By: Felipe Flores
Diabetes has aroused great interest in public health experts, physicians, patients and researchers because of its many accompanying conditions and complications, including stroke, blindness, and limb loss (1). However, research is promising to find better forms of treatment, and even a cure. To understand all of this research, one should first understand the disease’s mode of action and current treatment.
Mechanism
Diabetes is characterized by prolonged periods of excessively high blood glucose levels associated with a deficiency of the hormone insulin. This hormone’s major role is to promote glucose absorption from the bloodstream to the cells to power their function. Since the 1930’s, diabetes has been categorized into two main types (2). Type 1 diabetes, often called ‘insulin-dependent’, is an autoimmune disease. T cells from the immune system that would normally defend the body from infection, start attacking and destroying the insulin-producing Beta cells in the pancreas.1 Without cells to produce the hormone, the patient becomes dependent on insulin injections/a pump. The causes of this autoimmune attack are unclear. As researcher Dr. Anna Moore from the MGH Martinos Center for Biomedical Imaging explains, “Research has found genes responsible for predisposition to the disease, and some environmental factors that could be related. I don’t think anybody could point out one factor that triggers the disease.”
On the other hand, a systematic resistance to insulin is known as type 2 diabetes. As Dr. Bruce Fischl, also a researcher from the MGH Martinos Center, clarifies, “It’s a whole different disease. With type 2 diabetes the body still produces essentially the same amount of insulin, but it’s less effective.” This is a direct consequence of malfunctioning insulin receptors on cells.
Symptoms
The body’s inability to regulate blood glucose concentration causes an array of complications. At an excessive concentration level, glucose becomes toxic and particularly harmful to small blood vessels. Accumulated damage could potentially lead to limb loss, blindness, kidney disease, and impairment to other organs where small blood vessels play a major role. In fact, “In 2010, about 60% of nontraumatic lower-limb amputations among people aged 20 years or older occurred in people with diagnosed diabetes, […] and diabetes was listed as the primary cause of kidney failure in 44% of all new cases in 2011” (1).
While amputations can be dramatic, diabetes is often subtle and insidious. Dr. Fischl explains: “From the day to day perspective, the disease is a burden for the patient. Often they cannot go longer than 30 minutes without thinking about their blood glucose, what food they’ve eaten, how much exercise they’ve done, when was their last insulin injection. It’s a disease that takes no vacation and that requires constant monitoring.”
Current Treatment Methods
Treatment varies depending on which type of diabetes the patient has. Type 2 diabetes generally corresponds to simpler treatment. Changing to a healthier diet, doing more exercise, losing excess weight, and oral medication are generally enough to control blood glucose. Physicians may also prescribe insulin injections. This type of diabetes represents a bigger public health challenge because it accounts for around 90% of diabetes cases, but has a more effective treatment (1) .Conversely, Type I Diabetes implies an underlying mysterious autoimmune attack and will always require an insulin supply, in addition to the aforementioned self-care practices. Treating and curing type 2 diabetes may be work and education for the patient, but curing type 1 diabetes is up to scientists.
Recalibration of Treatment: Modeling the Disease
Dr. Bruce Fischl has focused his research on “reducing average blood glucose, essentially reducing the complications of uncontrolled peaks of glucose.” As he explains, the normal human pancreas releases insulin in two time-frames. Basal insulin is the ‘background’ insulin produced to maintain normal body function, for cells to intake glucose throughout the day- more of a long-acting insulin due to its slow and continuous release into the bloodstream. On the other hand is bolus insulin, a fast-acting insulin released after meals to avoid excess food-borne glucose. The treatment of insulin-dependent patients tries to resemble the pancreas’ natural time-frame with injections or a pump. However, the time-scale of glucose absorption from food and the effect of insulin are different. Insulin is much slower,” Fischl says, “so even though the patient did everything right with their injections, there will be peaks of excess glucose in the blood for a couple hours after every meal, and that is what we are trying to reduce.” Through computational simulations, Dr. Fischl is looking to create better scheduling and programming for insulin pumps, so that the average glucose level is lower throughout the day, and glucose peaks after meals are not as high and harmful as they currently are. His team has received NIH grants and approval for clinical trials starting in March 2016 with the Joslin Diabetes Center.
Unveiling the Disease: Visual Observation of Diabetes
Dr. Anna Moore researches imaging techniques able to detect the autoimmune attack while there are still Beta cells. In one of her projects, Dr. Moore studies the accumulation of T cells in mice pancreases, a clear sign of an autoimmune attack, before the appearance of high blood glucose level. In humans, this means there is a span of up to 2-3 years between visual accumulation of T cells and the onset of diabetes. As she explains, “When there is an autoimmune attack, gaps appear on the network of blood vessels that irrigate Beta cells in the pancreas. We can then pass a contrast agent through the blood, and the gaps would cause the contrast to remain around damaged tissue instead of circulating through the bloodstream. You would see the agents accumulating in the pancreas on the MRI.” The potential in this research lies in its ability to observe diabetes before diabetic imbalance. That type 1 diabetes generally appears during childhood: when the symptoms show up there are too few cells to be salvaged. However, a patient with a family history of diabetes could start immunosuppression early.
The most difficult task of Dr. Moore’s project is imaging living Beta cells. It is extremely hard to find a Beta cell-specific agent, but this method has great overlap with currently applied approaches to a cure.
The Edmonton protocol is a surgical procedure that consists of implanting donor purified Beta cells into the patient’s liver (an organ rich in nutrients and friendly new home for the cells) (3). The operation has shown promising results, achieving an astonishing insulin independence for 80% of the patients three years after the procedure (4). Five years after the operation, however, the number of insulin independent patients drops to 10% (5). The cells die from a lack of nutrients from the procedure itself, and/or from the difficulty of adapting to a different environment. Because the beta cells are foreign to the body, the immune system attacks them. Patients undergo an immunosuppression regimen, but this is often insufficient. Dr. Moore’s contrast agents are able to chemically label the living beta cells from the procedure and track them. The results with mice were so promising that they are now moving forward to try it with baboons. “Our imaging techniques are a tool for other researchers to conduct experiments that would lead us closer to a cure,” says Dr. Moore. She envisions her imaging protocols being used for research on drugs that would prevent immune destruction of the cells, or new surgical procedures that would better allocate transplanted cells. The future of diabetes research, it seems, will rely heavily on imaging techniques such as Dr. Moore’s; in fact, stem cell transplantation uses them all the time.
Stem Cell Research
Scientists are able now to make insulin-producing cells from pluripotent stem cells. These unique cells can differentiate into multiple tissue types, thus capturing great interest from researchers. A study led by Dr. Doug Melton in Cell showed that under the right conditions, the function of stem-cell-derived Beta cells (sc-beta) is comparable to adult, normal cells, including their response to changes in glucose levels in the blood (6). Unfortunately, there remained the difficulty of protecting new cells from immune attack, for which Dr. Melton’s laboratory started working with Dr. Daniel Anderson and Robert Langer’s team at MIT. Several media regarded their invention as a possible cure to type 1 diabetes (7): they created and implanted polymer capsules in mice that effectively shield newly-transplanted sc-beta cells from autoimmune attack (8). When the team removed the capsules after 6 months, they still retained living and working cells. With no inflammatory response or other ill effects, the device has overcome immune attacks, and is approaching clinical trial stages.
Conclusion
The battle is far from over, but scientists are making important headway into treating diabetes. There are many ways to tackle a disease, from mechanistic cures to treating symptoms and increasing diagnosis rates. As exemplified by the studies in this article, researchers are working to attack diabetes from all possible angles in the hopes of one day finding a cure.
Felipe Flores ‘19 is a freshman in Hollis Hall.
WORKS CITED
[1] WHO Center for Disease Control and Prevention. National Diabetes Statistics Report. 2014.
[2] Mandal, Ananya. History of Diabetes. News Medical [Online], December 24, 2012. http://www.news-medical.net/health/History-of-Diabetes.aspx (accessed Feb. 3, 2016).
[3] Shapiro, J. et al. J. Med. New England. 2006, 355, 1318-30.
[4] Robertson. R.P. et al. Diabetes. 2010, 59,1285-1291.
[5] Ryan, E. et al. Diabetes, 2005, 54, 2060-2069.
[6] Melton, D. et al. Cell, 2014, 159, 428–439.
[7] Colen, B.D. Potential Diabetes Treatment Advances Device Shields Beta Cells From Immune System Attack. Harvard Gazette [Online], January 25, 2016. http://news.harvard.edu/gazette/story/2016/01/potential-diabetes-treatment-advances/ (accessed Mar. 10, 2016).
[8] Melton, D. et al. Nature, 2016, 22, 3, 306-311.