New Hope For Diabetes Patients? Signal Pathway Found That May Be Involved In Type 2 Diabetes

Diabetes, a metabolic disease, affects about 246 million people throughout the world, about a quarter of a million of them in Switzerland. Obesity and lack of exercise often play a decisive role in the illness. During his thesis work in collaboration with researchers from Oxford and the University of Lausanne, Jens Zehetner, a doctoral student with Wilhelm Krek, Professor at the Institute of Cell Biology of ETH Zurich, has identified one of the mechanisms that may play a part in diabetes. The study reveals that the signal pathway for the secretion of insulin is controlled by the pVHL and HIF1a genes, which are familiar from cancer research and are known to play an important role in growth and in the cell’s energy supply. Not only do the results help understand the origin of diabetes, the knowledge could also be used to combat the illness.

Signal pathway for insulin production

Wilhelm Krek explains that, “Cells need energy in the form of adenosine triphosphate (ATP), the cell’s energy currency, to enable them to maintain their functions. In a healthy person, the b-cells of the pancreas, which are responsible for insulin production, recognise when food is ingested. Sugar is burnt in the mitochondria of the b-cells by what is known as oxidative phosphorylation, producing ATP which, in turn, initiates insulin secretion in the b-cells. This stimulates the muscle cells, among others, to absorb sugar, thus regulating and normalising the level of sugar in the blood. Krek says that some diabetics may have an abnormality in this signal pathway. The plan now is to investigate this in a follow-up study.

Changeover to glycolysis

In their study of the pVHL and HIF1a genes, the scientists began by modifying mice genetically to end up with four kinds of mice with different gene combinations: those in which both genes were intact and those in which one, or the other, or both had been deactivated.

Under normal conditions with an adequate oxygen supply, HIF1a is constantly suppressed and destroyed by pVHL. However, if there is a shortage of oxygen, ATP cannot be formed in the mitochondria, which in turn activates HIF1a to enable the cells to produce the necessary ATP via glycolysis – independently of the mitochondria. The researchers now studied what happens in the b-cells if HIF1a is activated in mice.

Zehetner says, “Even when the amount of ATP produced was equal to that in “normal” mice, the insulin secretion profile in the animals without pVHL changed dramatically.” The secretion of insulin is increased at basal glucose levels but is less efficiently upon glucose stimulation. He says that this shows that the ATP production taking place in the mitochondria activates yet more factors – at present unknown – that are important in regulating the secretion of insulin. ATP production on its own is not enough.

Oxygen deficiency as the cause

In obese mice, the mass of the b-cells increases. This causes newly formed b-cells to have a worse blood supply at first, due to a lack of oxygen. Krek explains that, “Our hypothesis states that this oxygen deficiency is exactly what leads to activation of the suppressed HIF1a gene to keep the oxygen-starved cells alive.” The result is a changeover from a regulated, effective secretion of insulin to a physically increased but less efficient glucose-stimulated insulin secretion – the possible start of Type 2 diabetes. The illness becomes apparent when all the b-cells gradually die off through permanent overloading.

Gene deactivation as a therapy

Krek explains that “The study enabled us to show that pVHL and HIF1a play an important part in insulin secretion and that they are decisive in the strategy of ATP production.” One of the next steps will now be to utilise this knowledge in the form of a treatment for diabetes, although this has yet to be developed. If one were to be able to inactivate the HIF1a signal pathway in the b-cells of diabetes patients, it might be possible to delay the outbreak of the illness perhaps for many years. This is because experiments in mice whose HIF1a was inactivated showed that their insulin secretion was stimulated by the ATP formed in the mitochondria and functioned with no problems.