Selected Topics in Diabetes Research: A Guide to Undergraduate Study
Joeseph Manring
Southern Utah University
Capstone: Biology of Disease
September 23, 2016
Introduction
The distribution, cost, and severity of diabetes illustrates with clarity that the disease is of clinical interest. The following text is designed to function as a report of both medical and academic relevance. For referential benefit, it has been divided into three subsections: Diabetes Phenotypes & Diagnostic Methodology, Pathology & Effects of Unregulated Hyperglycemia, and Treatment Targets & Strategies. Further, each subsect has been edited to include topics that are not covered in typical pre-medical or biological studies, so that genuine interest can be cultivated amongst undergraduate readers. As a whole, this text is intended to serve as a topical reference for some of the interesting diagnostic, pathological, and current research subjects that surround diabetes.
Diabetes Phenotypes & Diagnostic Methodology
In opening, it is of value to generate a straightforward summary of the two major diabetes phenotypes. This is a good way for the reader to clarify what level of understanding they have with regards to each of the types of diabetes, and to sort out any holes one may have in their knowledge base before going forward. Type-1 diabetes is an autoimmune disease that destroys B-cells in the pancreas. B-cells are responsible for producing insulin, which signals cells throughout the body to absorb and store glucose from the blood. When the B-cells die, the body does not produce enough endogenous insulin and hyperglycemia results. In addition, the body begins to break down fats for energy because the cells are not getting enough sugar. The breakdown of fats releases ketone bodies into the bloodstream that can become very dangerous if they reach high concentrations. This condition is called ketoacidosis and can be fatal or extremely disruptive to normal body function. In type-2 diabetes, the body develops a resistance to its own insulin as a result of consistently high sugar levels and an excess release of sugars from the liver. This often takes place in cells by simply lowering the amount of insulin receptors available, so that they take up less sugar. This can cause similar issues to type-1 diabetes but type-2 is much more easily managed; diet change, and exercise are usually advised to minimize or reverse type-2 diabetes. In rare and chronic cases, diabetes type-2 can cause the B-cells in the pancreas to become overworked to the point of cell death, at which point it acts very similarly to type-1 and comes with the same level of increased severity.
Formal education as it pertains to diabetes is often limited to the two well known phenotypes. As a result of studying molecular biology, one should know that it is rarely the case that there are simple on and off switches to a condition and that instead there is more likely to be a spectrum of interactions that proceed in vivo. In fact, it has been established recently that there are over 50 different loci that participate in the expression of diabetic phenotypes and that the promoter regions typically associated with the classical types do in fact show intermediary structures (Ionescu-Tîrgovişte, 2015). For this reason a third distinct classification of diabetes has been proposed and designated as Intermediary Diabetes Mellitus (IDM). The justification in adding a third quantized definition of diabetes could be argued against however, simply because the genetic information that we now have demonstrates that our current view of the possible diabetic phenotypes is incomplete and may need to be restructured to more accurately reflect the spectrum of the disease. Indeed, genetic analysis shows that although the phenotypic similarities exist between type-1 and type-2 diabetes their genetic bases are radically different. Students of biology should expect this fact, as the molecular basis for each is in essence very dissimilar. In contrast, genetic analyses show that IDM is much more genetically related to type-2 diabetes than type-1 is. As the numerous loci that participate in generating diabetes are investigated, I expect that our understanding of the disease will expand and result in a need for a new classification system so that treatments may be more properly tailored to each patient.
There are quite a few ways to test if a patient has diabetes, but the effectiveness of each analysis can vary due to physiological factors such as expressing a genetic variant of hemoglobin. The least effective of these methods is to test the current blood sugar levels and test for deviation from what would be biologically expected. This has obvious issues, in that a single spike in blood sugar is not conclusive proof that the patient has diabetes (hormonal changes and pregnancy as examples, can cause irregular shifts in blood-glucose levels). The second issue, is that this test does not let the physician know the extent to which this individual is affected by the disease and because of this, a snapshot of a patient’s current blood-glucose concentration cannot be the only test performed in order to make a diagnosis. One of the tests that could supplement this is a test of the fasting state blood-glucose concentration. This is usually performed by having the patient fast overnight and then looking at the change in glucose concentration that results. If the glucose level drops too far we can confirm the presence of diabetes phenotype, as well as know the severity of the condition. Blood sugar stress-tests can be done in the other direction as well. A glucose tolerance test is performed by giving the patient a solution containing a high amount of sugars, and then the blood-glucose concentration is monitored for change. In this way we can actively observe the way that a patient’s body is handling sugars after they are consumed, and this can give clues as to which type of diabetes this individual has. Finally, we can differentiate clearly between diabetes type-1 and type-2 by checking the urine for ketone bodies, though it can be argued that this test does not look for diabetics who started as type-2 and progressed to type-1 prior to testing.
The A1C test for diabetes is the most informational, conclusive, and quantitative of the available testing methods. The A1C is used less frequently than the other methods, simply due to the rigor and time that is required in order to complete the entire diagnostic procedure. In essence, it monitors how much of the hemoglobin of an individual is glycosylated over a three month period of time and thus, provides a very clear depiction of the type of diabetes this individual has, their tolerance to sugars, the rate that the disease is progressing, and the current severity of their illness. The reason that this test is so long is because it must last long as, or longer than, the approximate lifespan of one red blood cell so that the vast majority of the blood cells in the body have been replaced during the span of the examination. As mentioned, since several variables can cause blood sugar concentration changes a snap-shot of the blood-glucose level provides very little valuable information. This is especially true because red blood cells, once glycosylated, will remain so until they die. Thus, a single or small period of irregularity in blood-glucose control can leave the level of glycosylated hemoglobin at an unexpected level until the cells are replaced. By observing a three month period of the blood-glucose concentrations, this variation can be accounted for and a better, more accurate, diagnosis can be completed.
Pathology & Effects of Unregulated Hyperglycemia
Diabetes causes many problems in the body, but sometimes we just accept that as the case and don’t question why certain parts of the body fail when a person is diabetic. We become very concerned about the phenotype, but not nearly as interested in the processes that generate it. I would like to look at some of the bodily interactions cause diabetic retinopathy. When glucose concentrations are high in the blood for a long time, damage occurs in blood vessels. In the eye, these blood vessels are incredibly small and sensitive to being damaged. In early stages of diabetic retinopathy blood vessels can rupture and leak, causing temporary mechanical obstruction of the retina. As fluids leak into the eye, there is a potential for macular edema to occur. Macular edema manifests as sudden vision loss in the patient, and is caused by the fluid and protein deposition beneath the macula of the eye. This swelling changes the position of eye structures slightly and causes visual distortion or loss. Luckily though, there are treatments for this and it is not typically permanent. In fact, this sometimes serves as a red flag that signals an individual that something is very wrong with them that requires the attention of a physician. Later into disease progression, the neurons that have not been getting enough blood due to capillary damages will begin to die. The longer the disease remains untreated, the greater extent of blood vessel damage and nerve death in the patient's eye. Eventually, this becomes permanent.
Diabetic foot is a condition often experienced by diabetics, and it typically ends in the eventual amputation of the affected limb. The condition follows a pattern that we have become familiar with when discussing diabetic patients: blood vessel death, neuropathy, and continued ischemia in the affected area. In the case of diabetic foot however, we also have to consider the added component of infection. The feet often receive low blood pressure from the heart because of their distance away (and in fact there are mechanisms in the legs that typically help with this) so when there is a vascular issue in the legs it is often exacerbated in the feet. This circulatory issue is defined as peripheral artery disease and in the case of diabetics, it is a condition of extreme concern because it greatly increases the risks that result in amputation. Specifically, this could be in the form of an initial foot ulcer that will often go on to require amputation (Pendsey, 2010). As a result of the nerves in the foot dying, the patient will often not notice when they are damaging it, which will sometimes provide an entry of infection. In addition, the foot becomes somewhat clumsier (more prone to being injured accidentally) and the muscles begin to be used in unnatural ways to compensate for the neuropathy, and deformity of the foot results. The damage progresses further and eventually the lowered circulation, infection that cannot be accessed by the immune system, foot deformity, ischemic damage, and neuropathic damage become far too advanced and the foot must be removed in order to preserve the health of the patient.
Charcot arthropathy is a strange condition associated with diabetes that is not as well understood as many other diabetic complications. The basis for the disease is that the body reabsorbs bone density from the foot and ankle, but there are preconditions that serve as risk factors for Charcot arthropathy. These include renal dysfunctions, neuropathy, and low bone density (Petrova, 2016). The bone becomes brittle or deformed slowly (sometimes occurring over decades) and the condition leads to eventual breakage, loss of function, infection, or a pressing need for amputation. In addition, the skin near to the joints will also become uncontrollably inflamed, such that the skin temperature about the inflammation site is actually one of the disease indicators. Often, Charcot arthropathy is diagnosed too late because the patient does not see the issue as a danger when it is in its early stages. The patient feels little or no pain because of the extensive nerve damage already present in the foot, so the condition is often addressed by a health professional when it is far too late in its progression. The outlook for patients with this disease is pretty poor and intervention is an absolute necessity if any semblance of disease arrest is going to take place.
Treatment for Charcot arthropathy is quite difficult and in most scenarios optimistic prospects only are achieved when the disease is confounded during its early stages. The first step in treatment is to cast the limb in order to prevent further damage by limiting weight born by the unhealthy extremity. This casting time can last anywhere from nine weeks to eleven months, depending on the level of reduction in swelling that takes place. Once the swelling has gone down, the bones are examined via MRI or other imaging methods to determine if the bones contain fractures and breaks. If the foot appears to be in (relatively) good health, the patient can begin using a shoe for a specified amount per day, and they can also begin taking medication to halt the loss of bone density. Interestingly, because these medications are designed to correct an imbalance between bone formation and absorption, if they are taken after fractures and breaks have been identified those damages heal more slowly than they would in the absence of medication. Finally, anabolic steroids can be used in order to to accelerate the healing process in these patients, but this treatment has thus far only been examined in very small pilot studies. That is not to say that this set of treatment methods is not of absolute value. Currently in the United States the methods most commonly used therapeutically for Charcot arthropathy are to take weight off of the foot and cast it. The medications available in the United Kingdom that seem to stabilize the bone formation and absorption are not yet approved by the FDA. For now, there is a lot of research being done concerning this horrifically severe condition, and hopefully we will have more effective treatments in the near future. Our current hope is that the disease is identified early, such that the damage can be limited and amputations become less frequent.
Treatment Targets & Strategies
Diabetic nephropathy is the term used to describe a kidney disease that is often caused by diabetes, and its symptoms manifest as the kidneys slowly lose functionality. In the earliest stages of this disease, the patient usually does not even notice any physical symptoms that would give them cause for concern. This is in part, a result of the slow progression of the disease, and is also due to the amazing efficiency of a healthy kidney. It takes a very long time for the kidney to have become damaged enough to become inefficient at its biological function, and at that junction the kidney is already in pretty poor health. As a result of this, the damage to the kidneys is often very severe by the time the disease is known and the patient may require hemodialysis or even a kidney transplant, in order for the them to survive. There are several proposed mechanisms for the molecular progression of the disease, but we are certain that the end result is blood vessel destruction in the glomeruli of the kidney. The glomeruli become damaged which causes them to become radically less efficient at filtering toxins from the blood because the permeability of the glomerular basement membrane changes. Toxins build up in the blood and abnormally high levels of proteins permeate into the urine. This condition is called proteinuria and is a common way of confirming that damage has occurred in the kidneys. Once a diagnosis has been established, treatment is relegated to simply managing the symptoms and limiting any future damage (blood-sugar management, or ACE inhibitors) to the kidneys in order to preserve their remaining functionality.
The immune system of an individual with diabetes type-1 will attack and destroy their B-cells and cause that person to be unable to produce insulin. Researchers have been successful, in the past, in inserting healthy cells into a host organism that expresses the diabetes type-1 phenotype (usually mice) but the cells always die because the immune system turns on them. More recently, researchers have been able to cause human embryonic stem cells to differentiate into B-cells and that’s pretty great, but it doesn’t solve the issue of the immune system destroying them. The group of researchers who induced this differentiation in the stem cells was looking for a way to limit the access of the immunological response in a way where it couldn’t identify and destroy the implanted cells, and the solution they found was quite clever. Previous research has shown that the immunological response can be delayed by encasing transplant cells in alginate gel, but that this gel will eventually permit entry to the immune cells and allow the transplant to fail. After testing several hundred molecular variations of alginate gel, they found one that could not be crossed by immune cells (Vegas, 2016). The researchers then took the differentiated stem cells and the alginate gel, and implanted them into a mouse with type-1 diabetes. The mouse almost immediately became able to regulate its own blood glucose concentration, and remained in control until they harvested the cells for examination, 174 days after implantation. More research is needed here, as the paper was only released March 2016, but the results look quite promising and we should look forward to reading about their research progression as they move on to primate tests.
The islets of Langerhans are small areas in the pancreas that have high densities of important cells, such as B-cells. As the B-cells are responsible for producing insulin, some physicians came to a realization that transplanting these islets from one patient to another could reduce or remove the effects of diabetes type-1 and allow the recipient patient to produce their own insulin again. Some scientists have gone a step further and suggested that these islet cells could come from the bodies of a deceased donor, in the same way that many organs are harvested for transplants. Both of these routes have been tested, and they both work, but they are not without their hurdles. One important barrier to the islet cell transplant procedure is that there are consequences to receiving cells from another person's body. The recipient’s immune system recognizes that the donor’s islet cells are foreign and, as it should, the body attacks and kills the perceived invader. In order for the transplant to have an appreciable success rate, the recipient will have to take immunosuppressants for the rest of their life so that their immune system does not attack the donor cells and cause the recipient to be once again, unable to produce insulin. For many people this might prove to be worth it, as diabetes absolutely destroys the body over several decades of time, and those harmful effects could be stopped in their tracks. Most patients who undergo islet transplantation will eventually end up completely insulin independent as long as they continue to take their immunosuppressants.
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Pendsey SP. Understanding diabetic foot. International Journal of Diabetes in Developing Countries. 2010;30(2):75-79. doi:10.4103/0973-3930.62596.
Petrova N, Edmonds M. Medical management of Charcot arthropathy. Diabetes, Obesity & Metabolism [serial online]. March 2013;15(3):193-197. Available from: Academic Search Premier, Ipswich, MA. Accessed September 16, 2016.
Vegas A, Veiseh O, Gurtler M. Long-term glycemic control using polymer-encapsulated human stem cell–derived beta cells in immune-competent mice. Nature Medicine. March 2016;22:306-311
