Diabetes Mellitus type 1 is an autoimmune disease causing insufficient or complete lack of insulin production from the pancreas, which will negatively effect the sufferers blood glucose levels, over time leading to serious health problems1.The pancreas is a small gland located in the upper abdomen and in a healthy body should function as a part of the digestive and chemical messenger (endocrine) system. The gland has two purposes: excreting enzymes that aid digestion of food and producing a range of different hormones, each required to maintain the correct concentrations of glucose, sugar and salt in the blood2. The latter function includes but is not limited to the production of the hormones Insulin and Glucagon. Insulin is the hormone stored and released by Beta endocrine cells, located in structures known as the islets of langerhans inside the pancreas3.
The beta cells produce insulin in response to a spike in blood glucose level, most often due to food consumption and digestion. The hormone promotes the absorption of the excess glucose into cells for storage, thereby lowering overall glucose level in the blood. Glucagon is the hormone working to produce the opposite effects of insulin. It’s released by Alpha endocrine cells as a result of low blood glucose and therefore involves the stimulation of different sources to create additional glucose that will raise overall blood glucose content4. Those with type 1 diabetes will experience difficulty controlling these natural changes in glucose levels due to the pancreas inability to produce insulin. Unlike type 2 diabetes which is influenced by lifestyle and diet, type 1 is described as an autoimmune condition, meaning the immune system is responsible for incorrectly attacking the beta cells on the pancreas5 The exact reason for this attack is unknown and constantly theorised, though most often connected to genetics and considered to some extent a hereditary disease.
Management and RisksAn estimated 3.8 million people have type 1 and 2 diabetes in the UK, type 1 diabetes making up 10% of the number of diabetes cases. Without any form of treatment, the disease could have serious health complications. According to a Diabetes Prevalence model produced by the PHE and the NCVIN in 20166 1 in 4 people with diabetes are undiagnosed.
Extremely high glucose levels, known as hyperglycaemia, caused by undiagnosed or badly managed diabetes could cause damage to the sufferer’s blood vessels and circulatory system, leading to a heart attack or stoke. Poor circulation creates increased risk of foot ulcers and amputation in those with diabetes. Additionally, diabetic Retinopathy is an eye disease caused by damage to the blood vessels in the retina due to a high concentration of blood glucose7. Both of these complications can be prevented by frequent checkups. Current treatment of the condition involves insulin therapy, and consists of regular insulin injections, though there are some alternative administrative methods. With such a large population of those living with the disease, improving management methods and moving towards more permanent solutions could benefit the lives of many across the country.
Solution A Long-term solution currently in development and undergoing trial involves using molecular therapy to genetically engineer available cells in the body to replace the inactive pancreatic Beta cells. There are complications when carrying out a similar method of Beta cell replacement involving the transplantation of donor Beta cells, as the diabetic patients immune system will attack these insulin producing cells. These results caused significant doubt that the gene therapy method, which consists of a similar intention and outcome, would cause the same inflammation reaction from the immune system. However, the Research was successfully carried out at the University of Pittsburgh School of Medicine8 in which both toxin-induced diabetic mice and NOB (non obese diabetic: used as an animal model for type 1 diabetes) were tested on. The subjects were either treated with an empty virus that would show no effect or the engineered therapeutic virus responsible for reprogramming the alpha cells9. The therapeutic virus constructed is described as an adenoviral vector (or AAV – adeno-associated viral vector) carrying the transcription factors Pdx1, Neurog3 and Mafa.
The vector was injected into the mice to induce targeted cells to express genes for beta-cell insulin producing function10. Several cell types from different areas of the body are thought to be capable of conversion into Beta cells, though for many cells their exact reprogramming potential remains undetermined. For example, researchers have recently began investigation into altering liver cells, know as hepatocytes, which was found to be successful in responding to the transcription factors, producing insulin and controlling blood glucose, however, high, hyperglycaemic blood glucose was found to quickly return11. In order to produce more successful, long-term results, the diabetic mice study used pancreatic ductal Alpha cells which are more appropriate for reprogramming as they are in high frequency, located in the pancreas and resemble beta cells.
The virus was therefore injected into the pancreatic, activating insulin production. The progress of the diabetes within the mice was observed following the initial alpha cells reprogramming. The results show blood glucose levels were maintained for four months, successfully responding and correcting natural changes12.