August 2010 Issue | David R. Jacobs, PhD Mayo Professor of Public Health

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  • August 2010 Issue | David R. Jacobs, PhD Mayo Professor of Public Health




Welcome to Functional Medicine Update for August 2010. In this issue we’re going to explore a subject that I think for most of us is acknowledge as very important in understanding the etiology and management of chronic disease, but it is also fraught with a lot of confusion and misunderstanding and lack of specificity. I’m now talking about the environmental relationship to chronic illness.

I recall an Institute for Functional Medicine Symposium that occurred in Tucson, Arizona, more than a decade ago, where one of the world-renowned experts in the area of chemical carcinogenesis and mutatgenesis, Dr. Bruce Ames, spoke. Now Professor Emeritus at the University of California, Berkeley, Dr. Ames was Researcher of the Month just recently, talking about the work he has been doing in the area of long latency nutritional disorders associated with things like vitamin K deficiency. You’ll recall this very powerful interview we had with Dr. Ames on micronutrient deficiencies and metabolic tune-up.

This Symposium presentation that Dr. Ames gave years ago made a lot of the attendees quite upset. He made the comment that environmental chemicals were a fairly small contributor–in fact almost insignificant–to the rising tide and prevalence of chronic disease and specifically cancer, and that there were many other factors that played much more principal roles in the induction of chronic disease than environmental chemicals. I think ire was expressed by many of the participants at that meeting because of the perception of the environment and of the literally tens of thousands of new chemicals that have been introduced into it through the developments in petrochemical synthesis that have occurred since oil became the fuel powering the economic engine back in the early 20th century. The perception is these chemicals are the root culprit of many diseases as they have gotten into our environment and become persistent, get concentrated in lipophilic tissues, and ultimately adversely infect organ systems like the nervous system or the immune system. This then leads to regulatory signaling difficulties on all of function and produces a variety of different diseases based upon the individual’s genotype. That’s a model that has been held as a presumption within the field for some period of time, for which Dr. Ames’ comments seem to be contradictory.

This very complicated question about the relationship between the environment and our health opens up some important landscape principles that we need to define before we can really understand whether these connections are real or not). Those connections have to do with things like genetic variability and susceptibility, and the recognition of the diversity of genomic characteristics that relate to how we respond individually to our environment.

Single Nucleotide Polymorphisms Affect Variability and Response
The age of molecular genetics, which is now upon us, has really rapidly and dramatically changed since Dr. Ames made his comments more than 10 years ago. The human genome project has concluded. They are now starting to look at the number of single nucleotide polymorphisms present in the human genome (recognizing that there are over two million different SNPs that have been identified) and what effects they have on variability and response of an individual to their environment.. That would be number one.

Toxicology: Low-Level Exposure Over Time Can Have Subtle Effects
Number two is the difference between what I would call a toxicological view of environmental exposure (one chemical at a time, looking for a specific mutational injuries), and how exposures can induce alteration in the mechanics of the cell (the hard wiring of the cell) to actually produce disease later. There are now very significant emerging suggestions that the role of chemicals, taken multiple at a time at very low levels, may be much more subtle on physiological function than the traditional toxicological injury model. In fact, the analogy to this is a little bit like the analogy between looking at drug effects (pharmaceutical drugs) on physiology versus nutrient effects: we say drugs hit single metabolic steps very hard, so they have a jackhammer effect, versus nutrients that influence each step maybe very mildly, but the complex nature of modulation of systems biology by nutrients may produce a more remarkable effect over time than a drug which is influencing one step very hard and locking down that physiological function.

It is a different kind of effect. It is a systems effect versus a step-wise effect. It is a web versus a pathway effect. That may be what we are looking at here as it relates to low-level exposure to multiple chemicals in the environment and how they influence cell signaling. This whole question of intercellular signal transduction-how outside environmental messages get transduced into intracellular function and finally into the phenotype of the cell-is only now emerging as a well recognized component of biomedicine. The tools that come out of informational science/computational biology are allowing the large amounts of data that is required to be assessed, compiled, and analyzed to evaluate systems effects to now start to be approachable. We are starting to see more and more studies that are looking at systems-wide influence on function as a consequence of exposure to a complex array of different environmental signals and chemicals.

That is the context for the discussion this month. By the way, I’m very excited to say we will actually carry over this discussion into September. We are going to follow on from our interview with world-renowned researcher this month, Dr. David Jacobs, from the Division of Epidemiology and Health at the University of Minnesota School of Public Health, and speak with Dr. Randy Jirtle next month, who I’m sure is familiar to many of you who have beenFunctional Medicine Updat subscribers for awhile.

Dr. Jirtle is at Duke University Medical Center in the Department of Radiation Oncology. Two years ago we discussed the work he had done on the Agouti mouse, showing what happens when you supplement the pregnant mouse with high levels of methylating nutrients. He was able to produce for the first time what is called a pseudo-Agouti mouse. The fur color changed, but more than that, the physiochemistry of the mouse changed. This Agouti mouse, which is known to be diabetic, obese, and get heart disease and cancer suddenly didn’t get obese. Not only was its fur a different color, but it also didn’t get diabetes, it didn’t have the same incidence of cancer, and it lived longer. This was done without changing its genes, but rather just changing the environmental signaling of its genes through epigenetic imprinting. We’ll talk more about that, obviously, in September with Dr. Jirtle, but I just want to alert you to the fact that this topic that we are describing-environmental modulation of intercellular signaling-will be kind of a two-part series, starting this month with Dr. Jacobs and moving next month into a subsequent discussion with Dr. Jirtle

With that in mind, let’s talk a little bit about what we mean by environmental signals influencing the cellular phenotype. There’s probably no better example of this than the role that low level chemicals seem to be having on signaling that associates it in the phenotype with diabetes, cardiovascular disease, certain cancers, and even obesity. We have discussed this in previous issues of Functional Medicine Update over the last several years. We started discussing this because of the recognition that there seemed to be some connection between persistent organic pollutants (POPs) and later stage onset of metabolic syndrome, insulin resistance, hyperinsulinemia, obesity, and even type 2 diabetes.

Connecting POPs to Later Stage Onset of Disease: The Research of Dr. David Jacobs and Dr. Duk-Hee Lee
This construct of correlation-epidemiological/statistical correlation-was seen through an analysis that was done of the NHANES III (the Health and Nutrition Examination Survey III data) by Dr. Jacobs and Dr. Lee. They showed that there was no direct relationship between body mass index and diabetes (meaning fat people didn’t correlate well with diabetes), but they did see an association when they included another variable, which was elevated plasma levels within the normal range of activity of an enzyme called gamma-glutamyl transpeptidase (GGT).

Gamma-Glutamyl Transpeptidase (GGT): An Enzyme Involved with Glutathione Recycling
In clinical chemistry, most of us know this enzyme, GGT, is used for evaluating drug or alcohol addiction and for sobriety programs. Generally we differentiate it from ALT and AST, the traditional liver test enzymes, which are related to things like hepatitis and cirrhosis. GGT is more related to alcohol and drug-related functions. Not to get too deeply into biochemistry, I just want to remind you that gamma glutamic acid is a very unusual amino acid. It actually doesn’t appear in normal protein synthesis, where we have alpha amino acids that are involved with protein synthesis and the poly peptides that we call proteins. Gamma glutamic acid is connected to its neighbors in a different kind of configuration-a gamma linkage versus an alpha linkage-and in this case, there is really only one place where gamma glutamic acid is seen in prevalence in human physiology and that is in the tripeptide that we call glutathione. Gamma-glutamyl transpeptidase is an enzyme that is involved with glutathione recycling/resynthesis, and therefore, in part, GGTP may have a functional significance related to the synthesis of a very important biomolecule in cellular physiology: glutathione.

The Functions of Glutathione in Cellular Physiology
Glutathione has three general principal functions in cellular physiology. First, it has a role in antioxidation; in the redox control it is the most prevalent intercellular antioxidant in human physiology. It shuttles itself between glutathione disulfide (the oxidized form) and reduced glutathione. There are enzymes, glutathione peroxidase (selenium-containing enzyme), and glutathione reductase (requires FADH2 which is a riboflavin-related cofactor-stimulated enzyme). Glutathione reductase and glutathione peroxidase work as a shuttle to keep glutathione in the right balance between the reduced and oxidized forms. Generally we say that in a cellular milieu we have more reduced glutathione (GSH), than we have of the oxidized glutathione disulfide (GSSG). As the oxidative reductive chemistry changes and that individual’s tissues or organs are under more oxidative stress, the ratio of the reduced glutathione to the oxidized glutathione goes down, so they get a reduction in the reduced and an increase in the oxidized glutathione. That’s one role of the glutathione molecule: establishing proper intercellular reduction/oxidation, particularly in mitochondrial bioenergetic oxidative physiology.

The second role of glutathione is as a conjugating nutrient in xenobiotic detoxification. It forms mercapturates as a consequence of Phase II conjugation with glutathione-S-transferase as the principal detoxifying enzyme that connects glutathione to a detoxified Phase I xenobiotic to then render it into this more water soluble mercaptuate form. When a glutathione molecule is used, say in a hepatocyte for detoxification of a xenobiotic molecule, it connects itself to that transformed molecule in a covalent way, making it unavailable in the cell. In fact, it ultimately gets excreted in the bile or in the urine as a mercapturate. That depletes the glutathione stores in the cell. A combination of oxidant stress and inflammation that requires more glutathione in the reduced form coupled with the detoxification through mercapturate formation can produce, then, a temporal insufficiency of intercellular glutathione that could have adverse effects on bioenergetics and oxidative chemistry.

The third role of glutathione is that of conjugation with partially oxidized long chain polyunsaturated fatty acids. These could be derivatives of linoleic acid, or derivatives of arachidonic acid, or derivatives of eicosapentaenoic acid (omega-3 fatty acids). The formation of these oxidized derivatives and then their conjugation with glutathione produces molecules that we call leukotrienes, like leukotriene b4, the most proinflammatory molecule known in pulmonary physiology, or leukotriene d4. So this also removes glutathione out of the intercellular milieu.

Glutathione as a Xenobiotic Detoxifying Nutrient
Let’s go back to our discussion of glutathione as this second phase reactant (that is, as a xenobiotic detoxifying nutrient). In this particular role, as glutathione is reduced in its abundance by conjugating with an oxidized transformed pollutant molecule, or xenobiotic, or drug, it then has to be replaced–it has to be regenerated–and that is where the glutathione recycling becomes important, and where activation of inducible enzymes like gamma-glutamyl transpetidase starts to play a role.

Now, doyou start to see a potential association? You might say, “Does that mean that the higher activity levels in the plasma of GGTP in a person who is not an alcoholic or abusing a drug substance is a consequence of the body trying to accommodate by upregulating the activity of this enzyme, or the abundance of this enzyme in the plasma, to try to accommodate the need to get more glutathione available and to activate detoxification of things like drugs and alcohol, or things like persistent organic pollutants?” Could it be, going back to the observations of David Jacobs and Duk-Hee Lee, that the elevated normal levels of GGTP that are associated with those people with elevated BMI who have diabetes is a surrogate marker for the fact that they are suffering from some type of metabolic poisoning from xenobiotics that is requiring their physiology to upregulate detoxification, and therefore what we are really looking at is the connection between an xenobiotic exposure and obesity and later diabetes? Meaning that diabetes does not necessarily come from obesity, but there is a metabolic disturbance that results in the outcome in the phenotype of both obesity and diabetes that happens to occur concomitantly, and that this connection, then, renders the person at higher risk to conditions that we say are obesity-related conditions (or obesity-risk-related conditions) like diabetes, heart disease, and various forms of cancer. So really the effect is below that and the symptom is above that, which is obesity.”

That’s a pretty long-winded introduction to what you’re going to hear from Dr. Jacobs today in much greater detail. What I would like to say is that there is increasing evidence that connects together these persistent organic pollutants with obesity, and in fact these have even been given the name “obesogens,” as substances that can induce and modify the function. One of the really interesting recent papers that describes this very nicely is a paper that appeared in one of the Nature magazine journals, titled Obesity. This occurred in the June of 2010 issue. I think the title alone gives you a sense as to the topic. The title is “Obesity and Persistent Organic Pollutants: Possible Obesogenic Effect of Organochlorine Pesticides and Polychlorinated Biphenyls [PCBs].”1

Now let’s take this from the esoteric down to kind of the ground level of language and understanding. What we are talking about are persistent organic fat soluble or lipophilic toxins that, at low level, could accumulate in tissues, and, in so doing, can modify physiological function in such a way as to set in motion a process that leads to obesity and to type 2 diabetes. We know that persistent organic pollutants are endocrine-disrupting chemicals; they are sometimes called xenohormones. They are associated with the development of metabolic syndrome and type 2 diabetes; increasing numbers of papers about animal studies and in epidemiological studies in humans seem to indicate this.

Unfortunately, in humans, little is known about the role and the potential origin of obesity. Recently this topic has come under much more exact review, looking at the correlation between serum levels of persistent organic pollutants and the prevalence of obesity in cohorts of obese and lean adult men and women. In this paper in Obesity they studied 98 obese and 47 lean participants, aged greater than 18 years, men and women. Serum samples were analyzed for the presence of polychlorinated biphenyl and various congeners within that family, as well as organochlorine pesticides, and dichloro-diphenyl-dichloroethylene, and beta-hexachlorocyclohexane (these are metabolites of organochlorine pesticides). What was found is a significant negative correlation between BMI, waist, fat mass percentage, total and subcutaneous abdominal adipose tissues, and the serum levels of PCBs, and the sum of PCBs. There was a positive correlation, however, with BMI, waist fat, fat mass percentage, and total and subcutaneous abdominal fat with the chlorinated hydrocarbons. Also, the chlorinated hydrocarbon persistent levels in the tissue correlated significantly with HOMA scores (the homeostasis model for insulin sensitivity). So what you see is people that have the higher levels have lowered insulin sensitivity, meaning more insulin resistance. These results suggest there is a diabetogenic effect of low-dose exposure to these persistent organic pollutants, and it is more complicated than just that of producing body fat alone (an accumulation of body fat). There are many subtleties of this metabolic disturbance that cut across different potential disease states

Does that also relate to things like Agent Orange and herbicides? To answer that question, maybe we want to go back to Vietnam and Cambodia and Laos and start looking at people now 50 years downstream from the experience, from the Vietnam War and the use of defoliants, and ask, “Is there any evidence of increasing prevalence of diabetes?” In Cambodia, as you probably know, the population works very hard. It is still reasonably non-industrialized. There is still a lot of family agriculture to produce the foods of need, and the people are generally very lean. We don’t see central adiposity, we don’t see obesity, so you might say, “We would expect there to be very low prevalence of type 2 diabetes because it’s just not seen in very lean highly active people.” Yet there is rising epidemic of type 2 diabetes in Cambodia.2 People have scratched their heads and said, “Why? I don’t understand it. It doesn’t follow with our traditional identification of risk factors for diabetes. These people are lean, they are hard acting, they are eating principally vegetarian diets, they don’t have McDonald’s on the street corners. What’s going on?”

Studies on Agent Orange Exposure Decades After the Vietnam War
The variable could be exposure and accumulation of these fat soluble biocides. In fact, there are now papers that are being published on individuals and population groups that have been exposed to these defoliant materials, including US veterans that were exposed during the Vietnam War to Agent Orange, showing how their levels in fat tissues of these POPs (persistent organic pollutants) were correlated with a variety of chronic diseases, including type 2 diabetes and cardiovascular disease, as well as neurological conditions and other problems, including potentially cancer.3,4 There is more and more evidence that these POPs really play roles in inducing metabolic disturbances that result in kind of mitochondrial poisoning, and alteration in bioenergetics, and accumulation of body fat, and having a neuroendocrine effect as endocrine disrupters. The data confirm, then, the lifelong accumulation of POPs does occur in the human body, and as we are exposed these things get into our tissues and our tissue levels rise. Studies say plasma concentration over time can rise in kind of equilibrium with that of our fat soluble levels within fat tissues. Studies have clearly demonstrated that the capability of persistent organic pollutants can accumulate in the body throughout lifespan and there is a relationship between age and serum levels of POPs that’s been observed in lean, obese, and severely obese people. In fact, Nichols, two years ago, presented age-specific reference ranges for PCBs based on the United States Health and Nutrition Examination Survey 2001-2002.5

Is there a threshold where the level of these persistent organic pollutants starts triggering certain metabolic disturbances that are seen clinically? Or asking it a different way, could this be one of the factors that lead to increasing prevalence of chronic disease with age? Are these accumulating levels of a potpourri mixture of biocides increasing the relative risk to metabolic poisoning? When I use the word “poisoning” I’m using it here very advisedly because we’re not talking about traditional toxicological effects; we’re talking about subtle effects on intercellular signal transduction, gene expression modulation, and ultimately effects on things like insulin signaling and inflammatory pathways, and cell replication, and things that are much more subtle in their influence.

I think that there is a case that is emerging to support the fact that body fat accumulation may be more than just eating luxurious calorie-rich diets, and that it is also potentially associated with factors that modulate our cellular physiology. These obesogens that are in our environment may be partially contributing. There is a very interesting article that appeared recently in Molecular Endocrinology, about the case for obesogens and how there is now very significant research that is accumulating indicating that the conventional wisdom that obesity is primarily the result of a positive energy balance (meaning too many calories in and too few calories burned), is not the full explanation for the story of the rapid rising tide of obesity, not just in the United States, but elsewhere in the world.6 What are the bioenergetics of food being used as fuel, and how does it ultimately get released from the body as a non-polluting form of energy which we call heat, and water, and carbon dioxide versus stored for a rainy day that never comes? That particular process is all mitigated through bioenergetics related to mitochondrial function.

What we are saying, here, in this story that is emerging, is that lipid accumulation may be the result of blunted metabolism, and it occurs while other things are happening at the gene expression level that are associated with rising risk to inflammatory disorders and to risk of diabetes and cardiovascular disease. I think these are really dramatically frame-shifting principles that set a new stage as to how low-level substances in the environment could participate in altering metabolic function. In animal models it appears as if this concept is correct. You can induce some of these factors that we are talking about through low-level exposure to these “obesogens” in the animals’ environment and watching the effect it has on adipocyte size, adipocyte cellularity, and adipokine profiling after exposure. If you do DEXA scanning on these animals you find that their intra-abdominal fat increases as a consequence of low-level exposure to these persistent organic pollutants.

Expansion of this research may help us to understand why we’re seeing such a rising tide of various chronic diseases in the developing world that we can’t correlate directly with obesity. It’s not like the United States, where there is a direct link between obesity and some of these metabolic disturbances; it’s more of an indirect relationship. Even in the United States, as was pointed out by Jacobs and Lee, the association between diabetes and obesity is only seen when focused through the lens of the GGTP level. The person has to have an elevated normal quintile of GGTP couple with their elevated BMI to have a strong correlation with type 2 diabetes

There is a wonderful review that just appeared in Nature Reviews of Endocrinology. Ana Soto and Carlos Sonnenschein did a very nice job reviewing the connection between endocrine disruptors and cancer incidence.7 Again, this is a different kind of model than what Bruce Ames was talking about at the Institute for Functional Medicine meeting over ten years ago. In this case we are talking about subtle effects-not mutagenic effects, but subtle effects-on intercellular signal transduction, signaling that relates ultimately to gene expression patterns that associated with cellular proliferation and the oncogenic process.

We call this oncogenic potential or oncogenic burden. It is now recognized that environmental endocrine disrupting chemicals, including pesticides and industrial chemicals that have been released into the environment, have bioconcentrating effects on wildlife, and ultimately get into our food supply, get concentrated up the food chain, and ultimately are delivered to humans. The effects that have been observed in animal models after exposure to these substances correlate positively with increased incidence of malformations of the male genital tract, with neoplasms, and with decreased sperm quality (observed in both the European and United States populations in independent studies). We now also see changes in the female reproductive system and changes in neuroendocrinology, including alterations in the phenotype of behavior, obesity, prostate cancer, and thyroid and cardiovascular endocrinology. These are all unequivocal and multiple-study-documented cause-and-effect relationships. In fact, even things like plasticizers like bisphenol A, at very low levels, have been found to modulate signal transduction in such a way as to increase this endocrine-mediated pathway that increases the risk to obesity, type 2 diabetes, and other chronic diseases.

What’s the impact of endocrine disruptors on endocrine targets? Do we have a specific ligand agonist understanding of how these things fit together? You have to get the signal from outside the cell inside the cell. There must be some antennae sitting on the cell that picks up that signal (that environmental disruptor signal), and that is now also starting to be well-understood. There is a paper that was published in Hormone Metabolic Research in 2010 that looks at endocrine disruptors in human health from this structure/function relationship: how these chemicals have mimic effects on modulating receptor sites for various hormones and influencing (through signal transduction, right to the genome) the production of messenger RNA, and altered proteins in the cells, and altered metabolism.8

There are a whole series of substances that are on the hit list of concern: phthalate esters, you’ve heard about; pesticides, I mentioned; dioxin, obviously; bisphenol A; diethylstilbestrol; heavy metals, including lead and cadmium and mercury; various types of polychlorinated biphenyls, I’ve talked about PCBs; even things that are benzene derivatives have been demonstrated to be xenohormones (xenoestrogens, so to speak). I think that we are starting to see heavy metals, persistent organic lipophilic toxins, secondary metabolites, and biocides all playing roles, as well as substances that are used in home products that may result in things like precocious puberty, delayed puberty, fertility-related problems, structural reproductive tract abnormalities, endometriosis, or mammary gland developmental problems that may be associated with increasing risk to breast cancer like proliferative breast problems. These are not insignificant issues.

What we are starting to recognize is the environmental connection to our function is symphonic, rather than hard-hitting, single-agent toxicology. The neuroendocrine targets of endocrine disruptors, as pointed out by Andrea Gore in a recent review in Hormones, are the same receptor sites that modulate subtle function within the development of an organism from fetal development all the way up through adulthood, and maintain a homeostatic function in the organism.9 The combination of all these chemicals put into our environment at low level, along with differing metabolic susceptibilities, genetic uniqueness, and detoxification abilities among people, makes this area very complicated to study, and to lockdown, and to demonstrate a clear cause-and-effect relationship.

I think as you hear Dr. David Jacobs describe the work he is doing you’re going to understand much more why this topic is rising into prominence and why we are starting to get a read on methods for evaluation, The research is focusing on how detoxification processes (through enzymes like gamma-glutamyl transpeptidase, and glutathione synthesis and conjugation) play roles in detoxification and lowering burdens of these chemicals, and why persistent organic pollutants are being seen much more now as possible contributors to the rising tide of chronic disease, not just in the United States, but in these developing countries where you don’t see the kind of anthropomorphic changes that are often associated with chronic disease in the United States. People in these countries don’t necessarily look like they are obese. Rather they are lean, they are active, they are eating fundamentally similar diets to that of their ancestors. But the variable that they are exposed to might be these persistent organic pollutants.

With that in mind, let’s hear from a person with a great deal of knowledge. He is one of the discoverers of this area, and a person whose work I have followed very carefully over the last fewyears as he has had multiple publications in top-tier journals, Dr. David Jacobs.


Researcher of the Month
David R. Jacobs, PhD
Mayo Professor of Public Health
Division of Epidemiology and Community Health
University of Minnesota School of Public Health
1300 South Second Street, Suite 300
Minneapolis, MN 55454

Here we are once again at that section of Functional Medicine Update. I know you look forward to it like I do, and that’s talking with the experts, the clinicians and researchers who are creating the field of 21st century medicine, which will hopefully help us to address better the rising burden of chronic age-related disease, give us new ways of looking at the etiology of disease, and ultimately provide new ways of intervening, both preventively and therapeutically.

You’re not going to be disappointed this month. The researcher this month is a person whose work I’ve been following very carefully and closely. Every time one of his publications comes out I can hardly wait to read it. I think this work is really creating a whole new paradigm. I’ve cited his work on several instances over the last few years on Functional Medicine Update.

I’m speaking about Dr. David R. Jacobs.

Dr. Jacobs is a Mayo Professor of Public Health, Division of Epidemiology and Community Health, at the University of Minnesota School of Public Health. He has what you might consider a fairly interesting background, not one that you’d immediately connect to an investigator in the type 2 diabetes area. He is a mathematician from his undergraduate training, and then later earned a PhD in mathematical statistics at Johns Hopkins. Working in epidemiology means he’s a person looking at associations, and he has done an extraordinary amount of work in a whole variety of areas. Let me give you kind of a thumbnail of some of the areas that he has had interest during his professional career.

I think where I first became familiar with Dr. Jacobs’ was with regard to the work he has done on whole grains and refined grain intake and the relationship to chronic disease. This is some epidemiological association work that I’m sure we’ll touch upon in this interview. He’s also looked at inflammatory processes, oxidation, and how that relates to chronic disease. The area that we’re going to be speaking to quite a bit in this interview is related to pioneering work in type 2 diabetes and its relationship to xenobiotics and persistent organic pollutants and how that translates into function. And then there is this other area, which I know we’ve talked about in Functional Medicine Update, and that’s periodontal disease and its relationship to the etiology of cardiovascular disease. That’s just kind of a tip of the iceberg when it comes to the areas that Dr. Jacobs has been involved in, but we’re going to focus, in this discussion, principally on xenobiotics and the emerging understanding of their relationship to type 2 diabetes.

With that long-winded introduction, Dr. Jacobs, thanks so much for being with us. How did an undergraduate degree in mathematics translate ultimately into looking at the epidemiology and the association between persistent organic pollutants and type 2 diabetes?

DJ: Thank you, Dr. Bland, for that really nice introduction. I don’t know if you want to do the whole biographical course or not, but population science is basically, in a certain way, a branch of applied mathematics. It’s very applied. An interesting little story is that when I was doing mathematical statistics, which is really heavy-duty math, the mathematical statisticians kind of said, “Well, the biostatisticians, they’re just applied, they don’t really know the answers.” But it turns out that the substance, of course, is so important, and I have striven throughout my career to really understand the substance and I’m much more interested in the substance than in the mathematical principles. That’s the short answer.

JB: I think that’s a good one. I think one of the things that has been a hallmark of your work is this collaboration that you have had with Duk Lee at the Medical University in South Korea, which is looking at this xenobiotic connection and how you went back and looked at NHANES II and III data. Maybe you could take us through that whole story because it sounds just fascinating how this whole hypothesis emerged. I’d love to know where it came from.

Complementary Skill Sets Leads to New Research Ideas
DJ: Okay. Actually the story with Duk-Hee Lee is really a fun story because I had written three papers with her before I met her. She is just an incredible vigorous and bright scientist. I got to know her through colleagues. You know, we English speakers control literature, for better or for worse. I am often called on for my English language skills, to help people who have written in a foreign language or have a native language other than English. We hit it right off because I not only fixed the English but I made a few comments on the first paper that we worked on. Ultimately she came to Minnesota and she’s been here several times and worked with me for months to years at a time. We’ve had a relationship in which we actually talk to each other by email now over the past eight years or something probably at least once a week. I think we have written something like 50 papers together.

The way that the science came about is that she was interested in a variety of things and it turned out that our skill sets were complementary. I depend on her very heavily for ideas and she has depended on me heavily for logic of expression and various different ways of critiquing different ideas that she has, which are in epidemiologic or medical principles. I would have to say she is the leader of the team as far as this kind of work with the pollutants goes.

Examining the Association Between GGT Elevations and Health Risks
JB: Let’s go back to…it’s probably not the beginning because I’m sure I don’t really know the beginning, but I’m going back to my beginning in reading your literature, which is extraordinarily prolific. I want to compliment you just on the volume of extraordinary publications that you have authored with her over the last 10 years; it is quite amazing.

Talk a little bit about gamma-glutamyl transpeptidase to begin with. That’s some of the first work that sealed this association between GGTP elevations in the normal range and health risks.10,11,12 It sounds like you must have had some presumption, or did that just jump out of the literature unexpectedly?

DJ: You know, it has been a learning experience for me, and as I said, Duk-Hee is really the person who has motivated the specific scientific ideas. When I first met her she was dabbling in studies of hypertension and sort of things not being exactly the way you expect them to be. And when she came to Minnesota the first time, which must have been…I don’t know, 2002 or 2003 or something…she was very interested in oxidative stress. Now, we’ve had a study on oxidative stress-myself, and my colleague Myron Gross at the University of Minnesota, and Michael Steffes, again at the University of Minnesota-which is attached to our study, CARDIA, that is an NHLBI-funded study that’s been going on since 1985.13 We’re currently following people for their eighth examination. That’s been a big part of my life, and we have, as I said, an RO1 NIH grant to study oxidative stress. So I had some knowledge of oxidative stress.

Duk-Hee was very interested in the possibility that GGT-I call it GGT rather than GGTP, I’m just used to its older name-was actually somehow or other involved in oxidative stress and was involved somehow through glutathione. So the function-sort of the biology-of GGT is that it sits on the surface of cells widely distributed through the body, and it facilitates the breakdown of circulating glutathione, which is three proteins, and then the transfer of those components back into the cell. The GST (glutathione) is reassembled and it serves as a primary antioxidant in the intracellular environment.

So it seems as though somehow or other GGT would be important in that. We started studying iron, which is a very difficult area because free iron is so fleeting that you almost never see it, or perhaps never actually see it in vivo. But anyway, we went from the iron over to the possibility that GGT might itself be a pro-oxidant or might be somehow or other indicating a very high level of oxidation because of a lot of glutathione activity. Duk-Hee did the work on that (the preliminary/primary biologic reading).

It was very interesting because GGT has primarily been thought of in two respects: one is a marker of alcohol abuse, which is really happening secondary to something like cirrhosis or fatty liver disease caused by high alcohol intake; or liver disease itself, and GGT is then thought of as a liver enzyme. Actually GGT, as I said, is scattered widely throughout the body, and it has these very important functions in maintaining one of the most important body systems, namely the intracellular antioxidant or oxidative balance.

That was how we got into it, and, sure enough, when we started looking at the data, the data really perked up the epidemiologist’s eyebrows because it was a very strong finding and it seemed to go beyond the alcohol idea. It wasn’t just liver because there were other more specific liver enzymes (ALT and AST), and they didn’t behave the same way as GGT. So that’s really sort of our first findings and how we got started with that.

JB: For those listening that may not be looking at their recent biochemistry, what I would want to remind you is that when you talk about an amino acid/glutamic acid (that’s the “G” in “GGT”), that most amino acids are alpha amino acids, so when we put a prefix “gamma” in front of “glutamic acid (gamma-glutamyl),” it raises the question: Why is a funny amino acid like a gamma linked? Of course, as Dr. Jacobs pointed out, in human biochemistry the only place that you have prevalence of a gamma glutamic acid is in that tripeptide called glutathione. This is what I think was a very skillful perception that Duk-Hee came up with because it seems that (having been a clinic biochemist for 30 years) there has always been this presumption that GGT is shed from a damaged liver just like ALT and AST in the case of an alcohol and drug abuse relationship. Now suddenly we start talking about the functional nature of that enzyme, GGTP (gamma-glutamyl), and its connection to glutathione. I think that was a really brilliant connection.

And then you go to your epidemiological evaluation of NHANES. Can you tell us a little bit about that? And how did you come up with the POPs concept, to start looking at the correlation between persistent organic pollutants and levels in the serum of GGT?

Connecting GGT Data to Persistent Organic Pollutants
DJ: Right. I really appreciated that addition about the amino acids. There is another issue (just before I get to the POPs). When we measure just about anything in the blood-I mean even if we measure things in hair, toenails, urine-we’re looking for the lost penny in the best light. It’s hard to get to the cell surface and measure GGT or anything else (soluble ICAM is another great example that we are working with a lot). It is hard to get it in its natural environment where it is really working, so what we are working with is the circulating element, and why is it circulating? You know, it should be sitting on the cell surface doing its job. Nevertheless, I really do agree that Duk-Hee Lee is just brilliant and this was an amazing connection to make and it has been so much fun for me to watch it work and then look at the epidemiology.

She was sitting around in her office in South Korea and thinking about GGT. We had another study which was prominent in the thought process, and that was that she was the biostatistician/epidemiologist/physician working with a steel company called POSCO in South Korea. So they had eight years of observations, and that included GGT.14 I think it was between ’96 and 2003, something like that. And what we showed was about 180{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} increase in GGT graded over time and independent of age during that time period. So the mean level of GGT in the beginning of the period was about 8, and I think it went up to a mean of about 25. Those are activity units for the enzyme. This was really surprising. At the same time in Korea, in the same people, the serum cholesterol went up by about 8{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}, so the GGT was really changing fast. And she was wondering, now, what could it be that would cause such a rapid change and such a profound change over time?

She was looking at various different delivery sources of some kind of a provocateur for this, and she finally came to, “It must be in the diet.” It had to be something that was changing rapidly and that was very commonly eaten or commonly exposed, so everybody in the population would get a fair exposure. She thought, though, that it probably was not the food itself because the records on that seemed to indicate coffee, meat, and fruit as the main factors that affect GGT. So it just didn’t seem as though it could be the food itself.

The other thing which might have changed a great deal was these pesticides and other industrial chemicals, and then especially the ones that were persistent. Persistency in a chemical like this-we’ll take PCB, polychlorinated biphenol, or something (the abbreviations are easier to remember than the long words), or organochlorine pesticides, which have now all been banned since the late 1970s, and among this group also is dioxin (dioxin is the most famous of them and was used in Agent Orange to defoliate Vietnam, which was another unfortunate story)-these things enter into the body and then they sit there. They are difficult to metabolize. They are difficult to clear. They probably cause oxidative stress. They probably cause hormone disruption. But they just sit there, especially in fat tissue, and their half-life may be on the order of 10 years or more.
Duk-Hee had done independent reading about those things, and she thought that they might somehow or other be connected to the GGT story. She’s very good at going back to the basic biochemistry textbooks and trying to understand the way that things work, far better than I am or will be. She drew a picture of another action of GGT, and that is in forming conjugates of xenobiotics with glutathione. It turns out that within the cell, in that particular reaction where you have some kind of a xenobiotic and have glutathione as transferase, which is a really important constituent of this whole antioxidant system, and GGT plays an important role, again, in disassembling the glutathione so that it can be conjugated with whatever xenobiotic it is. The xenobiotic conjugate, then, becomes water soluble and can be excreted in the urine. Now whether it would be the POPs themselves that would be so conjugated, which seems less likely, or they wouldn’t be persistent, or, say, the reactive oxygen species, which are developed because the POPs are sitting there and the body is complaining about it and trying to react to it, it sort of doesn’t matter. So we finally came to the theory after several years of working with this that the GGT is actually working not only as a marker of oxidative stress, but more specifically as a marker of the activity of the attempts of the body to clear some of these xenobiotics.

Connecting Obesity and Type 2 Diabetes to Previous Research
JB: This, to me, is such an amazing representation of discovery. This whole process of how you two collaborated along this path is fascinating because it takes us into part of the next chapter. Maybe it’s not the next chapter in your lineage, but in my thinking it is the next chapter, and that’s the connection between obesity and type 2 diabetes. If there is anything that had rocked perceptions about the origins of the relationship between type 2 diabetes and obesity it would be, I think, your sieving of epidemiological evidence from NHANES and looking at that connection and finding (I believe) that it was not a strong connection in the absence of a marginal elevation within normal range of GGT. Can you tell us about that next step, because this is just a fascinating journey into discovery?

DJ: At least in our preliminary cross-sectional study of NHANES we had 2000 or more people, and I think we had 218 cases of diabetes that were prevalent (in other words, they existed at the time of measurement of the different POPs, persistent organic pollutants). There were 463 (I’m quoting these numbers by memory, so I may not be exactly right), but I think there were 463 people in the lowest quartile of the POPs. We actually took six POPs and we put them together, statistically, and so when I said a quartile of POPs that means that these were the people who had the least exposure to some combination of these six POPs, each of which had a pretty powerful relationship with diabetes. Among those 463 people, about one-third of them were obese, so a BMI (body mass index) over 30. There were only two cases of diabetes in those 463 people. One of them was in the middle BMI group (in the 25 to 30 group) and the 30-plus also had one, but that was a half a percent of the people who had diabetes, and overall, 218 people over about 2000 (it was about 10{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}). So in the top three quartiles, actually, I think we had 13{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} percent versus a half a percent in the bottom quartile of the POPs. As I just said, there was no gradient of the diabetes within that particular group of people who did not have very much in the way of POPs.

Obesity has always been a difficult and an interesting thing to understand. The history of obesity and total mortality is a strong U-shape. And the history even with cardiovascular disease is sometimes on/sometimes off depending on the data set. For many years at the beginning of my career, we really thought that obesity was not a factor because if you regressed, say, cardiovascular disease on obesity and the triad of blood pressure, smoking, and cholesterol (sort of a Framingham score), the obesity would drop out of the model. Then over the years people got a little more sophisticated and they started to think that there are these secondary paths. So obesity causes hypertension. Obesity causes hyperlipidemia. It’s related to smoking in that the smokers are thinner, and when they quit smoking they tend to gain quite a bit of weight. So it is really, in a certain way, a marker of all these things. It is an indirect player, and similarly (perhaps) with diabetes.

The third line of thought was that the obesity was actually sometimes leading to hypertension and hyperlipidemia and sometimes it was not. It’s a little hard to know, and now with this added concept…there are two added concepts, which are really important with obesity. One is that adipose tissue is not only adipose cells. The adipose tissue also contains adipose cells that have died, and those will then be quickly surrounded by macrophages, a similar mechanism for body defense as happens in atherosclerosis. The macrophage colony will be throwing off IL-6 (Interleukin-6) and a variety of other cytokines, so actually the adipose tissue is pretty interesting because it is more than just the adipocytes and the fat storage; it’s also storage of some decaying and inflammatory matter. The other thing is that there are lots and lots of fat soluble substances that we encounter, and so where are they going to sit? Well, besides the fat in the adipocytes, there are going to fat soluble substances, and the pollutants that we have been talking about are basically fat soluble.

There are a lot of reasons for thinking that sometimes funny things are going to happen with obesity. I’m not a proponent of obesity, but I’m a little more skeptical, perhaps, having done some of this work. If people are actually burying POPs in their fat tissue, there may be a penalty for losing weight. It would be better to be thinner to begin with, to be lean all the way through your life, but if you do get heavier, maybe there is some penalty phase that you have to go through as you’re losing, and you would actually, then, be releasing these fat soluble substances.

JB: For the clinician, as they start to make this kind of “aha” connection between the potential, let’s call it, “surrogate” biomarker of this relationship between xenobiotic accumulation and physiological function, it seems that your work would point us towards the direction of looking at what the normal range is. Because the elevation of these GGT levels that were associated with increasing risk of type 2 diabetes were within the upper quartile, I think, of normal, so what is normal range? What does it really mean?

How Can Clinicians Apply GGT Data in Practice?
DJ: We do have to be careful with GGT because, as with any lab measure, it has its range and its laboratory-specific value. Cholesterol, for example, is extraordinarily well-standardized across virtually every lab in the US, but there are different tests for GGT and different ranges, so absolute numbers are a little bit difficult, although I was citing some earlier. People typically talk about values such as 40 for women and 50 for men as being the end of a normal range. If you send a participant in a research study to a physician with a GGT of 60, they are going to say, “I don’t really know what to do with this. It’s got to be 2 or 3 times the upper limit of normal.” And then they are going to be thinking of treating liver disease, so they will be doing other liver tests and that kind of thing. What should you do with all this stuff in the normal range?

I think that in many ways this research points to the connectedness of life and the connectedness of the organs within the body equally well. When I say connectedness of life, we really enjoy…say the flame retardants, which are brominated chemicals much like the chlorinated ones that we’ve been dealing with. And we enjoy the ease of eradicating mosquitoes, which might carry malaria. We enjoy the PCBs in out computers. We are so dependent on all of these things. The oil spill in the Gulf is directly related to all of this and how industrial we are. But it is not without a penalty; it is not without its risks. One of the risks is that the chemicals that we use are not necessarily compatible with life.

We should be suspicious when we use a pesticide. If we have a chemical that is noxious to one form of life, then it also is going to do some kind or other of subtle damage to you. If we are going to put humans in a special place, let’s not forget that we are life forms and we have a lot in common with bacteria, for example, in that way. So this connectedness of life, we really have to be careful, politically and socially, about what we do. Maybe the physicians can be raising a hue and cry about this and saying, “Look, we have to be really careful about the way that we develop the technology and the way we use things. We do like our nice cozy lives, but we better be careful about how we are doing things.”

I mean, I don’t know a medical solution to this. As far as the connectedness of organs, well, we were thinking liver, but what about the kidney? And what about blood vessels? And what is it exactly that insulin resistance is and where is the defect? Is it just in the pancreas or in the insulin receptors throughout the body? And so on, and so on. I’m not so sure what to say to a clinician.

One thing I should mention-I think maybe we are running short on time at this point-but I want to mention that in our studies of GGT, it has not been as predictive, and maybe even not predictive, say, of cardiovascular disease and diabetes in the elderly. Once you get above 65 or 70 years old, the GGT seems to stop with its very powerful predictive capacity. Duk-Hee’s idea about this (not well substantiated, but she has a pretty good history of making really clever guesses), is that as we age we lose the capacity for good Phase II enzyme systems and clearing of xenobiotics and that sort of thing. Maybe that’s the case. So clinically, the GGT might be very helpful if you have a sort of standard measurement scale, and you have a 40-year-old person, and that person comes in with, say, a 45 or a 50 GGT. That might be something that you should be thinking about as a warning sign that this person may be on a path towards diabetes, or towards hypertension, or towards heart disease. If you saw the same thing in a 70-year-old person, maybe you would not and even say, “Why am I measuring this thing. It’s not really relevant.” That would be sort of the current status, I think, of the way that a clinician might use GGT.

Does the Data Indicate Ethnic Variability in Relative Risk?
JB: Let me, if I can given just the few minutes we have remaining, ask kind of a combination question. The scope of your involvement in looking at the field in a broader sense has been very, very large. Recently you were one of the authors on a paper, along with Dr. Lee, that looked at the association between certain genotypes that are associated with type 2 diabetes and how that might relate ultimately even into ethnic risks, the GWAS studies and type 2 diabetes Is there any ethnic difference looking at Koreans versus Caucasians? Do you feel that there are ethnic specificities of relative risk from what you have seen so far? In other words, certain individuals might have a higher susceptibility?15

DJ: Mostly I think that the differences among human beings are trivial compared to, say, the differences between our neighbors, the noble apes and chimpanzees. As a human species we are pretty alike. Nevertheless, when you look at the genetic information, you see lots and lots of single nucleotide polymorphisms that vary depending upon who you mate with. I like the term “mating pool” better than “race,” actually. There are some differences, and I think that they are mostly overblown. One of the interesting differences, though, is obesity and its relation to diabetes in Asians versus Caucasians. It seems as though, at a level or a body size that would not look particularly fat, the Asians are already developing diabetes at a much higher rate than we are. So far, the Asians have not been getting the level of obesity that we have in the West. But that does seem to be a difference.

Now, could that have something to do with the POPs? I mean, that is very difficult to know. Duk-Hee has been starting to do some of these studies in Koreans. But the POPs take two or more mLs of blood, which is a huge amount in the world of covert studies that I live in. We save half mL vials. Sort of the money in the bank for these cohort studies is the vials-the blood vials-that are in the blood bank, and who wants to give up four of them to measure POPs? And then the other problem is that you need very specialized equipment and tandem mass spectrometry to measure the POPs, and it is like at least $300 a shot to measure these things. So it makes them rather difficult to study, and we are kind of waiting for the field to catch fire, where people reserve special aliquots and they say, “Yes, this is important enough to do it.” And maybe other breakthroughs are made and analytic methods so we can study them. But they are in very low concentrations. That, itself, is a big warning: that they could be apparently causing quite a bit of damage at very low concentration. So that’s that.

Research on Whole Grain Consumption
JB: Good. Let me ask one last follow-on question. You have also been very actively involved in looking at the relationship between whole grains versus refined grains and things like cardiovascular disease.16,17,18 Do you think there is any connection that you’ve seen in your work that might correlate dietary persuasions of whole versus refined grains plants, POPs, and diabetes? In other words, these diet persuasions, could they also translate into relative risk of exposure or something related to metabolism of these POPs, putting people at higher risk with increasing GGTs?

DJ: Well, I said earlier that POPs are delivered by food, and I didn’t emphasize that very much, but they are in the fatty tissues, and since they are persistent, when an organism is slaughtered or it is carrying pesticides as a plant for us to eat, that is still there and it in fact perpetuates itself through the ecologic cycle. That means if POPs are delivered through food, even though they’ve already been banned, they are stuck in the food supply and that really messes up nutritional epidemiology. We used to think that nutritional epidemiology could be done with a table of nutrients, a list of food names, and you would know an apple is an apple, a piece of pork is a piece of pork, and you could study what you were eating. But now, with the recognition that POPs are in the food supply, and mercury and heavy metals are another really good example of the same kind of thing, or bisphenol A is another one that we are getting through plastics so it is in the containers that our food is contained in, it makes it very hard to know exactly what you are getting when you eat a food.
Having said that about this sort of unfortunate disjuncture between POPs and nutrition, the work that I’ve done with whole grains led me in another direction, and that is to the concept of nutrient-rich plant foods in general. I was trying to think: what could it be about the whole grains that, in study after study, independent of who was looking at it, independent of the nature of the population, the people who were eating whole grains were having a lower risk? Of course, it turns out that whole grain consumption-the act of going out and looking for the whole wheat bread, or eating the oatmeal, or not eating the breakfast cereals that are made with refined grains, looking for brown rice, that kind of thing-it indicated a person with a high level of health consciousness. So you see all of the popular behaviors like if you would say to me or say to any random scientist, “What’s good for you?” The people who are eating whole grains are also, for example, taking vitamin supplements. Now I don’t think vitamin supplements are a good idea at all, but popularly it’s believed that they are. So they are also better educated. The women are taking hormone replacement, which is another thing that, in the past years, there have been questions raised about it, but say in the 1980s it was strongly believed that that was a good thing to do. They are more physically active. There are less smokers. So is it really the whole grains?

I think it is the whole grains, and I think that it has to do with this rich layer of bioactive substances that the plant uses for its own survival, which is sitting on the outer layers-the aleurone layer, which is right under the bran in the grain. I think more generally that you have many of the same kinds of substances and you have the same idea of mechanical benefit should translate into human consumption benefit. So there are lots and lots of plant foods that work like that.

Not among those plant foods is sugar. Why not sugar? There’s nothing wrong with sugar in a plum, for example, because that comes with everything else in the plum, and so it has been naturally organized by evolution for the virtue of the plum and the plum tree’s survival. That sugar is probably great, the same as everything else that comes with the plum. But the sugar which is just poured in great mounds into water and then served up as sugar-sweetened beverages provides a lot of calories and it provides none of these other nutrients that you would get, and the same thing would hold for refined grains because you’ve laboriously gone through and chopped off all the good stuff and you are left with a starch, which is not in itself bad, but it is not in its natural proportion and it is missing an opportunity, I say, to maximize nutrients per bite. It’s missing the opportunity to actually give the person a bunch of extra nutrients.

And then another bad category would be something like french fries, where the cooking method is such that you are oxidizing the oil. You just heat it and heat it and heat it, and you get changes in the chemistry of the oil, and those changes are not necessarily so good. The margarine thing was another example of this preparation thing. It is kind of akin to the pollution chemicals in that we wanted to have margarine, we thought that saturated fat was bad for us, so we engineered something so we would still have the nice solid feel of butter, but, you know, it would be all vegetable oil. Unfortunately the hydrogenation doesn’t occur to any extent in nature, and we had a whole lot of isolated trans fats, which have become everybody’s whipping boy these days. So those are a few of the principles of nutrition that I’ve been thinking about in the last couple of years, and actually doing all that work in connection. The work on POPs has been very illuminating and a mind-opening thought process.

JB: I think you said that beautifully. I’m struck, as I listen to you, thinking about all of the various secondary metabolites in plants and whole grains that modulate gene expression associated with these enzymes that you discussed earlier that have Phase II detoxification effect: quinone reductase, glutathione s-transferase, and so forth. This web that you described–this interconnectedness, these systems of biology–really argues for all of these variables you’ve been describing having some interesting symphonic orchestrated relationship. I think that’s a whole different view of the biology of life than probably many of us grew up with in our training, which was more compartmentalized, isolated, insular, and reductionistic. I want to compliment you. This work you are doing is just very pioneering.

I’m hopeful that as you heard Dr. Jacobs’ story told by him and had a chance to let this process over your frontal lobes, you’ll recognize that this is not an esoteric topic. This is a very important clinical topic with really important clinical outcome potential. And when we tie that together with what we are going to be discussing in the September issue with Dr. Randy Jirtle, it frames a whole new step forward in the evolution of functional medicine



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