Bradley Waggoner, MD

Gastric Bypass Alters Sweet Taste Function

Gastric bypass surgery decreases the preference for sweet-tasting substances in obese rats, a study finding that could help in developing safer treatments for the morbidly obese, according to Penn State College of Medicine researchers.

"Roux-en-Y gastric bypass surgery is the most common effective treatment for morbid obesity," said Andras Hajnal, associate professor, Department of Neural and Behavioral Science and Surgery. "Many patients report altered taste preferences after having the procedure."

This surgery involves the creation of a small gastric pouch and bypassing a portion of the upper small intestine. Unlike other weight-reduction methods, it produces substantial and durable weight loss and significant improvements in obesity-related medical conditions including diabetes.

Study results in obese rats suggest that post-surgery changes in the gastrointestinal anatomy affect change in the brain that relate to taste.

Obese rats given gastric bypass surgery showed a reduced preference for high concentration sucrose water when compared to obese rats that did not have surgery. Researchers observed a similar decrease in preference with other sweet-tasting substances, but not for salty, sour or bitter substances. Researchers observed no change in preference in lean rats that had gastric bypass surgery.

The obese rats used do not have the ability to produce the receptor for feeling satiated shortly after a meal because they lack the gut hormone CCK-1. As a result, these rats consumed larger meals and, over time, became obese and developed type-2 diabetes. Interestingly, previous studies lead by the Penn State investigators found an increased sweet preference in these rats, which is also often seen in people struggling with weight management.

"It appears that an uncontrolled appetite may get further boost from altered taste functions during development of obesity and diabetes," Hajnal said. "How much of this vicious circle is due to changes in the neurons inside the brain, which receive taste sensations from the tongue and report to the higher order motivational brain centers, we don't know."

The researchers recorded the activity of 170 taste-responsive neurons in the brain. These showed a shift in the neurons' firing activity similar to the behavioral response, which was measured in lick rates of the rats within a ten-second time period. Neurons in the obese rats' brain responded more vigorously to higher-concentration sucrose water placed on the tongue when compared to lean rats. These effects were reversed by gastric bypass surgery and matched the response of lean rats -- a preference for lower concentration sucrose.

The rats that had gastric bypass surgery lost weight comparable to humans who received the surgery -- 26 to 30 percent of their weight -- and maintained the loss for a long period of time after surgery. Following surgery, the obese rats also showed a higher tolerance for glucose, indicating improvement in diabetes.

"This supports the applicability of this rat model of Roux-en-Y gastric bypass to humans and also suggests that the observed taste changes following the surgery were not related to 'human factors' such as awareness and compliance to dietary and behavioral interventions," Hajnal said.

The researchers published their findings in the October issue of the "American Journal of Physiology, Gastrointestinal and Liver Physiology." The National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of General Medical Sciences funded this work.

"These findings confirm obesity-related alterations in taste functions and demonstrate the ability of gastric bypass surgery to alleviate these modifications," Hajnal said. "We do not suggest, however, that the findings reported in this paper are the only neural consequences of gastric bypass surgery related to altered postsurgical food preferences. Nevertheless, understanding the underlying mechanisms by which gastric bypass surgery affects taste may help in identifying therapeutic targets that mimic the beneficial effects of the surgery on appetite control and food choices, without the risks and complications of an invasive surgical procedure."

Further research is needed to determine what causes the neural and behavioral changes, according to Hajnal.

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Source: Reprinted with editorial adaptations from materials provided by Penn State University. http://live.psu.edu/tag/research

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Patients With Diabetes May Need Fewer Medications After Bariatric Surgery

Bariatric surgery appears to be associated with reduced use of medications and lower health care costs among patients with type 2 diabetes, according to a report in the August issue of Archives of Surgery, one of the JAMA/Archives journals.

"The rapidly growing epidemics of obesity and diabetes threaten to overburden the world's health care systems," the authors write as background information in the article. "From an epidemiological standpoint, once these diseases develop they are rarely reversed. Dietary, pharmaceutical and behavior treatments for obesity are associated with high failure rates, and medical management of diabetes is also often unsuccessful. Despite many efforts to improve the control of glucose levels in diabetes, including clinical guidelines and patient and provider education, less than half of all patients with type 2 diabetes mellitus achieve the American Diabetes Association recommendation of a hemoglobin A1C level of less than 7 percent."

The use of bariatric surgery—that results in long-term weight loss, improved lifestyle and decreased risk of death—has tripled in the past five years, the authors note. Martin A. Makary, M.D., M.P.H., and colleagues at the Johns Hopkins Bloomberg School of Public Health and The Johns Hopkins University School of Medicine, Baltimore, studied 2,235 U.S. adults (average age 48.4) with type 2 diabetes who underwent bariatric surgery during a four-year period, from 2002 to 2005. They used claims data to measure the use of diabetes medications before and after surgery, along with health care costs per year.

Of the 2,235 patients, 1,918 (85.8 percent) were taking at least one diabetes medication before surgery, with an average of 4.4 medications per patient. Six months after surgery, 1,669 of 2,235 patients (74.7 percent) had eliminated their diabetes medications. Of the 1,847 patients with available data one year after surgery, 1,489 (80.6 percent) had eliminated medications; after two years, 906 of 1,072 (84.5 percent) had done so. This reduction was observed in all classes of diabetes medications.

"We observed that independence from diabetes medication was almost immediate within the initial months after surgery and did not correlate with the gradual weight loss expected," the authors write. "This supports the theory that the resolution of diabetes is not due to weight loss alone but is also mediated by gastric hormones, with the three most implicated being peptide YY, glucagonlike peptide and pancreatic polypeptide. As a known mediator of insulin regulation, glucagonlike peptide levels have been noted to increase immediately after bariatric surgery and may explain why surgeons have noted complete resolution of diabetes in some cases within days after surgery."

Health care costs averaged $6,376 per year in the two years before surgery, and the median or midpoint cost of the surgery and hospitalization was $29,959. Total annual health care costs increased by 9.7 percent ($616) in the year following the procedure, but decreased by 34.2 percent ($2,179) in year two and by 70.5 percent ($4,498) in year three.

"Based on these data, we have identified several important implications for health care delivery and public policy," the authors conclude. "Foremost, eligible obese patients should be properly informed of the risks and benefits of bariatric surgery compared with non-surgical health management. Health care providers should consider discussing bariatric surgery in the treatment of obese patients with type 2 diabetes. Health insurers, private and public, should pay for bariatric surgery for appropriate candidates, recognizing a potential annualized cost savings in addition to the benefit to health."

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Source: Reprinted from materials provided by JAMA and Archives Journals. http://pubs.ama-assn.org/media/

Journal Reference: Martin A. Makary; Jeanne M. Clarke; Andrew D. Shore; Thomas H. Magnuson; Thomas Richards; Eric B. Bass; Francesca Dominici; Jonathan P. Weiner; Albert W. Wu; Jodi B. Segal. Medication Utilization and Annual Health Care Costs in Patients With Type 2 Diabetes Mellitus Before and After Bariatric Surgery. Arch Surg, 2010; 145 (8): 726-731

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Study Finds Lap-Band Weight Loss Surgery in Very Obese Adults Improves Mental Health

One year after weight loss surgery with laparoscopic gastric banding, extremely obese adults demonstrate not only better physical health but also improved psychological health, a new study shows. The results were presented recently at The Endocrine Society’s 92nd Annual Meeting in San Diego.

“Surgical treatment, such as laparoscopic gastric banding, is increasingly recognized as the most effective means of achieving weight loss and improving blood sugar control in morbidly obese patients with Type 2 diabetes,” said study co-author Andrew Johnson, MD, of Southmead Hospital in Bristol, U.K.

“However, until now, the long-term psychological status of morbidly obese individuals undergoing gastric banding has been unclear despite its increasing use,” said Johnson, a consultant physician specializing in diabetes and endocrinology.

Laparoscopic gastric banding, also called the “Lap-Band” procedure, is a minimally invasive weight loss surgery. It involves repeated adjustment of a band to gradually make the stomach smaller and limit food consumption.

Four men and 21 women (ranging in age from 30 to 58 years) participated in the study and had the weight loss surgery. Of these 25 patients, 16 had Type 2 diabetes and nine did not. All had a body mass index (BMI, a measure of body fat) that classified them as morbidly obese.

Participants completed psychological testing before surgery and six and 12 months after surgery. These tests measured general anxiety and depression, quality of life, and social anxiety, that is, anxiety related to what others might think of one’s appearance.

Compared with before surgery, patients’ psychological test scores improved significantly at both six and 12 months after surgery. They had better psychological and physical quality of life, reductions in levels of general anxiety and depression, and reductions in their levels of social anxiety.

As shown in other studies, gastric banding significantly reduced BMI and hemoglobin A1c, a measure of blood sugar control over time.

“These results provide evidence one year after gastric banding that psychological health improves in parallel with physiological health,” Johnson said.

Researchers at the University of the West of England in Bristol also contributed to this study.

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Source: The Endocrine Society. http://www.endo-society.org

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Managing the Emotions Behind Eating

How many times have you, after a particularly hard day, reached for some chocolate or ice cream? It's common for many people, but for those trying to lose weight, it can be detrimental to their long term success, and most weight-loss programs never even address it.

They focus on choosing healthier foods and exercising more, but they never answer a key question: how can people who have eaten to cope with emotions change their eating habits, when they haven't learned other ways of coping with emotions?

Researchers at Temple's Center for Obesity Research¹ are trying to figure out the answer as part of a new, NIH-funded weight loss study. The new treatment incorporates skills that directly address the emotional eating, and essentially adds those skills to a state-of-the art behavioral weight loss treatment.

"The problem that we're trying to address is that the success rates for long-term weight loss are not as good as we would like them to be," said Edie Goldbacher, a postdoctoral fellow at CORE. "Emotional eating may be one reason why people don't do as well in behavioral weight loss groups, because these groups don't address emotional eating or any of its contributing factors."

The study has already had one wave of participants come through, and many participants have seen some success in the short term, but have also learned the skills to help them achieve long term success.

Janet Williams, part of that first cohort, said she lost about 17 pounds over 22 weeks, and still uses some of the techniques she learned in the study to help maintain her weight, which has not fluctuated.

"The program doesn't just help you identify when you eat," said Williams. "It helps you recognize triggers that make you eat, to help you break that cycle of reaching for food every time you feel bored, or frustrated, or sad."

Williams said that the program teaches various techniques to help break that cycle, such as the "conveyor belt," in which participants, when overcome with a specific emotion, can recognize it and take a step back, before reaching for chips or cookies, and put those feelings on their mental "conveyor belt" and watch them go away.

"I still use the skills I learned in the study," she said. "I've learned to say, 'I will not allow this emotional episode to control my eating habits.'"

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¹Temple University. http://www.temple.edu/

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New Eating Device Retrains Dietary Habits and Helps Children Lose Weight

A new computerized device that tracks portion size and how fast people eat is more successful in helping obese children and adolescents lose weight than standard treatments, according to research published on bmj.com¹.

The Mandometer device, a portable computerized weighing scale, was developed at the Karolinska Institutet in Stockholm. It helps to retrain individuals to eat less and more slowly by providing real-time feedback during meal times. The device plots a graph showing the rate at which food actually disappears from the plate, compared to the ideal graph programmed in by a food therapist.

Childhood obesity is an increasing global problem and there is little evidence to support one specific treatment program. While it is unknown whether specific eating patterns are common in all obese people, in this study the patients ate large portions very quickly.

Researchers at Bristol Royal Hospital for Children and the University of Bristol, led by Professor Julian Hamilton-Shield, carried out a randomized controlled trial of 106 obese patients aged between 9-17 years.

One group of participants received Mandometer therapy to lose weight and the other were provided with standard care. Both groups were encouraged to increase their levels of physical activity to 60 minutes of exercise a day and to eat a balanced diet based on the Food Standards Agency "eatwell plate."

Participants were assessed after 12 months and followed up at 18 months. During the research period they were also regularly monitored and offered telephone support and encouragement.

After 12 months, the Mandometer group not only had a significantly lower average body mass index and body fat score than the standard care group, but their portion size was smaller and their speed of eating was reduced by 11% compared with a gain of 4% in the other group. Levels of 'good cholesterol' were also significantly higher in the Mandometer group.

The improvement in body mass index was maintained six months after the end of treatment, suggesting an element of longer term behavioral change, add the authors.

"Mandometer therapy, focusing on eating speed and meal size, seems to be a useful addition to the rather sparse options available for treating adolescent obesity effectively without recourse to pharmacotherapy," say the authors.

They acknowledge that the Mandometer requires further evaluation in other settings and with different groups of patients, but conclude that "Retraining eating behavior and reinforcing feelings of satiety, however, does seem to improve weight loss in obese adolescents."

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¹ http://www.bmj.com. Full text of this study can be found at the BMJ Journal's website.

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What You Eat After Exercise Matters

Many of the health benefits of aerobic exercise are due to the most recent exercise session (rather than weeks, months and even years of exercise training), and the nature of these benefits can be greatly affected by the food we eat afterwards, according to a study published in the Journal of Applied Physiology

“Differences in what you eat after exercise produce different effects on the body’s metabolism,” said the study’s senior author, Jeffrey F. Horowitz of the University of Michigan. This study follows up on several previous studies that demonstrate that many health benefits of exercise are transient: one exercise session produces benefits to the body that taper off, generally within hours or a few days.

“Many of the improvements in metabolic health associated with exercise stem largely from the most recent session of exercise, rather than from an increase in ‘fitness’ per se,” Dr. Horowitz said. “But exercise doesn’t occur in a vacuum, and it is very important to look at both the effects of exercise and what you’re eating after exercise.”

Specifically, the study found that exercise enhanced insulin sensitivity, particularly when meals eaten after the exercise session contained relatively low carbohydrate content. Enhanced insulin sensitivity means that it is easier for the body to take up sugar from the blood stream into tissues like muscles, where it can be stored or used as fuel. Impaired insulin sensitivity (i.e., “insulin resistance”) is a hallmark of Type II diabetes, as well as being a major risk factor for other chronic diseases, such as heart disease.

Interestingly, when the research subjects in this study ate relatively low-calorie meals after exercise, this did not improve insulin sensitivity any more than when they ate enough calories to match what they expended during exercise. This suggests that you don’t have to starve yourself after exercise to still reap some of the important health benefits.

The paper, “Energy deficit after exercise augments lipid mobilization but does not contribute to the exercise-induced increase in insulin sensitivity,” appears in the online edition of the journal. The authors are Sean A. Newsom, Simon Schenk, Kristin M. Thomas, Matthew P. Harber, Nicolas D. Knuth, Haila Goldenberg and Dr. Horowitz. All are at the University of Michigan. The American Physiological Society published the research.

The study included nine healthy sedentary men, all around 28-30 years old. They spent four separate sessions in the Michigan Clinical Research Unit in the University of Michigan Hospital. Each session lasted for approximately 29 hours. They fasted overnight before attending each session, which began in the morning.

The four hospital visits differed primarily by the meals eaten after exercise. The following describes the four different visits:

• They did not exercise and ate meals to match their daily calorie expenditure. This was the control trial.

• They exercised for approximately 90 min at moderate intensity, and then ate meals that matched their caloric expenditure. The carbohydrate, fat, and protein content of these meals were also appropriately balanced to match their expenditure.

• They exercised for approximately 90 min at moderate intensity and then ate meals with relatively low carbohydrate content, but they ate enough total calories to match their calorie expenditure. This reduced-carbohydrate meal contained about 200 grams of carbohydrate, less than half the carbohydrate content of the balanced meal.

• They exercised for approximately 90 min at moderate intensity and then ate relatively low-calorie meals, that is, meals that provided less energy than was expended (about one-third fewer calories than the meals in the other two exercise trials). These meals contained a relatively high carbohydrate content to replace the carbohydrate “burned” during exercise.

The exercise was performed on a stationary bicycle and a treadmill. The order in which the participants did the trials was randomized.

In the three exercise trials, there was a trend for an increase in insulin sensitivity. However, when participants ate less carbohydrate after exercise, this enhanced insulin sensitivity significantly more. Although weight loss is important for improving metabolic health in overweight and obese people, these results suggests that people can still reap some important health benefits from exercise without undereating or losing weight, Dr. Horowitz said.

The study also reinforces the growing body of evidence that each exercise session can affect the body’s physiology and also that differences in what you eat after exercise can produce different physiological changes.

The research team is now performing experiments with obese people, aimed at better identifying the minimum amount of exercise that will still improve insulin sensitivity at least into the next day.

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Story Source: Adapted from materials provided by  The American Physiological Society.

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If you are considering weight loss surgery, you owe it to yourself to choose a physician who is not only highly skilled, but caring and compassionate as well. Many physicians out there will treat your obesity. Dr. Waggoner will treat you!

Contact Bradley Waggoner, MD:

• If you are ready to set-up an appoint to discuss your weight loss options.
• Reserve your seat at the next free informational seminar outlining your obesity surgery options (including lap-band system procedures) and meet Bradley Waggoner in person.

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New Research Findings Link Fat to Decreased Heart Function

Researchers from Boston University School of Medicine (BUSM)¹ have shown that fat collection in different body locations, such as around the heart and the aorta and within the liver, are associated with certain decreased heart functions. The study, which appears on-line in Obesity, also found that measuring a person’s body mass index (BMI) does not reliably predict the amount of undesired fat in and around these vital organs.

The prevalence of obesity is rising rapidly in the United States. Recent estimates suggest that approximately 30 percent of the adult population meets this criterion. Past studies have shown that fat accumulation in the liver and around the heart are linked to cardiovascular disease and type 2 diabetes.

BUSM researchers compared fat volumes in obese persons (BMI over 30), all of whom had high blood pressure and/or diabetes, and lean healthy persons (average BMI of 22). All subjects underwent magnetic resonance imaging (MRI) and proton MR spectroscopy to quantify pericardial and peri-aortic lipid volumes, cardiac function, aortic compliance and intra-hepatic lipid content. Fasting plasma lipoproteins, glucose, insulin, and free fatty acids were also measured among the subjects.

The researchers found fat collections in anatomically separate locations, such as within the liver and around the heart, to be associated to cardiovascular function – including a decrease in cardiac pumping function – as fat around the heart increased. However, they also found that the amount of fat around the heart and aorta was not predicted by the BMI of the individual in this population.

“Our study found that fat collection around the heart, the aorta and within the liver is clearly associated with decreased heart functions and that an MRI can quickly and noninvasively measure fat volume in these areas. Our study also found that looking at BMI of the individual does not reliably predict the amount of undesired fat in and around organs,” said James Hamilton, PhD, senior author and project leader, and a professor of biophysics, physiology and biomedical engineering at BUSM.

According to the researchers, this method of measuring cardiac function and fat deposits can be done in less than one hour, and may provide a basis for future individualized treatment.

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¹Digravio, Gina M. (2009, November 13). Boston University School of Medicine.  http://www.bu.edu/research/highlights/news/

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Helping the Obese Fight Loss of Muscle Function

Experts at The University of Nottingham¹ are working on ground-breaking research to determine, for the first time, precisely what damage obesity can inflict on the muscles in our body.

It is hoped their research, funded by the Biotechnology and Biological Sciences Research Council (BBSRC), will lead to more effective treatment strategies for the obese to minimize muscle complications.

Professor Paul Greenhaff in the School of Biomedical Sciences along with Professor Michael Rennie in the School of Graduate Entry Medicine and Health has been awarded nearly £600,000 [$982,200 U.S.] to carry out the research. Professor Greenhaff said: “This work is essential because it will further our understanding of the health consequences of obesity which is all the more important given the purported obesity epidemic threatening to face the western world in future years.”

Based in the School of Biomedical Sciences, Professor Greenhaff and his team have already shown the release of cytokines — small inflammatory-inducing proteins — to coincide with molecular events that slow down the skeletal muscle making process and speed up the rate of muscle breakdown. Cytokines, released from the fat cells of the body, are elevated in obese individuals at low levels for long periods of time and the researches will be investigating what consequences this has on muscle.

Skeletal muscle plays an essential role in our daily lives — it helps us move, control our posture, and acts as an important fuel source when we become ill. Despite the increasing incidence of obesity and the potential loss of muscle function, the effect of low level and persistent inflammation — induced by obesity — remains largely unknown. Furthermore, the potential negative effects of obesity —induced inflammation on muscle processes — may become even more pronounced as we age due to the natural loss of muscle mass in later years.

Researchers are recruiting a group of obese and healthy normal-weight volunteers. Scientists will measure the rates of synthesis and breakdown of muscle proteins in conjunction with rates of carbohydrate oxidation in obese individuals and compare them to rates determined in healthy non-obese volunteers and see how they differ. Muscle biopsies will be taken to examine the molecular signaling events that underpin these processes. 

The researchers also want to know if an insulin sensitizing drug, known to limit the release of cytokines from fat cells, can reverse any effect of obesity on the synthesis and breakdown of muscle proteins and whether this could lead to functional improvements. These studies will determine, for the first time, the effect of obesity associated low-dose chronic inflammation on essential muscle events.

Professor Greenhaff said: “Despite the serious implications, there is a dearth of information on this topic. Our research is of such magnitude that if we can find the answers, it will create a multitude of future research avenues that could be explored by the wider scientific community. This could have wide-reaching implications for the many disease states characterized by low-grade chronic inflammation.”

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¹The University of Nottingham. September 16, 2009. http://research.nottingham.ac.uk/NewsReviews/newsDisplay.aspx?id=635. Nottingham was designated as a Science City in 2005 in recognition of its rich scientific heritage, industrial base and role as a leading research center. Nottingham has since embarked on a wide range of business, property, knowledge transfer and educational initiatives (www.science-city.co.uk) in order to build on its growing reputation as an international center of scientific excellence. The University of Nottingham is a partner in Nottingham: the Science City.
 
More information is available from Professor Paul Greenhaff on +44 (0)115 823 0133, paul.greenhaff@nottingham.ac.uk.

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Pancreatic Fat Levels May Help Predict Diabetes

Researchers have long suspected that overweight people tend to have large fat deposits in their pancreases, but they’ve been unable to confirm or calculate how much fat resides there because of the organ’s location.

Until now.

Scientists at UT Southwestern Medical Center¹ are the first in the U.S. to use an imaging technique called magnetic resonance spectroscopy (MRS) to measure the amount of pancreatic fat in humans. Though scientists worldwide already use MRS to investigate a number of diseases including breast cancer and epilepsy, the UT Southwestern group has successfully used the noninvasive method to measure pancreatic fat.

Findings from a new UT Southwestern study available online and in a future issue of the Journal of Clinical Endocrinology and Metabolism suggest that measuring pancreatic fat content in people could one day serve as an effective clinical tool to identify those at high risk of diabetes and monitor interventions designed to prevent the disease.

“These are very early results, but if they hold true, pancreatic MRS would be a fast and noninvasive test to screen people at risk for diabetes either because they’re obese or they have a family history of type 2 diabetes, or metabolic syndrome,” said Dr. Ildiko Lingvay, assistant professor of internal medicine at
UT Southwestern and lead author of the study. “It could potentially tell physicians which patients are most likely to develop diabetes in the near future and thus are in need of more aggressive interventions.”

MRS is a specialized technique similar to magnetic resonance imaging (MRI). It uses no radiation and is completely noninvasive. The test generally takes 20 to 30 minutes. Whereas an MRI can tell clinicians where a tumor is located, MRS can tell those physicians whether the tumor is malignant by providing biochemical information about specific tissues in the body rather than simply detecting the existence of those tissues, Dr. Lingvay said.

For this study, researchers used MRS to measure the amount of pancreatic fat in 79 adult volunteers. The research team obtained duplicate measurements one to two weeks apart from 33 study participants to make sure the results could be replicated over time.

The volunteers were divided into four groups according to their body mass index (BMI) and glucose tolerance. BMI is a weight-to-height ratio commonly used in to gauge obesity. A normal BMI is between 18.5 and 25; someone with a BMI of 40 or more is considered morbidly obese. All participants underwent numerous physical measurements including height, weight and blood pressure in addition to extensive clinical evaluations.

Using MRS, the researchers found that the overweight and obese volunteers had significantly more pancreatic fat than did those in the lean group. The volunteers who had similar BMIs but had already developed either pre-diabetes or diabetes had even more pancreatic fat.

MRS has not been approved for routine clinical use, but Dr. Lingvay said this research shows that it could be a very valuable tool for studying the pancreas without a biopsy. “This technology represents a good opportunity for clinicians to pursue research that hasn’t been possible because of the lack of advanced tools,” she said.

The next step, Dr. Lingvay said, is to determine whether reducing the amount of fat in the pancreas lowers diabetes risk.

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¹UT Southwestern Medical Center. September 22, 2009. http://www8.utsouthwestern.edu/utsw/cda/dept353744/files/549975.html. Other UT Southwestern researchers involved in the study included Dr. Victoria Esser, associate professor of internal medicine; Jaime Legendre, recipient of a Clinical Research Fellowship from the Doris Duke Charitable Foundation; Dr. Angela Price, postdoctoral clinician trainee in internal medicine; Kristen Wertz, research associate in internal medicine; Beverley Adams Huet, assistant professor of clinical sciences; Dr. Song Zhang, assistant professor of clinical sciences; Dr. Roger Unger, professor of internal medicine; and Dr. Lidia Szczepaniak, former assistant professor of internal medicine and radiology.

The study was supported by the National Institutes of Health and the Doris Duke Charitable Foundation.

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If you are considering weight loss surgery, you owe it to yourself to choose a physician who is not only highly skilled, but caring and compassionate as well. Many physicians out there will treat your obesity. Dr. Waggoner will treat you!

Contact Bradley Waggoner, MD:

• If you are ready to set-up an appoint to discuss your weight loss options.
• Reserve your seat at the next free seminar on Lap-Band Surgery and meet Bradley Waggoner in person.

If you'd like to set-up an appointment to further discuss your weight loss surgical options, please contact us.

How Obesity Increases the Risk for Diabetes

The Battle for CRTC2

Obesity is probably the most important factor in the development of insulin resistance, but science's understanding of the chain of events is still spotty. Now, researchers at the Salk Institute for Biological Studies have filled in the gap and identified the missing link between the two. Their findings, published in the June 21, 2009 advance online edition of the journal Nature, explain how obesity sets the stage for diabetes and why thin people can become insulin-resistant.

The Salk team¹, led by Marc Montminy, Ph.D., a professor in the Clayton Foundation Laboratories for Peptide Biology, discovered how a condition known as ER (endoplasmic reticulum) stress, which is induced by a high fat diet and is overly activated in obese people, triggers aberrant glucose production in the liver, an important step on the path to insulin resistance.

In healthy people, a "fasting switch" only flips on glucose production when blood glucose levels run low during fasting. "The existence of a second cellular signaling cascade—like an alternate route from A to B—that can modulate glucose production, presents the potential to identify new classes of drugs that might help to lower blood sugar by disrupting this alternative pathway," says Montminy.

It had been well established that obesity promotes insulin resistance through the inappropriate inactivation of a process called gluconeogenesis, where the liver creates glucose for fuel and which ordinarily occurs only in times of fasting. Yet, not all obese people become insulin resistant, and insulin resistance occurs in non-obese individuals, leading Montminy and his colleagues to suspect that fasting-induced glucose production was only half the story.

"When a cell starts to sense stress a red light goes on, which slows down the production of proteins," explains Montminy. "This process, which is known as ER stress response, is abnormally active in livers of obese individuals, where it contributes to the development of hyperglycemia, or high blood glucose levels. We asked whether chronic ER stress in obesity leads to abnormal activation of the fasting switch that normally controls glucose production in the liver." The ER, short for endoplasmic reticulum, is a protein factory within the cell.

To test this hypothesis the Salk team asked whether ER stress can induce gluconeogenesis in lean mice. Glucose production is turned on by a transcriptional switch called CRTC2, which normally sits outside the nucleus waiting for the signal that allows it to slip inside and do its work. Once in the nucleus, it teams up with a protein called CREB and together they switch on the genes necessary to increase glucose output. In insulin-resistant mice, however, the CRTC2 switch seems to get stuck in the "on" position and the cells start churning out glucose like sugar factories in overdrive.

Surprisingly, when postdoctoral researcher and first author Yiguo Wang, Ph.D., mimicked the conditions of ER stress in mice, CRTC2 moved to the nucleus but failed to activate gluconeogenesis. Instead, it switched on genes important for combating stress and returning cells to health. On closer inspection, Wang found that in this scenario CRTC2 did not bind to CREB but instead joined forces with another factor, called ATF6a.

What's more, like jealous lovers CREB and ATF6a competing for CRTC2's affection—the more ATF6a is bound to CRTC2, the less there is for CREB to bind to. "This clever mechanism ensures that a cell in survival mode automatically shuts down glucose production, thus saving energy," says Wang.

This observation led the researcher to ask what happens to ATF6a following the kind of persistent stress presented by obesity? They found that the levels of ATF6a go down when ER stress is chronically activated, compromising the cells' survival pathway and favoring the glucose production pathway; hyperglycemia wins in conditions of persistent stress.

Explains Wang, "Our study helps to explain why obese people have a stronger tendency to become diabetic. When ER stress signaling is abnormal glucose output is actually increased."

"It is possible that mutations in the highly conserved CRTC2 lead to a predisposition to inappropriate gluconeogenesis," says Montminy, who is now trying to identify natural mutations in CRTC2 that may lead to insulin resistance in carriers.

In addition to Drs. Wang and Montminy, researchers contributing to this study include research technician Liliana Vera, and Wolfgang H. Fischer, Ph.D., director of the Mass Spectrometry Core Facility.

The work was supported by grants from the National Institutes of Health, the Clayton Foundation for Medical Research, the Kiekhefer Foundation and the Vincent J. Coates Foundation.

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¹Salk Institute for Biological Studies. June 21, 2009. http://www.salk.edu/news/pressrelease.php?page_num=3. Focused on both discovery and mentoring future generations of researchers, Salk scientists make groundbreaking contributions to our understanding of cancer, aging, Alzheimer's, diabetes, and cardiovascular disorders by studying neuroscience, genetics, cell and plant biology, and related disciplines. Founded in 1960 by polio vaccine pioneer Jonas Salk, M.D., the Institute is an independent nonprofit organization and architectural landmark. For more information about the Salk Institute for Biological Studies, visit http://www.salk.edu/.

* * *

If you are considering weight loss surgery, you owe it to yourself to choose a physician who is not only highly skilled, but caring and compassionate as well. Many physicians out there will treat your obesity. Dr. Waggoner will treat you!

To contact us for more information and/or to reserve your seat for the next free seminar, please click here.

The Battle for CRTC2

Obesity is probably the most important factor in the development of insulin resistance, but science's understanding of the chain of events is still spotty. Now, researchers at the Salk Institute for Biological Studies have filled in the gap and identified the missing link between the two. Their findings, published in the June 21, 2009 advance online edition of the journal Nature, explain how obesity sets the stage for diabetes and why thin people can become insulin-resistant.

The Salk team¹, led by Marc Montminy, Ph.D., a professor in the Clayton Foundation Laboratories for Peptide Biology, discovered how a condition known as ER (endoplasmic reticulum) stress, which is induced by a high fat diet and is overly activated in obese people, triggers aberrant glucose production in the liver, an important step on the path to insulin resistance.

In healthy people, a "fasting switch" only flips on glucose production when blood glucose levels run low during fasting. "The existence of a second cellular signaling cascade—like an alternate route from A to B—that can modulate glucose production, presents the potential to identify new classes of drugs that might help to lower blood sugar by disrupting this alternative pathway," says Montminy.

It had been well established that obesity promotes insulin resistance through the inappropriate inactivation of a process called gluconeogenesis, where the liver creates glucose for fuel and which ordinarily occurs only in times of fasting. Yet, not all obese people become insulin resistant, and insulin resistance occurs in non-obese individuals, leading Montminy and his colleagues to suspect that fasting-induced glucose production was only half the story.

"When a cell starts to sense stress a red light goes on, which slows down the production of proteins," explains Montminy. "This process, which is known as ER stress response, is abnormally active in livers of obese individuals, where it contributes to the development of hyperglycemia, or high blood glucose levels. We asked whether chronic ER stress in obesity leads to abnormal activation of the fasting switch that normally controls glucose production in the liver." The ER, short for endoplasmic reticulum, is a protein factory within the cell.

To test this hypothesis the Salk team asked whether ER stress can induce gluconeogenesis in lean mice. Glucose production is turned on by a transcriptional switch called CRTC2, which normally sits outside the nucleus waiting for the signal that allows it to slip inside and do its work. Once in the nucleus, it teams up with a protein called CREB and together they switch on the genes necessary to increase glucose output. In insulin-resistant mice, however, the CRTC2 switch seems to get stuck in the "on" position and the cells start churning out glucose like sugar factories in overdrive.

Surprisingly, when postdoctoral researcher and first author Yiguo Wang, Ph.D., mimicked the conditions of ER stress in mice, CRTC2 moved to the nucleus but failed to activate gluconeogenesis. Instead, it switched on genes important for combating stress and returning cells to health. On closer inspection, Wang found that in this scenario CRTC2 did not bind to CREB but instead joined forces with another factor, called ATF6a.

What's more, like jealous lovers CREB and ATF6a competing for CRTC2's affection—the more ATF6a is bound to CRTC2, the less there is for CREB to bind to. "This clever mechanism ensures that a cell in survival mode automatically shuts down glucose production, thus saving energy," says Wang.

This observation led the researcher to ask what happens to ATF6a following the kind of persistent stress presented by obesity? They found that the levels of ATF6a go down when ER stress is chronically activated, compromising the cells' survival pathway and favoring the glucose production pathway; hyperglycemia wins in conditions of persistent stress.

Explains Wang, "Our study helps to explain why obese people have a stronger tendency to become diabetic. When ER stress signaling is abnormal glucose output is actually increased."

"It is possible that mutations in the highly conserved CRTC2 lead to a predisposition to inappropriate gluconeogenesis," says Montminy, who is now trying to identify natural mutations in CRTC2 that may lead to insulin resistance in carriers.

In addition to Drs. Wang and Montminy, researchers contributing to this study include research technician Liliana Vera, and Wolfgang H. Fischer, Ph.D., director of the Mass Spectrometry Core Facility.

The work was supported by grants from the National Institutes of Health, the Clayton Foundation for Medical Research, the Kiekhefer Foundation and the Vincent J. Coates Foundation.

* * *

¹Salk Institute for Biological Studies. June 21, 2009. http://www.salk.edu/news/pressrelease.php?page_num=3. Focused on both discovery and mentoring future generations of researchers, Salk scientists make groundbreaking contributions to our understanding of cancer, aging, Alzheimer's, diabetes, and cardiovascular disorders by studying neuroscience, genetics, cell and plant biology, and related disciplines. Founded in 1960 by polio vaccine pioneer Jonas Salk, M.D., the Institute is an independent nonprofit organization and architectural landmark. For more information about the Salk Institute for Biological Studies, visit http://www.salk.edu/.

* * *

If you are considering weight loss surgery, you owe it to yourself to choose a physician who is not only highly skilled, but caring and compassionate as well. Many physicians out there will treat your obesity. Dr. Waggoner will treat you!

To contact us for more information and/or to reserve your seat for the next free seminar, please click here.