Type 1 diabetes, an autoimmune disease that typically emerges before the age of 20, wipes out the body’s ability to produce insulin–a hormone that’s essential to life. Diagnosis often comes after symptoms arise, at which point the disease has taken hold. But if there were a way to test at-risk patients for very early signs of the disease, it may be possible to delay its onset. Roughly 1.25 million American children and adults have type 1 diabetes, and the incidence rate is increasing for reasons that aren’t fully understood. In new research published in Science Immunology, scientists at Scripps Research have discovered what may be the earliest possible biological marker of type 1 diabetes, formerly known as juvenile diabetes. If their mouse study can be replicated in humans, which they are now attempting to do, the timing of therapeutic intervention may be drastically improved for patients who are on course to develop the disease. Luc Teyton, MD, PhD, professor of Immunology and Microbiology at Scripps Research, led the research. The scientific community has known for a long time–ever since a landmark genetic study of type 1 diabetes more than 25 years ago–that among people with type 1 diabetes, a distinct genetic signature is always present among a certain class of immune-regulating molecules known as HLAs (short for human leukocyte antigens). HLA proteins sit on the surface of cells, telling the immune system whether to attack. While this signaling is normally helpful in destroying dangerous cells, it can become life-threatening when the molecule is sending the wrong messages.
In the case of type 1 diabetes, the mutated HLA protein binds to fragments of insulin made by beta cells, prompting destruction by the immune system. While the connection between the HLA and type 1 diabetes is well-established, the scientific community could never discern the mode by which the immune system’s T cells are drawn to this molecule. That’s what Teyton’s team set out to answer through experiments spanning five years. Their work involved evaluating blood samples of non-obese diabetic mice during the very early phase of disease, using structural and computational biology techniques to understand how the cells bring about disease. The single-cell analysis they conducted had never been done before for these types of cells, unearthing new information. Working in concert with Scripps Research’s Department of Integrative Structural and Computational Biology, the team sequenced the DNA of individual T cells for an extremely high-resolution view of cell function and genetic variation. In all, the study produced more than 4 terabytes of data. Among their key findings was a structural mechanism they dubbed the “P9 switch” that allows CD4+ T cells to recognize the mutated HLA protein and attack beta cells. They also discovered that the dangerous anti-insulin T cells always reside in islets, which are small tissue structures in the pancreas where beta cells are located. Previously, it was not known where the anti-insulin T cells originated, and some suspected they may be produced in pancreatic lymph nodes.
Notably, the P9 switch drove an early burst of anti-insulin response in mice, then rapidly disappeared. If this phenomenon carries over to humans, immune cells equipped with the P9 switch would be detectable only in those who are in early stages of developing the disease. Thus, a blood test that reveals the presence of these cells could provide the earliest-possible indication of disease and enable intervention. Armed with this research, Teyton has received approval to move forward with a study in humans. His team will collect blood samples from up to 30 at-risk individuals per year and analyze the samples for precursors to disease. Type 1 diabetes has a strong genetic link; those who have an immediate relative with disease are up to 20 times more likely than the general population to get it themselves, making this a well-defined group to monitor for biomarkers. An early diagnosis during the five years of pre-clinical progression and the ability to monitor beta cell destruction in real time, will allow a series of new therapeutic interventions aimed at preventing type 1 diabetes and insulin dependence. But there is another question linked to diabetes: why do people with type 1 or type 2 diabetes have an increased risk of developing some forms of cancer? Today, researchers report a possible explanation for this double whammy. They found that DNA sustains more damage and gets fixed less often when blood sugar levels are high, compared to when blood sugar is at a normal, healthy level, thereby increasing one’s cancer risk. The researchers will present their results at the American Chemical Society (ACS) Fall 2019 National Meeting & Exposition. ACS, the world’s largest scientific society, is holding the meeting here through Thursday. It features more than 9,500 presentations on a wide range of science topics.
In addition to controlling blood glucose levels, the hormone insulin can stimulate cell growth, possibly leading to cancer. Also, most people with type 2 diabetes are overweight, and their excess fat tissue produces higher levels of adipokines than those at a healthy weight. These hormones promote chronic inflammation, which is linked to cancer. The most common idea is that the increased cancer risk has to do with hormones. That’s probably part of it, but there hasn’t been a lot of solid evidence. This is why Joe Termini, PhD and study leader, had a different hypothesis. He wondered if the elevated blood glucose levels seen in diabetes could harm DNA, making the genome unstable, which could lead to cancer. So Termini and colleagues looked for a specific type of damage in the form of chemically modified DNA bases, known as base adducts, in tissue culture and rodent models of diabetes. Indeed, they found a DNA adduct, called N2-(1-carboxyethyl)-2′-deoxyguanosine, or CEdG, that occurred more frequently in the diabetic models than in normal cells or mice. What’s more, high glucose levels interfered with the cells’ process for fixing it. Therefore, exposure to high glucose levels leads to both DNA adducts and the suppression of their repair, which in combination could cause genome instability and cancer, Recently, Termini and colleagues completed a clinical study that measured the levels of CEdG, as well as its counterpart in RNA (CEG), in people with type 2 diabetes.
As in mice, people with diabetes had significantly higher levels of both CEdG and CEG than people without the disease. But the team didn’t stop there. They wanted to determine the molecular reasons why the adducts weren’t being fixed properly by the cells. They identified two proteins that appear to be involved: the transcription factor HIF1α and the signaling protein mTORC1, which both show less activity in diabetes. HIF1α activates several genes involved in DNA repair process and it becomes stabilized in a high-glucose environment, that increases DNA repair and reduce DNA damage. And mTORC1 actually controls HIF1α, so if one stimulate mTORC1, you stimulate HIF1α as well. Since drugs that activate HIF1α or mTORC1 are already available, the team will now investigate whether their administration decreases cancer risk in animal models of diabetes. If so, the researchers will test the drugs in humans. Termini also points out that the commonly used diabetes drug metformin, which lowers blood sugar levels, also promotes DNA repair. Meanwhile, it is possible that a more immediate way for people with diabetes to lower their risk for cancer could be to better control their blood sugar level. Termini acknowledges that although this may sound like a simple solution, it’s extremely difficult for most people to maintain glycemic control, despite accuracy, discipline and strict observance of the daily therapy. The reasons have been recently published by another research team, and involve the metabolism of fats (lipids).
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Hladik D et al. Stem Cell Res Therap. 2019;10(1):218.
Shuck SC et al. Chem Res Toxicol. 2018;31(2):105-15.
Jaramillo R et al. Chem Res Toxicol. 2017;30(2):689-98.
Caramori ML et al. J Clin Endocr Metab. 2015; 100(6):E883.
Tamae D et al. Biochemistry. 2011 Mar; 50(12):2321-29.