While the jury is still out on whether diabetes is one disease or a spectrum of metabolic disorders, clinicians mostly encounter cases classified as Type I (where the body’s immune cells attack the pancreatic insulin-producing cells) and Type II (where the pancreatic cells fail to recognize and utilize insulin). Thanks to multi-national collaborative efforts we now have fairly good knowledge of how either of these types’ manifests, their symptoms and some methods of management. However, it is imperative that we find a more permanent solution to cure the disease.
While Type II is dubbed as a lifestyle disease which can be monitored, managed and reversed in some cases with a specific diet, exercise, and minimal medication, it is the Type I which is seen in children and younger people, although with prevalence lower than Type II. It causes severe disruption and affects the patients’ quality of life due to their dependence on insulin injections and the risk of hypoglycemia, making a cure much needed to help these patients reclaim their lives.
The scientific community across the world contributed immensely to our understanding of the etiology of the disorder in the 60s and 70s. The 80s and 90s were instrumental in the identification of insulin, glucagon and the recombinant production of insulin for sub-cutaneous administration. Recent research has focused mainly on understanding the way pancreas can be remodeled to improve insulin production and/or its utilization. It has also improved monitoring and management of diabetes with the use of non-invasive and wearable technology. Listed below are some of the recent advances in diabetes research.
Smart insulin- The major drawback of Type I is the dependence on regular external doses of insulin. While technology has made it more and more manageable with insulin pens, it results in the patient’s life to be largely centered around their medication. In 2015, researchers at the University of North Carolina devised a glucose-monitoring, insulin-delivery system using nanotechnology and biomedical engineering. The smart insulin patch consists of an array of tiny needles which can be used anywhere on the body to detect glucose levels and release insulin accordingly. The technology is currently undergoing revision and pre-clinical testing.
Islet transplant- Recovering healthy pancreas from cadavers and transplanting islet cells into the liver of the patient is an experimental procedure in practice since 2008 to assist with Type I. However, the success rate of this intervention is low due to rejection by the patient’s immune system and dependence on immune-suppressants which increase the risk of infection. It also does not completely reverse the patient’s insulin-dependence and requires regular low doses of insulin. A variation of this therapy at the University of Miami in 2017 was a successful transplant of pancreatic islet cells into the stomach lining of the patient which resulted in her complete remission from Type I and independence from constant insulin injections.
Stem cell therapy- With the evolution of cell biology techniques, we now have the ability to program immature cells to develop into a specific lineage of cells. Viacyte, a California based biomedical engineered a direct delivery device in April 2017, which when placed under the skin delivers stem cells into the bloodstream. These stem cells are programmed to home into the pancreas and develop into mature insulin-producing cells to replace those eliminated by the immune system. While this device is still in its nascent stages of the trial, it would be a life-saver for patients with highly variable glucose levels and severe risk of hypoglycemia.
Immature beta cells- Another variation of the stem cell therapy may be derived from our ability to now image the pancreatic tissue at unprecedented resolution. Scientists from the University of California, Davis identified an immature population of beta cells which can produce insulin but, unlike mature beta cells, are unaffected by the presence of glucose in the blood since they do not have glucose receptors. This discovery could lead to a deeper understanding of how beta cells function, and these immature cells can be manipulated to produce more insulin to keep the glucose levels in check. In February 2018, researchers at the University of Miami identified the exact anatomical location of pancreatic stem cells which can be stimulated to be glucose-responsive insulin-producing cells. Subsequently, University of California, San Francisco reported that beta cells can be ‘trained’ to adapt to a deficiency in oxygen and nutrients due to exposure before and during the transplantation, ideally ensuring an endless supply of insulin-producing beta cells.
IgM immunotherapy- The antibody IgM has been used as a diagnostic marker for Type I since the early 2000s. A team of researchers at the University of Virginia have found a new role for IgM as a vaccine against Type I autoimmunity. Injecting human IgM into diabetic mice resulted in a reduction of autoimmune reactivity, restoration of the balance of cells in the pancreas and reversal of Type I.
Methyldopa- This is a classic case of serendipity in science. Methyldopa is a clinically approved drug to treat hypertension. Scientists at the University of Colorado and the University of Florida screened all FDA-approved small molecules to check if any of them could prevent the autoimmune pathway of Type I from getting activated and Methyldopa was a successful candidate. After successful experiments on mice and a pilot clinical study, the drug can be developed as a vaccine to prevent Type I in those at risk.
Vaccines- Enteroviral infections are known to cause Type I in newborns by triggering an autoimmune response against islet beta cells. At the University of Finland, scientists have developed a vaccine that can potentially eliminate enteroviruses and thus prevent Type I. Another common vaccine B.C.G. used routinely against tuberculosis has been used by doctors at the Massachusetts General Hospital as a vaccine against Type I. They have been successful in a pilot clinical trial by reducing the insulin dosage to one-third of the patient’s initial requirement even after 5-10 years of the vaccination.
The DiRECT study from the Newcastle University, the UK with 300 diabetics aged 20-65 demonstrated that a severely calorie-restricted diet can result in remission of Type II in around 86% of the patients. This is a very promising result since there is a rapid increase in obesity and Type II. A strict weight loss intervention may be a means of both prevention and cure of Type II diabetes. Interestingly, Lorcaserin, a weight loss drug was reported by Harvard University to reduce the incidence of diabetes and the risk of hypoglycemia in patients being treated for obesity. This is supported by multiple recent findings from the neurobiology community that obesity results in activation of the microglia cells in the brain and results in impaired modulation of hormones and increased glucose levels or resistance to insulin and hence treating obesity would also reduce the likelihood of an array of metabolic disorders.
Wearable technology has translated to better diagnostic and monitoring devices for diabetes. We have had home kits for monitoring blood glucose levels since 1981, but almost all variants require blood by pricking the finger with a lancet. A proof-of-concept study in South Korea of a wearable glucose monitor in the form of contact lenses has been successfully tested in rabbits. The silicon lens has an outward facing LED which is switched off in response to high levels of glucose in the tears as detected by a sensitive nano-sized glucose monitor. While this technology needs more work before it can be available for humans, it is a step in the direction of real-time, non-invasive glucose monitoring. Another variant of the wearable monitor is a color-changing tattoo ink with liquid biosensors developed by MIT and Harvard Medical School which can detect changes in the glucose levels, pH or salt in the interstitial fluid between the cells. This study is currently in research mode with no plans for clinical trials. However, the possibility of using the human skin as an interactive display for physiological monitoring is extremely attractive for developing non-invasive diabetes management products as is the case with an armband that can monitor the glucose in sweat via an ionic sensor. The simple bioengineered product from the University of California, Berkeley is primed for continuous monitoring of not just glucose, but also sodium, potassium, body temperature and other physiological parameters with a fully integrated electronic system that can log and update the data into a mobile device, making non-invasive continuous monitoring a possibility.
The Mexican cavefish has been established as a new model organism for studying diabetes. It’s a blind fish that lives deep in the sea with no access to light and food for long periods of time. It has evolved to survive these harsh conditions by having an insatiable appetite and insulin receptors which do not respond in the presence of high blood sugar. As a result, the cavefish is severely diabetic but can function normally. While this physiological make-up is fatal to humans, understanding the function of the glucose regulation in cavefish may be vital to developing novel therapies for diabetes management and cure.
With medical technology advancing fast, we may be looking at a future with the potential to decrease healthcare costs worldwide to deal with diabetes in its diagnosis, management, and prevention.
Sahana Shankar is a Ph.D. candidate in Structural and Molecular Biology at Academia Sinica, Taiwan. When she is not extracting protein, she loves to travel, read and writes scicomm articles. Her passion is to translate the science in fascinating research papers in health and medicine into common parlance. She believes understanding the science behind the world around us is indispensable to our engagement with it. She has contributed to Brainwave, a children’s science magazine from the Amar Chitra Katha family and Newslaundry, an independent news portal.