The Brain Controls Insulin Action

Insulin regulates blood glucose primarily by two mechanisms:

1. Suppressing glucose production by the liver
2. Enhancing glucose uptake by other tissues, particularly muscle and liver

Since the cells contained in liver, muscle and other tissues respond directly to insulin stimulation, most people don't think about the role of the brain in this process.  An interesting paper just published in Diabetes reminds us of the central role of the brain in glucose metabolism as well as body fat regulation (1).  Investigators showed that by inhibiting insulin signaling in the brains of mice, they could diminish insulin's ability to suppress liver glucose production by 20%, and its ability to promote glucose uptake by muscle tissue by 59%.  In other words, the majority of insulin's ability to cause muscle to take up glucose is mediated by its effect on the brain. 

Read more »

NEW GUIDELINES FOR REIRRADIATION OF HEAD AND NECK CANCER

When head and neck cancer recurs and surgery is not an option, reirradiation provides the only potentially curative option. However, because the tumor often recurs in the same place or very close to tissue that has already been irradiated, this treatment approach represents a "significant challenge."
For this reason, it should be handled at a tertiary-care center, according to a new guideline issued by the American College of Radiology. Specifically, it stipulates that the tertiary center should have a head and neck oncology team that is equipped with the resources and the experience to manage the complexities and toxicities of retreatment.
In the guideline, published in the International Journal of Radiation Oncology, Biology and Physics, a panel of experts outline appropriateness criteria for various clinical scenarios that arise with such patients.
"This is an important document because it is the first set of guidelines for the potentially curative treatment of patients who have regrowth of head and neck tumors. It provides a consensus on how patients should be managed," coauthor Madhur Kumar Garg, MD, said in a statement. Dr. Garg is from the Department of Radiation Oncology at Montefiore Medical Center, in the Bronx, New York, where about a dozen reirradiation procedures are performed annually.
Commitment to Retreatment
Retreatment is justified because clinical trial results have shown that local treatment improves overall survival, the panel of experts notes.
However, they emphasize that, before a commitment to retreatment is made, patients presenting with recurrent or second primary tumors need to undergo careful restaging evaluation. In addition to computed tomography (CT) or magnetic resonance imaging to evaluate the extent of the recurrent tumor, the panel urges that strong consideration be given to positron emission tomography with CT to evaluate for metastatic disease, or "at a minimum, a CT scan of the chest should be performed."
In addition, a detailed history and assessment is needed, which includes documentation of the sequelae of previous treatment, such as fibrosis, carotid stenosis, dysphagia, xerostomia, and osteoradionecrosis.
Retreatment options include surgical resection and palliative chemotherapy — both are regarded as standard of care, the panel writes. But for patients with unresectable disease, reirradiation is the "only potentially curative treatment," they add.
Two phase 2 clinical trials conducted by the Radiation Therapy Oncology Group (RTOG) have shown survival outcomes with reirradiation plus chemotherapy that appear to be superior to those seen with chemotherapy alone in other studies. However, "whether this apparent improvement is the result of selection bias is uncertain," the panel explains. A larger phase 3 comparing reirradiation plus chemotherapy with chemotherapy alone was closed because of poor accrual.
In terms of the dose of radiation delivered in the second treatment course, it appears that at least 50 to 60 Gy is needed, the experts report. Both of the phase 2 studies conducted by the RTOG delivered a total dose of 60 Gy, using an accelerated hyperfractionated regimen delivering 1.4 Gy twice daily in 4 week-on/week-off cycles. Multiple single-institution reports of reirradiation have used once-daily standard fractionation in a planned continuous treatment course with less toxicity, they note. However, differences in study designs and in the chemotherapy regimens make it difficult to discern what independent effect, if any, differences in radiation fractionation had on the toxicity that was seen.

Harvard Food Law Society "Forum on Food Policy" TEDx Conference

Last Friday, it was my pleasure to attended and present at the Harvard Food Law Society's TEDx conference, Forum on Food Policy.  I had never been to Cambridge or Boston before, and I was struck by how European they feel compared to Seattle.  The conference was a great success, thanks to the dedicated efforts of the Food Law Society's presidents Nate Rosenberg, Krista DeBoer, and many other volunteers. 

Dr. Robert Lustig gave a keynote address on Thursday evening, which I unfortunately wasn't able to attend due to my flight schedule.  From what I heard, he focused on practical solutions for reducing national sugar consumption, such as instituting a sugar tax.  Dr. Lustig was a major presence at the conference, and perhaps partially due to his efforts, sugar was a central focus throughout the day.  Nearly everyone agrees that added sugar is harmful to the nation's health at current intakes, so the question kept coming up "how long is it going to take us to do something about it?"  As Dr. David Ludwig said, "...the obesity epidemic can be viewed as a disease of technology with a simple, but politically difficult solution".

Read more »

Losing Fat With Simple Food-- Two Reader Anecdotes

Each week, I'm receiving more e-mails and comments from people who are successfully losing fat by eating simple (low reward) food, similar to what I described here.  In some cases, people are breaking through fat loss plateaus that they had reached on conventional low-carbohydrate, low-fat or paleo diets.  This concept can be applied to any type of diet, and I believe it is an important characteristic of ancestral food patterns.

At the Ancestral Health Symposium, I met two Whole Health Source readers, Aravind Balasubramanian and Kamal Patel, who were interested in trying a simple diet to lose fat and improve their health.  In addition, they wanted to break free of certain other high-reward activities in their lives that they felt were not constructive.  They recently embarked on an 8-week low-reward diet and lifestyle to test the effectiveness of the concepts.  Both of them had previously achieved a stable (in Aravind's case, reduced) weight on a paleo-ish diet prior to this experiment, but they still carried more fat than they wanted to.  They offered to write about their experience for WHS, and I thought other readers might find it informative.  Their story is below, followed by a few of my comments.

Read more »

The Case for the Food Reward Hypothesis of Obesity, Part II

In this post, I'll explore whether or not the scientific evidence is consistent with the predictions of the food reward hypothesis, as outlined in the last post.

Before diving in, I'd like to address the critique that the food reward concept is a tautology or relies on circular reasoning (or is not testable/falsifiable).  This critique has no logical basis.  The reward and palatability value of a food is not defined by its effect on energy intake or body fatness.  In the research setting, food reward is measured by the ability of food or food-related stimuli to reinforce or motivate behavior (e.g., 1).  In humans, palatability is measured by having a person taste a food and rate its pleasantness in a standardized, quantifiable manner, or sometimes by looking at brain activity by fMRI or related techniques (2).  In rodents, it is measured by observing stereotyped facial responses to palatable and unpalatable foods, which are similar to those seen in human infants.  It is not a tautology or circular reasoning to say that the reinforcing value or pleasantness of food influences food intake and body fatness. These are quantifiable concepts and as I will explain, their relationship with food intake and body fatness can be, and already has been, tested in a controlled manner. 

1.   Increasing the reward/palatability value of the diet should cause fat gain in animals and humans

Read more »

CHEMOTHERAPY CAN BE USED SAFELY AFTER FIRST TRIMESTER OF PREGNANCY

A cancer diagnosis can be devastating, but is even more traumatic when the patient is pregnant. A new study offers some reassurance to pregnant patients and their physicians.
The results of the small study, presented during a presidential session here at the 2011 European Multidisciplinary Cancer Congress, show that children who were exposed to chemotherapy in utero did not appear to suffer any detrimental effects in terms of general health and neurologic and cardiac functioning.
Treating cancer in pregnant women is complex. One issue, in particular, is the ethics of treating a woman with chemotherapy, "but there are no good data that describe the ethics," said lead author Frederic Amant, MD, PhD, assistant professor, gynecologic oncologist, and head of the scientific section of gynecologic oncology at Katholieke Universiteit in Leuven, Belgium.
In Europe, there are approximately 2500 to 5000 cases of cancer diagnosed during pregnancy every year; however, it remains unclear how systemic chemotherapy affects the development of the fetus, he said.
This is a common situation, and one that many doctors face, said Michael Baumann, MD, PhD, a radiation oncologist from the University of Technology, Dresden, Germany, and president of the European CanCer Organisation. "That is why this study is so important," he said.
There are a lot of data related to radiotherapy and its use in pregnancy, said Dr. Baumann, who moderated a press briefing during which the highlights of this study were presented. " That there are now good data on chemotherapy.... This is a paradigm shift that we see here."
Neuro and Cardiac Function Normal
In their study, Dr. Amant and colleagues looked at the potential negative effects of in utero exposure to chemotherapy. Participants ranged in age from 18 months to 18 years. Of the 140 children currently in the study, complete data are available for 70.
The children were all evaluated at birth and approximately every 2 years after. Their general health was assessed, and they underwent neuropsychologic testing to assess intelligence, verbal and nonverbal memory, attention, working memory, and behavior.
The mean gestational age at cancer diagnosis was 18.1 weeks, and a total of 236 cycles of chemotherapy were given in the cohort.
About half of the women were diagnosed with breast cancer (51%), and 26% were diagnosed with hematologic cancers. Other diagnoses included cervical cancer, ovarian cancer, and malignancies of the brain, skin, and colorectum. Half of the patients (50%) received chemotherapy, and 38% underwent surgery and received chemotherapy. Treatment was given at a median gestational age of 17 weeks (range, 12 to 37 weeks).
The median gestational age of the children at birth was 35.7 weeks, and intrauterine growth retardation was observed in almost 21% of the children.
Cardiac function was evaluated by electrocardiography and echocardiography. It was necessary to assess for possible cardiac problems because the majority of these women were given anthracyclines, explained Dr. Amant. In breast and gynecologic cancers, "anthracyclines are very important. The majority of children — almost 80% — were exposed to anthracyclines, which can pass through the placenta, so it is very important to assess heart function."
The median follow-up was almost 2 years, although some were followed for up to 18 years.
At birth, no congenital heart defects were observed, and cardiac function was normal. Most of the children had adequate neurologic function and normal cardiac function, explained Dr. Amant; rates were similar to those seen in the general population.
High Rate of Premature Birth
Premature birth was very common in this population, with 47 of the 70 children born before 40 weeks of gestation (66%), and 7 born at 26 to 32 weeks.
Although cognitive development was in the normal range for the majority of the cohort, children who fell below the normal parameters tended to be premature. Because developmental delay is common in children who are premature, Dr. Amant explained, they are unable to tell if these issues are related to chemotherapy exposure.
"We can't exclude the effects of chemotherapy in preterm children," he told Medscape Medical News. "They do worse, we know that, but whether it's the prematurity or the chemotherapy — that is an unanswered question."
Because the majority of the children have done well, Dr. Amant surmised that the cognitive issues in those born premature are not related to the chemotherapy.
Normal findings were observed in 64 children (91.4%), which conforms to the general population.
Developmental Issues in Twins
Two serious problems emerged with a set of twins who were born at 32.5 weeks of gestation. The mother had been treated for leukemia. The male twin was autistic and had other serious neurodevelopmental delays and problems; the female twin also had some degree of neurodevelopmental delay.
Although prenatal exposure to chemotherapeutic agents cannot be completely ruled out, Dr. Amant feels that it was probably not the cause of the severe problems observed in the male twin. Geneticists who studied the data tend to think that the child had some sort of syndrome, he pointed out, which was not related to the chemotherapy. "But we can't rule it out right now," he said.
The high rate of prematurity seen in this study was not caused by chemotherapy, but was most likely related to the strategy of delivering the baby as soon as it becomes viable and then beginning chemotherapy, explained Dr. Amant.
Chemotherapy Should Not Be Feared
"Our message is that we prefer to give chemotherapy until the baby is mature; after the baby is delivered, we continue maternal treatment," said Dr. Amant. "The baby loses 2.5 IQ points for each week that he or she is delivered early."
"We think that the baby has less trauma from chemotherapy than from prematurity," he explained. "In our setting, this changes how we treat patients."
This is not a perfect study, Dr. Amant acknowledged; it was both retrospective and prospective, and had a relatively short follow-up.
"But we think that the fear of chemotherapy should no longer be an indication to terminate a pregnancy, and it should no longer be a reason to delay maternal treatment, which can affect maternal prognosis," Dr. Amant explained.
More Data Needed
"We are quite confident that these children will continue to perform normally, but we need more follow-up and more children," he said. "Right now, the group is too small to make a statement on clinical practice change."
George Pentheroudakis, MD, PhD, who acted as discussant for the paper, agrees that a longer follow-up is needed.
Although the study showed that chemotherapy can be administered with reasonable safety after the first trimester of pregnancy, there are still a number of unanswered questions, noted Dr. Pentheroudakis, who is from the University of Ioannina, Greece.
There are a few children in the study with severe neurocognitive deficits, he pointed out, noting that more careful interpretation of the results is needed. In addition, the "course of these deficits over time" need to be determined.
Undetected cardiac toxicity is a potential problem for these children. Although the electrocardiogram and echocardiogram are good tools, they might not be sensitive enough for the early detection of subclinical cardiac damage, he said.
Also, there was a high incidence of prematurity in the cohort. "What are the causes of prematurity," he wondered. "Is it maternal age, the presence of cancer,...or the cancer treatment that was administered?
Much is still unknown about the long-term effects of chemotherapy exposure, said Dr. Pentheroudakis. "We don't know about fertility or germ cell mutagenesis in the children and their future offspring. More data are needed."
For now, on the basis of these data, the fear of chemotherapy is not a reason to delay treatment that can affect maternal prognosis, he said. "It seems that chemotherapy can be administered with reasonable safety after the first trimester, and there is emerging evidence that the mid- and long-term health of these children is normal."

The Case for the Food Reward Hypothesis of Obesity, Part I

Introduction

When you want to investigate something using the scientific method, first you create a model that you hope describes a natural phenomenon-- this is called a hypothesis.  Then you go about testing that model against reality, under controlled conditions, to see if it has any predictive power.  There is rarely a single experiment, or single study, that can demonstrate that a hypothesis is correct.  Most important hypotheses require many mutually buttressing lines of evidence from multiple research groups before they're widely accepted.  Although it's not necessary, understanding the mechanism by which an effect occurs, and having that mechanism be consistent with the hypothesis, adds substantially to the case.

With that in mind, this post will go into greater detail on the evidence supporting food reward and palatability as major factors in the regulation of food intake and body fatness.  There is a large amount of supportive evidence at this point, which is rapidly expanding due to the efforts of many brilliant researchers, however for the sake of clarity and brevity, so far I've only given a "tip of the iceberg" view of it.  But there are two types of people who want more detail: (1) the skeptics, and (2) scientifically inclined people who want mechanism.  This post is for them.  It will get technical at times, as there is no other way to convey the material effectively.

Read more »