and proteins into glucose. Next, insulin also has a direct effect on adipose (fat) cells where it stimulates the uptake of glucose in order to synthesize fat. Meanwhile, the final tissue that insulin acts on is the hypothalamus where it reduces appetite which reduces the amount of glucose ingested by the body.

The way in which insulin is able to trigger such responses at all of these sites is that all of the target tissues contain insulin receptors. These are generally transmembrane proteins that are embedded in the plasma membrane of the responding cells. These receptors are capable of both recognizing and binding insulin. Once insulin binds to its receptor, it creates a hormone-receptor complex which initiates the appropriate response in each of the target tissues. In this case, all of the actions induced by insulin are very efficient means of lowering blood glucose levels. In most cases, it does this by converting soluble nutrients absorbed by the small intestine into their storable forms which are usually insoluble energy-rich products such as glycogen, protein, and fat.

References:

http://nobelprize.org/nobel_prizes/medicine/laureates/1923/banting-bio.html
http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/P/Pancreas.html
http://en.wikipedia.org/wiki/Insulin
http://www.discoveryofinsulin.com/Home.htm
http://www.endocrineweb.com/diabetes/2insulin.html