October 2, 2009 (Newswise) - More than 18-million people in the United States, or 6.3% of the population, have diabetes, according to the American Diabetes Association.Unfortunately, when someone becomes diabetic, chronic non-healing wounds often develop, most often in the legs and feet. These wounds can be uncomfortable and even life-threatening.

There are many types of treatments. One of the most painless and successful is hyperbaric oxygen therapy (HBOT).

Hyperbaric oxygen therapy is a specialized medical treatment inside a pressurized chamber, in which a patient breathes 100 percent oxygen at greater than normal atmospheric pressure.
The Center for Wound Care at Northwest Hospital in Randallstown, Maryland uses HBOT to treat stubborn, non-healing diabetic ulcers.

When the oxygen, which is delivered into the bloodstream, it helps fight certain infections and stimulates the growth of new blood vessels, which generally improves circulation.

"Patients receiving HBOT can see dramatic results as early as two weeks from the start of treatment.
"Another big benefit is that this therapy is noninvasive," says Alan S. Davis, M.D., F.A.C.S, director of the Center for Wound Care and HBOT at Northwest Hospital. "If standard wound therapies prove to be inadequate within a certain time frame, HBOT should be considered and can be done at the same time patients are receiving other treatment."

Once the patient is comfortably positioned inside the HBOT chamber, air pressure is gradually increased.

A patient may experience fullness in the ears as a result. However, a technician instructs him or her about how to help clear the pressure and relieve any discomfort.

Most treatment sessions in the chamber last approximately two hours. During this time, patients watch TV or videos, relax or sleep.

In addition to treating diabetic wounds, HBOT also treats osteomyelitis, post-radiation complications and compromised skin flaps, among other things.

The HBOT program at Northwest Hospital has earned accreditation from the influential Undersea and Hyperbaric Medical Society. Fewer than 100 programs in the United States have achieved this designation.

October 2, 2009 (Newswise) - "Weight loss is emerging as one of the best and safest ways to treat type 2 diabetes," asserts Osama Hamdy, M.D., Ph.D., Medical Director of the Obesity Clinical Program at Joslin Diabetes Center.In a study concluded last year, 115 people with type 2 diabetes who participated in Joslin's Why WAIT (Weight Achievement and Intensive Treatment) program lost an average of 10.3 percent of their initial weight (or 24 pounds) and an average of 3.7 inches from their waists after 12 weeks. They maintained an average loss of 7.6 percent (or 18.8 pounds) on their own for at least a year and a half afterwards.

Participants' risk for coronary artery disease was down significantly and their blood glucose control so improved that fewer medications--and in some cases, no medications--are now necessary.
These results and related scientific studies have convinced Dr. Hamdy that weight loss is the best way to treat type 2 diabetes.

"For 30 years, the treatment for type 2 diabetes has been to add more medications to get blood glucose under control," points out Dr. Hamdy. "Many of those medications cause weight gain, so people end up with too much medicine and more weight."

A recent study showed that patients with diabetes who gain weight while taking diabetes medications have an additional health care cost of $1,719 per year compared to patients who don't gain weight.
Weight gain is particularly undesirable because about 85 to 90 percent of those with type 2 diabetes are already overweight or obese to start with. Excess weight, particularly around the waist, is a major risk factor for diabetes and one of its most deadly complications, cardiovascular events such as heart attacks and strokes.

Clinical studies conducted by Dr. Hamdy and his colleagues at Joslin and elsewhere have clearly shown that a 7 percent weight loss, combined with moderately intensive exercise, improves insulin sensitivity, lowers blood glucose levels, improves the function of blood vessels, and reduces the inflammation in these vessels that can lead to heart disease. A 7 percent loss of weight for someone who starts at 250 pounds, for example, is a modest 17.5 pounds.

Weight loss-guided by a structured diet, a gradual increase of daily exercise and adjustment of diabetes medications-helps control diabetes, says Dr. Hamdy, and if accomplished in the early stages, can even reverse the disease process, causing remission of the diabetes. About 20 percent of Why WAIT participants no longer require diabetes medication.

The Challenge
Surveys have found that one-third to one-half of primary care physicians don't recommend weight management to their overweight or obese patients. They don't believe patients are motivated enough or they think it will be too costly, as health care insurers don't typically cover the cost of weight loss programs. Studies also find that despite initial weight loss success, people typically regain the weight and only 25 percent can maintain the weight loss for a year
after treatment.

Is it possible to take what has been learned about making lifestyle changes in large clinical research trials like the Diabetes Prevention Program, in which people are intensively supported for six months and longer, and apply it to everyday clinical practice in a shorter timeframe? And what is the best way to help people reach that long-term goal: keeping the weight off?

These are the challenges that Dr. Hamdy and his multidisciplinary Why WAIT team set out to conquer. They developed a three-month program, mostly covered by insurance, and began to enroll 10 to 15 people per session in 2005. Participants come into Joslin once a week for two evening hours and apply what they learn at home.

The Results
The Why WAIT team reported on how the participants fared a year and a half after finishing the program at the American Diabetes Association's annual scientific meeting in June, 2009.
Though some had gained back some of the weight they lost, the average loss was 7.6 percent--still above the golden percentage it takes to achieve health benefits.

Just over half (51 percent) of the participants continued to lose weight; typically those who stuck with the program's meal and exercise plans. They were also the ones who maintained excellent blood pressure and diabetes control, and did it using less medication.

Over the course of the program, A1C levels dropped from a starting average of 7.5 percent to 6.6 percent. (Tests of A1C--short for "glycoslated hemoglobin A1C"--measure the glucose that clings to hemoglobin molecules in red blood cells. They are commonly employed in diabetes management to give a good indication of how much extra glucose has been in the bloodstream over the previous few months.) Almost 70 percent of participants lowered their A1C to below 6.5 percent and 82 percent to below 7 percent, which is within Joslin's Clinical Guidelines. Those who maintained their weight loss over the first year also maintained the lower A1C.

The program also resulted in positive changes in participants' cardiovascular disease risk profile-reflected in their improved levels of lipids, blood pressure, and C-reactive protein (a marker for inflammation linked to cardiovascular disease).

The reduction in diabetes medications saved an average of $561.37 per patient per year. Additionally, a recent study showed that just 1% of weight loss in patients with diabetes saved $256 on total health care cost and $131 on diabetes-related cost in a year. A 7.6% weight loss in the Why WAIT program could save $1,946 (or 27%) of the health care cost and $996 (or 44%) of the diabetes-related cost.

How They Did It
A key innovation of the Why WAIT model is how diabetes medications are managed. "We begin by switching participants from medications that cause weight gain to ones that either maintain body weight or help weight loss," says Dr. Hamdy. Every week patients' blood glucose values are reviewed and their diabetes medications are adjusted.

"In our model, the focus is on body weight as the core of diabetes treatment," says Dr. Hamdy. "We've allowed the weight loss itself to help people achieve blood glucose control."

Rooting for the participants and every pound lost along the way are a dietitian, an exercise physiologist, a behavioral psychologist and a nurse educator.

As a team, they deliver five major components of the Why WAIT program:

The principle is simple: eat less and properly and exercise more. "But doing these things and sticking to them is hard," admits Ann Goebel-Fabbri, Ph.D., a Joslin psychologist. "We're requiring people to make multiple changes in their lives simultaneously."

There are no eliminations or rejection like on a television show. There is no blame or shame, as overweight people can sometimes feel in the healthcare or gym environment. But there is gradual, steady weight loss.

Recipes for Success
In the Why WAIT program, calories per day are only cut down by 250 to 500-the equivalent of one-half to a full cup of rich ice cream. In concert with gradually increasing exercise, people lose about one to two pounds every week.

A big part of the program's success, Dr. Hamdy believes, is that the diet is high-protein and low-carb. It strictly follows Joslin's "Clinical Nutrition Guideline for Overweight and Obese Adults with Type 2 Diabetes, Prediabetes or Those at High Risk for Developing Type 2 Diabetes," which recommends the ratio of nutrients to be consumed in a day as 20-30 percent protein, around 40 percent carbohydrate higher in fiber and lower in glycemic index, and 30 percent fat (mono or polyunsaturated fat with less saturated fat and no transfat).

This is a higher percentage of protein and a lower percentage of carbohydrate than has been typically recommended for those with diabetes. "Our guidelines were developed to achieve slow but steady weight loss and better diabetes control, and especially to prevent cardiovascular complications," points out Dr. Hamdy. "It is safe and effective for weight loss, helps people feel more full, results in higher energy levels, and helps reduce blood pressure."

Protein should come from lean sources such as poultry or fish, rather than meat, which is higher in saturated fats, says Gillian Arathuzik, RD, CDE, the program dietitian.

Dealing with Set-Backs
A central theme is that improvement doesn't have to be all or nothing. "There are so many ways to slip up in eating, or by not exercising or monitoring enough," points out Dr. Goebel-Fabbri. "When this happens, it's very easy to move right into self-blame and negative thinking that this is never going to work."

The team uses a highway metaphor to turn this thinking around: If you are trying to drive to Boston and end up in Hartford, Conn., you don't say I'm going to have to get out and stay here; you get right back in the car and head in the direction you want to go.

A large part of what the team does is to help everyone stay motivated. But the "big bang" of motivation is the weight change people see every week. They find that they feel better; their blood glucose numbers are dropping and their energy, lung capacity and flexibility are improving.

On the Right Track
The average age of Why WAIT participants is 54, but 20 percent of them are over age 70. "One participant completed the program at age 81," says Joan Beaton, program coordinator. Most of them have never exercised before. So the emphasis is on gradually introducing varied exercise into their lives, from 20 to 30 minutes a day three to four times a week, to eventually 45 to 60 minutes a day six times a week.

During the program, Why WAIT participants go once a week to the gym at Joslin, a friendly "teaching gym" with equipment designed for larger bodies and those with orthopedic complications. "They experience different exercises, build confidence and become more comfortable with their bodies," explains Jacqueline Shahar, M.Ed., R.C.E.P., C.D.E., Joslin's Manager of Exercise Physiology.

The key is for participants to take home what they've learned. Not everybody has access to a gym. "Everyone leaves with an exercise program that is adapted to their particular lifestyle and medical needs," says Shahar.

The Million-Dollar Question
"Weight-based diabetes management through Why WAIT is a revolutionary new model for managing diabetes," says Dr. Hamdy. "It is totally different from classic model of medication-based diabetes management. The novel model results in less medication, better control, reduced cost, healthier weight, lower cardiovascular risk and above all improved quality of life."

Even those who are severely obese and choose bariatric surgery for weight loss would benefit from first losing weight through a program like this, Hamdy believes. He and his colleagues are about to start a study to compare the Why WAIT model to bariatric surgery.

But the million-dollar question is how to help people maintain weight loss beyond one to five years.
"We know people need consistent support afterwards and we are trying to create the best maintenance program," he says.

"Our recent study among Why WAIT participants showed that people who exercised most after the program are those who maintained the weight loss for 18 month," says Shahar.

The team offers each "graduate" a case manager who checks in with them monthly and is available for questions any time. Hamdy says this is like a booster shot to help with barriers to staying on track--be it fitting enough exercise in their lives or sticking to the diet at holidays.

September 22, 2009 (EurekAlert) - The SwitchTM programme, 'Switch what you Do, View, and Chew', has been shown to be capable of promoting children's fruit and vegetable consumption and lowering 'screen time'. Researchers writing in the open access journal BMC Medicine tested the programme and report that it offers promise for use in youth obesity prevention.Douglas Gentile, a psychology professor from Iowa State University, USA, worked with a team of researchers to evaluate the intervention in a group of 1,323 children and their parents from 10 schools. He said, "Reversing the pediatric obesity epidemic has been established as a critical priority. We tested Switch, a family-, school-, and community-based intervention aimed at changing the key behaviors of physical activity, television viewing/screen time, and nutrition".

The Switch programme features three components, Community, School and Family. The Community component is designed to promote awareness of the importance of healthy lifestyles using paid advertising (such as billboards) and unpaid media (such as letters to the editors of print publications). The School component reinforces the Switch messages by providing teachers with materials and methods to integrate key health concepts into the school day. Finally in the Family component, participating families receive monthly packets containing behavioral tools to assist families in altering their health behaviors.

Gentile said, "Family components are critical for youth obesity prevention programs because parents directly and indirectly influence children's activity and nutrition behaviors. Parents also influence the physical and social environments that are available to their children. The School and Community components are essential to integrate the programme into the places where families live, work and play".

The intervention yielded encouraging results, with the experimental group showing significant differences from the control group in both screen time and fruit and vegetable consumption. According to Gentile, "Although modest, these results are not trivial. The effects remained significant at the 6-month follow-up evaluation, indicating maintenance of these differences over time. Such maintenance may contribute to reduced weight risks in the future".

September 22, 2009 (EurekAlert) - Physical therapist-directed exercise counseling combined with fitness center-based exercise training can improve muscular strength and exercise capacity in people with type 2 diabetes, with outcomes similar to those of supervised exercise, according to a randomized clinical trial published in the September issue of Physical Therapy, the scientific journal of the American Physical Therapy Association (APTA).Type 2 diabetes is associated with numerous health complications, including a decline in muscular strength and exercise capacity. Studies show that a decline in muscular strength increases the risk of loss of physical function and that a decline in exercise capacity increases the risk of cardiovascular and all-cause mortality. "Improving muscular strength and exercise capacity in people with type 2 diabetes is crucial to preventing loss of physical function and decreasing comorbidity and mortality in these patients," said lead researcher J. David Taylor, PT, PhD, CSCS, assistant professor in the Department of Physical Therapy at the University of Central Arkansas.

Supervised exercise programs improve both muscular strength and exercise capacity in people with type 2 diabetes; however, Medicare and other health insurance programs do not currently reimburse physical therapists and other clinicians for these exercise programs.

In this study, 24 people with type 2 diabetes were randomly allocated to either an experimental group that received two months of physical therapist-directed exercise counseling and fitness center-based exercise training or a comparison group that received two months of laboratory-based, supervised exercise. Exercise training for all participants consisted of resistance training (chest press, row, and leg press exercises) and aerobic training (walking or jogging on a treadmill) as recommended for people with type 2 diabetes by the American Diabetes Association and the American College of Sports Medicine. Participants in the experimental group received a face-to-face counseling session at baseline and one month after baseline, weekly 10-minute telephone calls, and seven-day-per-week access to a local fitness center. Each participant in the comparison group received the same prescribed exercise program as the experimental group, but in a supervised environment.

Although both groups had significant improvements in muscular strength and exercise capacity following exercise training, the results showed no significant differences in improvements between these two groups. "The fact that there were no significant differences in improvements between patients who received exercise counseling and those in a supervised program suggests that physical therapists may make an evidence-based choice of prescribing either exercise counseling combined with fitness center-based training or supervised exercise training for patients with type 2 diabetes," said Taylor.

September 21, 2009 (Newswise) - Here are highlights from the fall issue of Discovery's Edge, Mayo Clinic's research magazine. You may cite and link to this publication as often as you wish. Reprinting is allowed with proper attribution. Please include the following subscription information as your editorial policies permit: Visit Discovery's Edge for subscription information.Diabetes and Heart Damage - an iPS Cell Approach

Building on recent discoveries in converting normal cells into cells with stem cell characteristics, Mayo researchers are exploring the potential of iPSCs or induced pluripotent stem cells in regenerating organs. Among the goals: alleviate heart damage and Type 1 diabetes.

http://discoverysedge.mayo.edu/ips-regenerative-medicine/

Discovery's Edge, Mayo Clinic's online research magazine, highlights stories of leading medical investigators. Many features cover ongoing projects long before they reach the journals. Science writers and medical reporters seeking story ideas will want to check out the articles, which span a wide range of conditions and feature visuals they can use in their own publications.

September 21, 2009 (EurekAlert) - Middle-aged women with large abdominal fat cells have a higher risk of developing type 2 diabetes later in life compared to women with smaller fat cells. Waist circumference divided by body height can also be used to determine which women are at risk. This is shown in a new study from the Sahlgrenska Academy at the University of Gothenburg, Sweden.The study, which will be published in the next issue of the scientific journal FASEB Journal, is based on the extensive population study of women in Gothenburg Kvinnoundersökningen i Göteborg.

'The results indicate that large fat cells contribute to the development of type 2 diabetes, and we will now begin investigating the mechanisms behind this finding. Increased knowledge about large fat cells and their effects may lead to new preventive and therapeutic alternativs, says Malin Lönn, associate professor in experimental medicine at the Sahlgrenska Academy.

The researchers analysed data on cell size collected from 245 women in 1974-75, and found that the 36 women who developed diabetes over the course of 25 years had larger abdominal fat cells than those who did not develop the disease. The larger the fat cells, the larger the probability of developing type 2 diabetes. Since a person's fat cells vary significantly in size, the researchers used an average for each person.

In addition, the study reveals a simpler and faster way to predict which women are at risk of developing type 2 diabetes: waist circumference divided by body height.

'Our study suggests that this ratio may be even better than fat cell size at estimating who is at risk of developing type 2 diabetes. The higher the waist-to-height ratio, the higher the risk', says Lönn.

The study is based on Kvinnoundersökningen i Göteborg, which was started in 1968 by Professor Emeritus Calle Bengtsson. Since the start, almost 1500 women aged 38-60 have been interviewed about their lives and examined by a physician regularly. New women have been recruited over the years, making it possible to both follow a generation over time and compare different generations.

September 11, 2009 (EurekAlert) - Reducing Americans' average intake of sodium to the amount recommended by health officials could save the nation as much as $18 billion annually in avoided health care costs and improve the quality of life for millions of people, according to a new RAND Corporation study.The study estimates that meeting national sodium guidelines could eliminate 11 million cases of high blood pressure nationally and extend the lives of thousands of people each year. The monetary value of the improved quality of life would be an estimated $32 billion annually, according to the findings published in the September/October edition of the Journal of Health Promotion.

"This study provides an important first step toward quantifying the benefits of reducing the intake of sodium by the American public," said Kartika Palar, the study's lead author and a graduate fellow at the RAND Pardee Graduate School. "These findings make a strong case that there's value in pursuing a population-based approach to reducing sodium intake among Americans."

The study is one of the first to estimate the economic benefits of lowering sodium consumption among the American public.

Excessive consumption of sodium is a persistent health problem in the United States, causing increased rates of high blood pressure and related illnesses such as cardiovascular diseases. The Institute of Medicine recommends that adults consume no more than 2,300 milligrams of sodium each day, with lower amounts recommended for older adults, black patients and those with high blood pressure -- groups that are at higher risk.

Researchers from RAND Health analyzed information about Americans' blood pressure levels, use of antihypertensive medications and sodium intake from the National Health and Nutrition Examination Survey, a federal study that routinely assesses the health and nutritional status of adults and children in the United States. The study is unique in that it combines interviews and physical examinations.

Palar and study co-author Roland Sturm, a RAND senior economist, using a cross-sectional simulation model, calculated that lowering sodium intake would trim a sizable portion of the $55 billion spent nationally each year to treat high blood pressure. About half of the $18 billion in annual health care cost savings would accrue to public sector health spending. Researchers say their estimates are conservative because they were not able to calculate the savings for illnesses such as cardiovascular diseases where sodium consumption plays a less-defined role.

In addition, researchers estimated that meeting sodium consumption guidelines would save in one year 312,000 quality adjusted life years -- a research measurement that adjusts increased longevity for the relative healthiness experienced during additional years of life.

"Our results are driven by the fact that nearly 30 percent of the nation's population has hypertension," Palar said. "One of the reasons that hypertension is so pervasive is that sodium consumption is so high."

Researchers say that better strategies for lowering sodium intake broadly across the nation's population still need to be developed. Studies estimate that more than 75 percent of Americans dietary sodium intake comes from processed foods rather than from salt added during cooking at home or at the dining table. Restaurant food also is generally high in sodium.

Population-based strategies that have been discussed include redesigning food labeling information to better highlight sodium levels, having manufacturers voluntarily lower sodium levels and adopting regulations that would require food processors to lower sodium.

September 10, 2009 (EurekAlert) - When it comes to assessing risk for type 2 diabetes, not only do waistlines matter to women, but so does the size of their fat cells. This new discovery by a team of Swedish researchers was just published online in the FASEB Journal (http://www.fasebj.org) and helps explain why some women of normal weight develop type 2 diabetes, despite not having any known risk factors."Increased knowledge of the link between enlarged fat cells and the development of type 2 diabetes may give rise to new preventive and therapeutic alternatives," said Malin Lönn, co-author of the study and associate professor in the department of clinical chemistry at Sahlgrenska University Hospital in Gothenburg, Sweden. "Our research also identifies the ratio waist-to-height, waist circumference divided by body height, as a simple tool that can be used to identify women at risk of developing type 2 diabetes."

The data for this discovery were obtained as part of the "Prospective Study of Women in Gothenburg," performed in Sweden and started in 1968 by Professor Emeritus Calle Bengtsson. For this study, a team of Swedish researchers invited women to free health examinations over the course of 25 years. In 1974-1975, scientists collected abdominal fat biopsies from some of the women and tracked who developed type 2 diabetes. They found that the number of abdominal fat cells remained relatively constant in women after adolescence, but the size of fat cells could change considerably throughout life and were larger in women with type 2 diabetes. In addition, they found that waist-to-height ratio may also be a good indicator of diabetes risk.

"Despite notions to the contrary, size does matter to women-at least when it comes to her fat cells, her waist-to-height-ratio and her risk for type 2 diabetes," said Gerald Weissmann, M.D., Editor-in-Chief of the FASEB Journal. "This is a remarkable study that should lead to preventive measures for this most common of serious diseases."

According to the U.S. Centers for Disease Control and Prevention, type 2 diabetes may account for 90 to 95 percent of all diagnosed cases of diabetes. The disease begins as insulin resistance, and as the need for insulin rises, the pancreas gradually loses its ability to produce insulin. Type 2 diabetes often is associated with older age, but is increasingly being diagnosed in children. Obesity, family history of diabetes, history of gestational diabetes, impaired glucose metabolism, physical inactivity, and race/ethnicity also play a role in whether or not someone develops the disease. In particular, African Americans, Hispanic/Latino Americans, American Indians/Native Americans, and some Asian Americans and Native Hawaiians or Other Pacific Islanders are at high risk for type 2 diabetes.

September 9, 2009 (EurekAlert) - Researchers at the Carnegie Institution's Department of Plant Biology have discovered a key missing link in the so-called signaling pathway for plant steroid hormones (brassinosteroids). Many important signaling pathways are relays of molecules that start at the cell surface and cascade to the nucleus to regulate genes. This discovery marks the first such pathway in plants for which all the steps of the relay have been identified.Since this pathway shares many similarities with pathways in humans, the discovery not only could lead to the genetic engineering of crops with higher yields, but also could be a key to understanding major human diseases such as cancer, diabetes, and Alzheimer's.

Steroids are important hormones in both animals and plants. Brassinosteroids regulate many aspects of growth and development in plants. Mutants deficient in brassinosteroids are often stunted and infertile. Brassinosteroids are similar in many respects to animal steroids, but appear to function very differently at the cellular level. Animal cells usually respond to steroids using internal receptor molecules within the cell nucleus, whereas in plants the receptors, called receptor-like kinases, are anchored to the outside surface of the cell membranes. For over a decade, scientists have tried to understand how the signal is passed from the cell surface to the nucleus to regulate gene expression. The final gaps were bridged in the study published in the advanced on-line issue of Nature Cell Biology September 6, 2009.

The research team unraveled the pathway in cells of Arabidopsis thaliana, a small flowering plant related to cabbage and mustard often used as a model organism in plant molecular biology.
"This is the first completely connected signaling pathway from a plant receptor-like kinase, which is one of the biggest gene families in plants," says Carnegie's Zhi-Yong Wang, leader of the research team. "The Arabidopsis genome encodes over 400 receptor-like kinases and in rice there are nearly 1,000. We know the functions of about a dozen or so. The completely connected brassinosteroid pathway uses at least six proteins to pass the signal from the receptor all the way to the nuclear genes expressed. This will be a new paradigm for understanding the functional mechanism of other receptor-like kinases."

Understanding the molecular mechanism of brassinosteroid signaling could help researchers develop strategies and molecular tools for genetic engineering of plants with modified sensitivity to hormones, either produced by the plant or sprayed on crops during cultivation, resulting in higher yield or improved traits. "We perhaps could engineer plants with altered sensitivity in different portions of the plant," says Wang. "For example, we could manipulate the signal pathway to increase the biomass accumulation in organs such as fruits that are important as agricultural products, an area highly relevant for food and biofuel production."

Another of the study's findings has potentially far-reaching consequences for human health. The newly identified brassinosteroid signaling pathway component shares evolutionarily conserved domains with the glycogen synthase kinase 3 (GSK3). "GSK3 is found in a wide range of organisms, including mammals," says Wang. "Our study identified a distinct mechanism for regulating GSK3 activity, different from what had been identified in earlier work. GSK3 is known to be critical in the development of health issues such as neural degeneration, cancer, and diabetes, so our finding could open up new avenues for research to understand and treat these diseases."

September 3, 2009 (Newswise) - University of Michigan researchers have identified a gene that acts as a master switch to control obesity in mice. When the switch is turned off, even high-fat-diet mice remain thin.Deleting the gene, called IKKE, also appears to protect mice against conditions that, in humans, lead to Type 2 diabetes, which is associated with obesity and is on the rise among Americans, including children and adolescents.

If follow-up studies show that IKKE is tied to obesity in humans, the gene and the protein it makes will be prime targets for the development of drugs to treat obesity, diabetes and complications associated with those disorders, said Alan Saltiel, the Mary Sue Coleman Director of the U-M Life Sciences Institute.

"We've studied other genes associated with obesity - we call them 'obesogenes' - but this is the first one we've found that, when deleted, stops the animal from gaining weight," said Saltiel, senior author of a paper to be published in the Sept. 4 edition of the journal Cell.

"The fact that you can disrupt all the effects of a high-fat diet by deleting this one gene in mice is pretty interesting and surprising," he said.

Obesity is associated with a state of chronic, low-grade inflammation that leads to insulin resistance, which is usually the first step in the development of Type 2 diabetes. In the Cell paper, Saltiel and his colleagues show that deleting, or "knocking out," the IKKE gene not only protected high-fat-diet mice from obesity, it prevented chronic inflammation, a fatty liver and insulin resistance, as well.

The high-fat-diet mice were fed a lard-like substance with 45 percent of its calories from fat. Control mice were fed standard chow with 4.5 percent of its calories from fat. The dietary regimen began when the mice were 8 weeks old and continued for 14 to 16 weeks.

The gene IKKE produces a protein kinase also known as IKKE. Protein kinases are enzymes that turn other proteins on or off. The IKKE protein kinase appears to target proteins which, in turn, control genes that regulate the mouse metabolism.

When the high-fat diet is fed to a normal mouse, IKKE protein-kinase levels rise, the metabolic rate slows, and the animal gains weight. In that situation, the IKKE protein kinase acts as a brake on the metabolism.

Knockout mice placed on the high-fat diet did not gain weight, apparently because deleting the IKKE gene releases the metabolic brake, allowing it to speed up and burn more calories, instead of storing those calories as fat.

"The knockout mice are not exercising any more than the control mice used in the study. They're just burning more energy," Saltiel said. "And in the process, they're generating a little heat, as well - their body temperature actually increases a bit."

Saltiel's team is now searching for small molecules that block IKKE protein-kinase activity. IKKE inhibitors could become candidates for drug development.

"If you find an inhibitor of this protein kinase, you should be able to obtain the same effect as knocking out the gene. And that's the goal," Saltiel said. If successful candidates are identified and drug development is pursued, a new treatment for obesity and diabetes is likely a decade away, he said.
First author of the Cell paper is Shian-Huey Chiang of the Life Sciences Institute. Co-authors are U-M researchers Merlijn Bazuine, Carey Lumeng, Lynn Geletka, Jonathan Mowers, Nicole White, Jing-Tyan Ma, Jie Zhou, Nathan Qi, Dan Westcott and Jennifer Delproposto. Timothy Blackwell and Fiona Yull of the Vanderbilt University School of Medicine also are co-authors.

The research was funded by the National Institutes of Health and the American Diabetes Association. All animal use was conducted in compliance with the Institute of Laboratory Animal Research's Guide for the Care and Use of Laboratory Animals and was approved by the University Committee on Use and Care of Animals at the University of Michigan.