Breakthrough In Understanding Development Of Type 1 Diabetes

Finnish scientists have reported a breakthrough in understanding the development of type 1 diabetes. They discovered disturbances in lipid and amino acid metabolism in children who later progressed to type 1 diabetes, also known as juvenile diabetes. The alterations preceded the autoimmune response by months to years. The study may prompt new approaches for prediction and prevention of type 1 diabetes in pre-autoimmune phase of the disease.

The results of the Finnish research team, which consists of scientists from VTT Technical Research Centre of Finland and the Universities of Turku, Oulu and Tampere, have been published on 15 December 2008, in the Journal of Experimental Medicine.

Type 1 diabetes is an autoimmune disease in which the immune system attacks the insulin producing pancreatic beta cells. The gradual loss of beta cells results in life-long dependence on exogenous insulin.

At the moment, the earliest identifiable process in the pathogenesis of type 1 diabetes has been the development of autoimmunity to pancreatic beta cells in the measurable form of islet autoantibodies. Although the autoimmunity usually precedes the clinical disease by months to years, its occurrence may already be too late for therapeutic approaches aimed at preventing progression to overt diabetes. The initiators of the autoimmune response have remained unknown and the mechanisms supporting progression towards beta cell failure have been poorly understood, making discovery of effective prevention a challenge. The results of the SYSDIPP project, which was supported by the Tekes FinnWell Program, bring significant new information for combating the disease.

The SYSDIPP project has made use of metabolomics. Metabolomics systematically studies the chemical fingerprints in cells, tissues and biofluids in a given physiological and environmental context. The metabolic phenotype is sensitive to subtle factors such as age, lifestyle, nutrition and the microbe environment of the intestines. Changes in the concentrations of metabolites may thus reflect both genetic and environmental factors influencing later susceptibility to chronic diseases.

In 1994, an ongoing birth cohort study (DIPP, the Type 1 Diabetes Prediction and Prevention study) was launched in Finland, supported by the Juvenile Diabetes Research Foundation International. Over a period of 14 years, more than 130,000 newborn infants have been screened for genetic risk and over 8000 at-risk children are being regularly followed.

The research team was led by Prof. Matej Orešič from VTT Technical Research Centre of Finland and Prof. Olli Simell from University of Turku. Also Professors Mikael Knip, Jorma Ilonen, and Riitta Lahesmaa together with Dr. Riitta Veijola and Dr.Tuula Simell took part in the study, which investigated metabolic profiles of DIPP children prospectively from birth. The research team has published the results in The Journal of Experimental Medicine on 15 December 2008. The article reports the discovery of metabolic disturbances that precede the autoimmune response in children who later progress to type 1 diabetes.

The investigators found that the individuals who developed diabetes had reduced serum levels of succinic acid and phosphatidylcholine at birth, reduced levels of triglycerides and antioxidant ether phospholipids throughout the follow-up and increased levels of proinflammatory lysophosphatidylcholines several months prior to autoimmunity to pancreatic beta cells. The metabolic profile was partially normalized following the autoimmune response, suggesting autoimmunity may be a relatively late physiological response to the early metabolic disturbances. The observed lipid changes were not attributable to HLA-associated genetic risk.

Metabolic profiling at early age may therefore aid in determining the risk of type 1 diabetes. The reported findings imply that metabolic or immunomodulatory interventions during the pre-autoimmune period may be used as a new potential strategy for prevention of type 1 diabetes.

The incidence of type 1 diabetes among children and adolescents has increased markedly in the Western countries during recent decades. The incidence has reached record levels in Finland, where currently 1 child out of 120 develops type 1 diabetes before the age of 15 years. The annual incidence is increasing at accelerated rate, with the number of new cases expected to double in the next 15 years.

Biologist Modifies Theory Of Cells' Engines

Biologists have known for decades that cells use tiny molecular motors to move chromosomes, mitochondria, and many other organelles within the cell, but no one has been able to understand what "steers" these engines to their destinations. Now, researchers at the University of Rochester have shed new light on how cells accomplish this feat, and the results may eventually lead to new approaches to fighting pathogens and neurological diseases.

Michael Welte, associate professor of biology, shows in a paper published in the December 11 issue of Cell that the mechanisms that control the molecular motors are quite different from what biologists have previously believed. Before these findings, scientists assumed that the number of motors attached to an organelle determined how far and fast the organelle could travel, but Welte and colleagues have discovered that it is not the number of motors, but yet-to-be-discovered molecules that are likely the master regulators.

"The fact that motor number has nothing to do with regulating transport is extremely surprising, and somewhat unsettling to people working in vitro," says Welte. "It says we're really missing something when we study these motors only in the test tube instead of in a living cell."

Intracellular transport is crucial to a cell's health, says Welte. For instance, during cell division, one copy of each of the cell's chromosomes migrates to one side of the cell while the other copy moves to the other side. If this movement is disturbed, it could cause an imbalance of chromosomes in the daughter cells, which might die or become cancerous. Similarly, neurons, some of which are as much as three feet in length, manufacture proteins and organelles at one end and then must move that precious cargo all the way to the far end where they'll be used. This is an enormous task, says Welte, and defects in this transport are thought to cause a number of neurological diseases.

Given the difficulty of investigating these tiny motors acting within the cell, biologists have performed basic experiments on them outside of the cell in a carefully controlled environment. This led them to believe that the speed and distance an organelle could be transported depended on how many motors were pulling it, says Welte. Thus, the scientists reasoned, perhaps the cell simply attaches the right number of motors to an organelle to send it the right distance. Although this "multi-motor" hypothesis is very simple and elegant, says Welte, whether it actually holds true within living cells had never been tested.

Welte's graduate student, Susan Tran, decided to perform that test. She created fruit-fly eggs lacking a type of molecular motor called kinesin and found that certain organelles stopped moving—strong evidence that kinesin is responsible for their transport. Tran then made another type of mutant eggs, this time ones that produced only about half the number of kinesin motors of a regular egg. In both types of eggs, organelles were transported with the same speed and the same distance.

Welte needed to know if this equality was because the normal egg was simply utilizing only half the available kinesin motors, or if some master regulator was controlling the organelle's progress, regardless of the number of motors moving it. To do this, Welte turned to Steven Gross, associate professor of developmental and cell biology at the University of California. Gross' group uses an apparatus called "optical tweezers" that employs laser light to measure the tiny forces the motors generate. The team found that organelles in regular cells are pulled with twice the force of Tran's mutant, low-kinesin cells.

"That clinched it for us," says Welte. "Yes, there are multiple motors moving organelles around, but exactly how many doesn't matter. There is something else in the cell that's controlling all the motors. That opens up a big area for research—find what's driving these motors and maybe we can control them all by controlling one thing."

Welte and his team are now looking at where in the cell this signal comes from and how it influence the motors. Although Welte's team studied fruit fly eggs, the motors moving the organelles are present in all animals and employed for many tasks, including transport in human neurons.

Welte also points out that viruses, including HIV, make use of the same kind of motors to move about the cell, first to get from the site of penetration to the nucleus, where they multiply, and then to get progeny viruses back to the cell surface. If Welte and others can figure out how cells normally control these motors, it may be possible to prevent HIV from taking control of the motors and thus to keep it, and other intracellular pathogens, at the edge of the cell where they can do little harm.

This research was funded by the National Institutes of Health, and includes researchers from the University of Rochester, the University of California Irvine, and University of Texas at Austin

Toothbrushing Can Prevent Hospital-borne Pneumonia

Hospital-borne infections are a serious risk of a long-term hospital stay, and ventilator-associated pneumonia (VAP), a lung infection that develops in about 15% of all people who are ventilated, is among the most dangerous. With weakened immune systems and a higher resistance to antibiotics, patients who rely on a mechanical ventilator can easily develop serious infections — as 26,000 Americans do every year.

Thanks to a proven new clinical approach developed by Tel Aviv University nurses, though, there is a new tool for stopping the onset of VAP in hospitals.

This new high-tech tool? An ordinary toothbrush.

Three Times a Day Keeps Pneumonia Away

“Pneumonia is a big problem in hospitals everywhere, even in the developed world,” says Nurse Ofra Raanan, the chief researcher in the new study and a lecturer at Tel Aviv University’s Department of Nursing. “Patients who are intubated can be contaminated with pneumonia only 2 or 3 days after the tube is put in place. But pneumonia can be effectively prevented if the right measures are taken.”

Raanan, who works at the Sheba Academic School of Nursing at The Chaim Sheba Medical Center, collaborated with a team of nurses at major medical centers around Israel. The nurses found that if patients — even unconscious ones — have their teeth brushed three times a day, the onset of pneumonia can be reduced by as much as 50%.

A Pioneering Study with Measurable Effects

It’s difficult to quantify the effects precisely, the researchers say. “While the research shows a definite improvement in reducing the incidence of hospital-borne pneumonia, it’s hard to say by exactly how much toothbrushing prevents VAP,” says Raanan, but the published evidence shows a direct correlation for intubated patients.

“Sometimes, however, doctors and nurses do everything right and the patient still gets pneumonia. But this approach will certainly improve the odds for survival.”

Normally, the teeth and oral cavity in a healthy mouth maintain a colony of otherwise harmless bacteria. Infection takes root when a breathing tube allows free passage of the “good” bacteria into the lower parts of the lung. The bacteria travel in small water droplets through the tube and colonize the lung. Once there, the bacteria take advantage of a patient’s weakened immune system and multiply. A regular toothbrushing kills the growth and subsequent spread of the bacterium that leads to VAP.

Augmenting the Preventative Routine

There are additional steps for preventing the onset of VAP. Today, nurses typically use a mechanical suction device to remove secretions from the mouth and throat. They also put patients in a seated position and change the position every few hours. Toothbrushing, say Tel Aviv University nurses, should be added to the routine.

Although nurses in some American hospitals already practice toothbrushing on ventilated patients, these new results may convince medical centers around the world to invest more resources in this routine practice, thereby saving lives.

The research and recommendations are scheduled for publication in a leading nursing journal.