New Hope For Diabetes Patients?

Researchers have identified a signal pathway that could be involved in the occurrence of Type 2 diabetes. If it is deactivated, it may be possible to delay the illness by many years.

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.

New Family Of Antibacterial Agents Uncovered

As bacteria resistant to commonly used antibiotics continue to increase in number, scientists keep searching for new sources of drugs. One potential new bactericide has now been found in the tiny freshwater animal Hydra.

The protein identified by Joachim Grötzinger, Thomas Bosch and colleagues at the University of Kiel, hydramacin-1, is unusual (and also clinically valuable) as it shares virtually no similarity with any other known antibacterial proteins except for two antimicrobials found in another ancient animal, the leech.

Hydramacin proved to be extremely effective though; in a series of laboratory experiments, this protein could kill a wide range of both Gram-positive and Gram-negative bacteria, including clinically-isolated drug-resistant strains like Klebsiella oxytoca (a common cause of nosocomial infections). Hydramacin works by sticking to the bacterial surface, promoting the clumping of nearby bacteria, then disrupting the bacterial membrane.

Grötzinger and his team also determined the 3-D shape of hydramacin-1, which revealed that it most closely resembled a superfamily of proteins found in scorpion venom; within this large group, they propose that hydramacin and the two leech proteins are members of a newly designated family called the macins.

New Research Lights Up Chronic Bacterial Infection Inside Bone

A new report demonstrates how a sensitive imaging technique gives scientists the upper hand in seeking out bacteria in chronic infections.Listeria monocytogenes is a type of pathogenic bacteria that can cause severe illness and death. Listeria outbreaks recently claimed twenty lives in Canada. Additionally, Listeria infection is the third most common cause of bacterial meningitis in newborns, and can cause abortion and stillbirth. When the infection is caught in time, treatment can be difficult and take weeks to clear with intravenous administration of antibiotics.

Therefore, in order to understand how this pathogen can be so elusive and difficult to treat, a research team from Stanford University School of Medicine studied mice infected with Listeria. Their report describes how they use a technique called in vivo bioluminescence to light up bacteria and allow them to see extremely tiny amounts of bacterial cells in living animals. Using this method, they found that small persistent patches of Listeria took up residence inside bone marrow in the mice. This is significant because it is thought that the bone marrow can act as a reservoir to the brain and spinal cord, potentially causing life-threatening infections, such as in bacterial meningitis in newborns.

Another interesting aspect of this study is due to the use of specially designed Listeria stains in treating cancer. Clinical trials are currently underway in which non-disease-causing strains of Listeria are administered to cancer patients to generate immune responses against tumors. The researchers thus also looked at these attenuated strains, and found that they too could be harbored in bone marrow. It is still unclear, however, if such bacterial persistence will increase or decrease therapeutic effects.

The report was written by Jonathan Hardy, Pauline Chu, and Christopher H. Contag of the Stanford University School of Medicine in California. The report is published in the January/February issue of a new research journal, Disease Models & Mechanisms (DMM), published by The Company of Biologists, a non-profit based in Cambridge, UK.