Professor Mike McGuckin's research found that the IL-22 cytokine protects the insulin-producing beta cells in the pancreas from stress, to restore natural control of blood glucose in type 2 diabetes.
|Head Researcher||Professor Mike McGuckin|
Dr Sumaira Hasnain
|Equipment Used||Biological drug|
|Process Used||Administration of biological drug to treat diabetes|
|Research Areas||Metabolism, Endocrinology, Immunology, Inflammation|
|Disease||Type 2 diabetes|
|Tags||Cytokines, insulin, beta cell, IL-22, oxidative and ER stress|
|Commercial Partnerships||Confidential collaboration with major industry partner|
Inadequate insulin production in type 2 diabetes, the form of diabetes often associated with obesity, which affects around 1.7 million Australians, occurs because the beta cells become stressed. This stress is due to increased demand on the cells to make insulin, and high levels of fats and glucose in the blood.
Previous research has shown that proteins from immune cells called cytokines that are released into the environment around the beta cells in diabetes, also contribute to stress. Professor McGuckin’s research identified new stress-causing cytokines and shows that blocking them partially improves control of blood glucose, offering several new targets for therapy. But their major finding was the discovery of a specific cytokine, known as IL-22, that protects beta cells from stress and completely restores control of blood sugar when given to mice with obesity and diabetes.
One of the major challenges was to determine how IL-22 blocks stress in beta cells. Beta cells are clustered in groups within the pancreas, known as the islets of Langerhans islets. And the average human pancreas contains several hundred thousand such islets, each of which contains around 200 beta cells. Every beta cell makes about one million molecules of insulin every minute, which means a healthy human needs to make a lot of insulin to adequately control blood glucose. The major form of stress for beta cells in diabetes is oxidative stress, a condition where reactive oxygen molecules are generated within a cell. Oxidative stress interferes with cellular metabolism, and activates the immune system.
Importantly for diabetes, oxidative stress interferes with the correct assembly of proteins (such as insulin) into their appropriate structures within a specialised organelle, the endoplasmic reticulum. Stress in the endoplasmic reticulum reduces production of insulin, alerts the immune system and can even trigger suicide of beta cells. IL-22 blocks these processes at their very start by preventing the generation of oxidative stress, which explains its effectiveness against a broad range of stress inducers. It turns off genes that encode proteins causing stress while turning on genes that encode antioxidant proteins, which dispose of the activated oxygen radicals. In other words, IL-22 is a powerful natural antioxidant for beta cells.
There are many different forms of treatment used currently for type 2 diabetes. Some of them push beta cells harder to make more insulin, while others use approaches unrelated to the pancreas, such as reducing glucose production in the liver or increasing glucose excretion in urine.
Although they lower blood glucose, these treatments don’t really address the underlying problem. And about 40% of type 2 diabetics become dependent on injecting themselves with insulin to deal with the surges in blood glucose that occur after meals.
Administering IL-22 is a completely different approach and one that promises to reduce glucose while preserving beta cells and limiting disease progression. The attraction of this therapy is that it addresses the underlying basis for the disease; IL-22 allows the system to naturally control glucose by fostering production of good quality, effective insulin.
Another key characteristic of diabetes is diminished response to insulin of cells in the muscles, fat, and liver that remove glucose from blood. Professor McGuckin found treatment of mice with IL-22 not only restored appropriate insulin release from the pancreas, but also led to restoration of normal insulin sensitivity.
His research has been conducted in cultured cells or in mice with diabetes, but it does have implications for treatment of human disease.
In collaboration with a group from Melbourne, Professor McGuckin obtained human pancreatic islets from organ donors and has shown that IL-22 also protects human beta cells from stress. While this supports the applicability of therapy to human diabetes, there is more research needed to translate IL-22 into an effective and safe therapy in humans.
Interestingly, IL-22 treatment caused weight loss in obese mice by mechanisms not yet fully understood. Needless to say this would be a desirable effect if it were replicated in overweight individuals with diabetes. We hope our discovery will foster new approaches to diabetes therapy that reduce morbidity and ease the burden of the disease.
This translational project emerged from basic research in Professor McGuckin’s laboratory that uncovered a previously unrecognised natural regulatory pathway, and then applied that knowledge to test its applicability to treatment in preclinical models of diabetes, demonstrating remarkable efficacy. The team has published this work in a major journal (Nature Medicine) and patented applications of the discovery for the treatment of diabetes. The team is now working with a pharmaceutical industry partner to provide further proof of efficacy and safety before clinical trials can commence.
Professor Mike McGuckin