Friday, January 23, 2009

High PCB exposure tied to diabetes risk

Last Updated: 2008-08-15 11:43:12 -0400 (Reuters Health)

NEW YORK (Reuters Health) - People who have been exposed to high levels of toxic polychlorinated biphenyls (PCBs) may face an elevated risk of type 2 diabetes, a new study shows.

The findings, reported in the journal Diabetes Care, come from a long-term study of Taiwanese adults who, in the 1970s, had been poisoned by cooking oil contaminated with PCB pollutants.

Once used in products ranging from fluorescent lights and appliances to insulation and insecticide, PCBs were banned in the late 1970s as carcinogens and general health hazards. They linger in the environment, however.

In the new study, Dr. Yueliang Leon Guo, from the National Taiwan University in Taipei, and colleagues examined the incidence of type 2 diabetes among 378 Taiwanese "oil disease" victims and 370 of their neighbors who had not been poisoned.
They found that women who had been exposed to the PCB-laced oil were twice as likely as other women to develop type 2 diabetes over 24 years. And women who had been most severely affected by the PCB exposure had a more than five-times higher diabetes risk.

There were no similar risks seen in men, however.

Other studies have found that people with diabetes tend to have relatively higher levels of organic pollutants, such as PCBs, in their blood. In comments to Reuters Health, Guo said that since "everyone" has detectable PCB levels in his or her body, it's possible that exposure to such pollutants has helped feed the widespread rise in diabetes in recent decades.

"The public health implication of these findings can be huge," Guo added, "considering the burden of diabetes and its multiple long-term complications."

.SOURCE: Diabetes Care 2008, August 2008.

Saturday, January 10, 2009

Using inositol for promoting brain wellness: an interview with Robert Belmaker, MD

Robert Crayhon: Joining us now to discuss his groundbreaking research on inositol and mental health is psychiatrist and researcher Robert H. Belmaker, MD. Dr. Belmaker, would you please give us your educational background?

Robert Belmaker: I received my Bachelors Degree in 1967 at Harvard University and my MD in 1971 at Duke University. I then started a psychiatric residency at Duke and then went to the National Institutes of Mental Health as a clinical associate from 1972-1974. I then came to Israel in 1974 and completed my psychiatric residency. Eventually, I became director of research at the Jerusalem Mental Health Center in Jerusalem. Later, I became in addition, an associate professor of psychiatry at the Hebrew University School of Medicine in Jerusalem. In 1985 I came to the new medical school in Beersheva at Ben Gurion University to become the Hoffer-Vickar Chair of Psychiatry.

RC: Can you just describe for us briefly, your daily duties?

RB: I am a professor of psychiatry; I am the assistant director of the Beersheva Mental Health Center, so I have administrative duties. Every Monday I have a full clinic day with my own patients. Sometimes with my own 30 patients. Two to three times a week I do rounds on inpatients with the residents as well. So I have clinical, teaching and research duties.

RC: What got you interested in the role of nutrition in brain function as a psychiatrist?

RB: I think it's partly derived from some skepticism about the pharmaceutical companies. It is also derived from the feeling that so much of what we ingest everyday is food, and that chemicals in food must have some effect on our brain, and perhaps some potential therapeutic effects on the brain. But actually the chair of psychiatry that I am incumbent of was endowed by a family that has been famous for their interest in nutrition and psychiatry. I haven't decided to this day whether they found me and endowed the chair, or whether the endowment of the chair influenced my thinking. But, of course, Abram Hoffer, MD, PhD, from Canada has been interested and influential in nutrition and psychiatry for fifty years now. He published in the 1950s about nutrition and psychiatry when it was very unpopular, and he very bravely continued.

RC: Is the connection between nutrition and psychiatry any more popular now in psychiatric circles?

RB: There is an increase in interest in nutrition and psychiatry. However, like the increased interest in nutrition and medicine, it goes with a healthy degree of skepticism. There are a fair number of people who are suspicious -- perhaps sometimes rightly so -- of excessive claims. Often people with severe mental illnesses reject any drug treatment. They do that partly because of their illness in their thinking. Sometimes they use arguments derived from the nutrition literature and don't get proper pharmaceutical treatment. This is a shame, and this makes some psychiatrists in this position skeptical about nutrition. Clearly, however, some patients with heart disease need surgery and sometimes need triple artery by-pass, and other patients with high blood pressure are clearly going to need hypertensive and anti-hypertensive medicine. All cardiologists today know and believe and preach the role of nutrition in preventing heart disease and high blood pressure. So, the two should not be seen as antagonistic. In psychiatry there is no question that the anti-psychotic drugs and the mood stabilizer drugs are effective. But I think perhaps we are a little behind cardiology and some of the papers show that folate supplementation can enhance the ability of lithium to prevent mood disorders and the ability of anti-psychotic drugs to reduce psychosis. These papers are not given as much publicity and as much acceptance as they really deserve. I don't know if it's because they do not have a pharmaceutical company pushing folate -- because it's too cheap -- or whether it's the skepticism that might be a result of excessive claims of the past. Or perhaps it is the skepticism that is coming as an antidote to the fact that some patients refuse pharmaceutical treatment, and only want natural treatment. Often those patients are too sick to be able to make a rational decision.

RC: Dr. Belmaker, do you feel the future of psychiatry is an intelligent integration of pharmaceuticals and nutrients? And, should nutrients be tried first?

RB: I think we have to answer that question empirically. There are going to have to be studies, like the ones we did with inositol. There is no way to know what comes first and what comes second. Certainly in most cases nutrients are milder. If a person finds changing his diet can prevent his headaches, we would like to see him do that before he tries a strong medicine like Valproate to prevent a headache. Ultimately, it has to be an empirical question. We have to do the studies.

RC: What got you interested in inositol?

RB: I had been interested previously in lithium and I am still interested in lithium. As you know, lithium is a very simple compound and a non-patented compound and a cheap compound. Those are some of the things that keep my interest. I have been interested in lithium for 30 years. Lithium has a major effect on inositol and the brain that was discovered by a wonderful man, name of Dr. Berridge from London, a Nobel prize candidate for that work. That work was done on flies, of the salivary gland of the fruit fly. For those people who sometimes make jokes about how animal research is not relevant, here is an example of how something that seems terribly funny, the salivary gland of the fruit fly, has become a major area of scientific research, with many important benefits for humanity. He discovered the whole cycle, the inositol cycle of the cell, and that lithium had an effect on it. So, as a lithium researcher, I read his papers and got interested in inositol. Professor Berridge was very interested in how inos itol can affect cell function. We were really the first to think that one could possibly give inositol as a nutrient in quantities that could get it to the brain.

RC: How does lithium affect inositol's function?

RB: It's a bit complicated, and there are still disagreements about it. Lithium inhibits a key enzyme called inositol mono-phosphatase. Some people say, as a result, inositol levels in some areas in the brain should go down. Other people believe because that enzyme is inhibited, the inositol phosphates actually go up, and we really don't know which of those two things are more important in lithium action.

RC: What is the difference between inositol and myo-inositol? Is there a difference? Is it just two terms for the same thing?

RB: For a biologist they are two terms for the same thing. The only inositol that exists naturally in the body of the human or any other mammal is called myo-inositol. For a chemist, inositol can exist in eight different forms that are mirror images of each other, although it might be hard to imagine how you can have eight different mirror images; but that's because there are eight different places on the inositol molecule that a carbon and a hydroxyl group can have a mirror image. But, only the myo-inositol is present naturally so when I talk about inositol as a medicine or a cell, I can just drop the myo and call it inositol, because that is the only one that we have.

RC: What happens when the human body is given inositol orally?

RB: It depends on the dose. The doses that we found are large enough to get inositol into the brain are the dose equivalent of 3 to 6 teaspoons a day. That's 12 to 18 grams. It could be teaspoons in tea or in juice. That's the quantities that we are talking about. In order for these doses to be effective, they need to be taken over a period of three to four weeks. We found those doses to be as beneficial as anti-depressants used in depression, panic disorders and in obsessive-compulsive disorders. We've done one study in normal volunteers, who were given a much larger dose at a single time in the morning in a large cup of juice. They were given 12 grams in one swallow and then every hour they were asked to fill out rating scales as to their tension, mood, feelings of relaxation, feeling of wellbeing, welfare, things that a normal person would write, called a profile of mood scale (the scale for normal mood), and we found that indeed, even a single dose peaking at about six hours reduced tension and increased feelings of well-being. In depressed patients we don't see those effects quite so early. Perhaps because the depression is strong enough to mask them, and in these patients, inositol did not work any faster than standard antidepressants. It only had a significant and beneficial effect after about three weeks.

RC: How does inositol work?

RB: That of course is a very good question. We have done quite a bit of animal work in rats to look at the mechanism and we think that the strongest findings relate to serotonin and particularly the 5HT2 serotonin receptor. In a rat if you drip serotonin on neurons with those receptors, and measure the response, after a while the nerve cell stops responding and if you add inositol it jumps up and starts responding again. So, it seems like cells can get depleted of inositol. Or, specific nerve cells might not have enough to be able to maintain neurotransmission in the serotonergic system. Of course, there are many things we have not investigated, but it could be that some patients have deficiencies in the brain of inositol to the point where their serotonin system cannot respond.

We did do a study with brains donated after death from patients with depression, manic-depression and other mental illnesses, and no illness. These were given to us by the Stanley Research Foundation in Washington DC, which was able to obtain these brains from people who consented before their death to donate their brains. They were diagnosed before their death as suffering from these diseases. We did find a group of patients especially with affective disorder with low, very low inositol levels in the brain.

RC: Is there a way for most people through their diet to get enough inositol? When you are talking about a therapeutic dose in the 12-18 gram range, I am wondering where someone may get a gram of inositol on a daily basis though food.
RB: The usual intake is about a gram a day through food. I think it would be really hard to get 12 grams a day through food, I think that is really a pharmacological dose. Of course, prevention of depression might require a lower dose, and we have been interested. I have a colleague now, a dietitian, whom I have asked to do some surveys of the diet of people who come complaining of depression, to see whether there are different amounts of inositol. We also have a study that will be published in May in the American Journal of Psychiatry on omega-3 fatty acids, another nutrient that we found to be anti-depressant in depressed patients, and on this we were not the first.

RC: Has there been an actual clinical trial of omega-3 fats in depression?

RB: Let me just say one thing about the omega-3s. There is one previous study by Andy Stull of Boston, a Clinical Trial with positive results. What I wanted to say is that the omega-3s also are given in much higher doses than are present in the usual diet, even though there have been reports of a correlation in the usual diet, such that the people who eat more omega-3s get depressed less. It might be with some of these nutrients you need more to correct real depression than you do to prevent it.

RC: Which will bring us back to a lesson taught to us by Abram Hoffer decades ago -- that is exactly the case. If you are missing a nutrient for decades you might need a lot more for the rest of your life to get back to normal. Regarding inositol and the diet, my understanding is that inositol in our food is largely in the form of inositol hexaphosphate, which is in a form of fiber that's hard to absorb. In other words, it might be in the food, but how well we absorb it, I think is perhaps open to question.

RB: I think you are asking a very good question, it's something I am just getting very interested in, and don't have the answer for you.

RC: Let's talk about inositol in some other applications, to say it's effective in depression at doses of 12-18 grams, but you've got to give it three weeks to really see the results?

RB: That's right.

RC: What about agoraphobia?

RB: We tend to call this panic disorder, with or without agoraphobia. Same doses seem to be effective, and also our statistical significant results occurred at three weeks. There was a strong trend before that, but our statistical significant results occurred at about three weeks.

RC: What about obsessive-compulsive disorder and inositol?

RB: In obsessive-compulsive disorder our studies use 18 grams. I can't say it doesn't work less than that, the way it works with depression with 12 grams, but we just haven't tried it. These people tend to be more ill -- and started with 18 grams. We've only seen statistically significant improvement by about six weeks, not before that. It does take longer, which is similar to drug treatment for obsessive-compulsive disorder.

RC: And only with inositol monotherapy, with no other nutrient or drug?

RB: That's right.

RC: Very impressive. Did you arrive at these doses by clinically examining the fact that the 3 and 6 grams doesn't work and then titrating upward to 18 grams?

RB: We arrived at the doses actually first with the pharmacokinetic studies. We tested to see what doses were necessary to get a good rise in inositol in human spinal fluid. Less than 12 grams a day didn't achieve much of a rise. At 12 grams a day, there is a 70% rise in human spinal fluid inositol levels. We have tried some patients in the early days more than now on lower doses, so we had some feeling of what the dose should be. I must say it has not been done in a systematic way because these kinds of controlled trials are expensive. We haven't had the funding that the pharmaceutical companies have. To really work up inositol in the way you are describing with very large trials in multiple doses -- is a one hundred million dollar project. No one would give us this to study a non-patentable compound. We had some grants from NIH and from the Stanley Foundation, but we have not done a good dose response study.

RC: What about SSRI medications and inositol, since they seem to be accentuating the same pathway. What if someone is taking a Zoloft or a Prozac and they ask their physician, "Can I take inositol at the same time?"

RB: We have studied that, and we have not had side effects with it. But, to our surprise and disappointment, we did not see synergism. We would have hoped for synergism, but it seems that inositol works and the SSRIs worked. If you put the two of them together it doesn't work any better than inositol alone or SSRIs alone. So that SSRIs in that sense are an alternative to inositol, or inositol is an alternative to SSRIs. We don't have reason to believe that it is a good addition to a SSRI non-responder, although we have not found it in any way unsafe if someone wants to try.

RC: What if someone wants to transition off of a SSRI? Would inositol be a logical stepping-stone to perhaps a more natural approach to accentuating serotonin metabolism?

RB: It is certainly an option, but we don't have data on that. We have data on people who have been treated in the past with SSRIs successfully and on their next depressive episode they were treated successfully with inositol. But we don't actually have people going from one to the other in the same depressive episode.
RC: Let's talk about inositol and safety. You've used doses of 18 grams in your trials and your practice. Any side effects from these doses?

RB: Well, people will have some loose stools and about the same with some of the SSRIs. I would say about quarter of the patients will move their bowels more frequently. We've had very few people who have to stop the medicine for that reason. We have not seen any significant changes. By now we've have a fairly large number of patients with hematological or chemical parameters. This is a large number of patients for a natural compound, but these are still fewer patients than would be expected, let's say for the FDA. If it were a new SSRI, they would want a considerably larger number of patients.

RC: Is there anyone who should not take inositol?

RB: I think it would make sense for someone who was diabetic to be careful. Someone with severe kidney disease or liver disease to be careful with inositol but I think this is a very general medical consideration.

RC: And that's because inositol has a molecular similarity to glucose and because of this theoretically could raise blood sugar in diabetics?

RB: That's right.

RC: Any other pearls here for nutritional pharmacology research? You spoke about folate and omega-3s, any other information you would like to share with our readers?
RB: Well, I think one of the most exciting things that we've been doing lately is with homocysteine. Homocysteine is the amino acid that's not used in protein synthesis and its been shown to be a risk factor for cardiovascular disease over the last few years. In more recent years it's been proven to be a risk factor for Alzheimer's and cerebral vascular disorders as well. We thought that this might mean that it's a risk factor for mental disorder and we have been surveying homocysteine levels in our patients and have found markedly elevated levels of homocysteine. We have begun a trial of folate, B12 and B6 in schizophrenic patients, because these are known to be homocysteine lowering vitamins that can lower homocysteine levels by up to 50% in combination. Homocysteine has been shown in a test tube to be neurotoxic, so we think we might be able to prevent the clinical deterioration and cognitive deterioration in schizophrenia with homocysteine lowering.

RC: Have you seen lowering homocysteine to be an effective strategy; perhaps in the treatment of depression?

RB: We have not looked at that.

RC: What happens when you give a patient a good-sized powder container of inositol and say "Take 6 teaspoons per day, please." Do they look at you and say "why is this doctor giving me a nutrient, and so much of it?"

RB: Well, I explain it. Most of the patients that consent to be on our program are people who are looking for this. That's how they get to us. So we find it very acceptable among patients, compliance is very high.

RC: Does it matter if inositol is taken with food or not?

RB: No it doesn't. It's absorbed very well. We recommend it be taken with some food

Metagenics Cenitol Powder with Inositiol