Belly Fat, Inflammation, Type II Diabetes, Anti-inflammatory Drugs and Anti-Oxidants: Studying Metabolic Syndrome, Possible Cures, & Discovering the Very Subtle Ways They Might Work at the Molecular & Cellular Level All at the Same Time

The pathway of medical and pharmaceutical research is often portrayed as straightforward : First, characterize a disease thoroughly,  and when that’s finished,  find a drug by some sort of trial and error process with rats and then humans. 

But in fact, at any given time, researchers are simultaneously characterizing the many manifestations of a disease and its interrelations with other diseases, trying out putative folk remedies and natural products that have  a fair amount of positive, anecdotal evidence, as well as doing research at the molecular and cellular level to determine what biochemical processes underlie or control some step of the disease process.

The doctors who treat the whole patient  continue to  do a kind of clinical epidemiology which tends to reveal new trends and apparent associations, which gives them something new to say  to the drug researchers, even as the work of molecular and cellular biologists gives them something to report  to the drug discovery people and the clinicians at any given time.

Research in understanding and hopefully curing disease  is better pictured as occurring at traffic intersections than at rest stops on a one-way highway.

A Case Study of Making Clinical Associations Between Well Known Diseases: Metabolic Syndrome

The  routine usage in diagnosis of the broadly encompassing term Metabolic Syndrome  is only about 40 years old, although the various diseases associated with it were very well known many decades before that.

Basically, a patient presents with an inordinate amount of belly fat, a sedentary lifestyle, and often, early signs of adult-onset diabetes. There is a strong association of this syndrome with heart disease, stroke, fatty liver, and various cancers, although it was probably rare for any one physician to have a patient show up with all of these diseases all at once.

For clinical internal  medicine, the first step was make the links that all these separate illnesses seemed tied together in a statistical sense. The  determination that Metabolic Syndrome was a useful diagnostic concept was far more driven as much by cumulative clinical chart reviews, than by well-worked-out “a priori”  theories of what the underlying cause was.  

What prolonged experience in the clinical realm suggested was that patients who had a lot of visceral fat tended to get adult onset diabetes. But it was also true that patients with abundant visceral fat also tended to have coronary artery disease and also get strokes. And patients with visceral fat also seemed to come down with certain cancers. Many of them also had livers as if they were alcoholics, even if they did not actually drink alcohol.

Even after this realization of a strong link was made, the treatments and clinical advice for the separate component diseases that were a part of this cluster tended to be very distinct, and not always transferrable from one disease to another. One did not give radiation treatment for diabetes. Insulin shots did not seem beneficial in cancer. The warning signs of stroke were very different from those of liver failure.

But even after the realization that these diseases were clearly linked, there was no stop in trying to find separate cures for each and every one of them. They all had their own separate research and treatment charities, advocacy groups, and even NIH institute buildings, and even if no one came up with the mythical all-in-one cure, they all regularly came up with some new information to share at that traffic jam intersection of differing researchers.

What Did Work to Ease the Very Different Manifestations of Metabolic Syndrome?

One of the first realizations of a clinical strategy that worked, at least for many, if not all patients with one of the cluster of diseases, was to encourage them to lose weight, and in particular, to exercise more, with the underlying goal of reducing that belly fat. This was bostered by the fact, that there was substantial evidence that for many patients, the fatter they got, the worse their metabolic syndrome and its consequent component diseases seemd to come into play.

But this simple  weight loss/exercise prescription was hard for patients to follow, and did not seem to have an underlying basis in science. It just seemed to be an association between two occurrences: weight loss and/or exercise and betterment of symptoms, not a unambiguous display that weight loss or exercise somehow caused improvement of symptoms by some definite mechanism.

A couple of other statistical associations also came on the scene.

First, as is the case with most seemingly promising cause-and-effect explanations, some patients did lose weight and got better, while others did not. Some patients who never lost weight, never got the syndrome, even if they  were quite fat around the stomach. And, of course, some people who were never fat got one or more of the component diseases anyway. 

What helped make sense of these seeming failures of fool-proof cause-and-effect predictions for outcomes, was yet another series of observations.

First, for  some patients (viscerally obese or not) these diseases ran in families, with perhaps the fattest family members having the worst of it, but even some slender ones were affected as well.

This suggested that there was a genetic component. This of course, put the nucleic acids and proteins  research community, the molecular biologists,  to work to sort out what genes might be involved, and then, what proteins might be encoded by specific segments of DNA. Their working theory was that if you could somehow shut off or counter those genes, you’d have a good shot at a cure.

Second, some people seemed to have in their geographic location, and on inspection, usually in their diet much more so than the particular the rhythms of their daily lives, some protection against developing the component diseases of metabolic syndrome, in many cases despite having  what should be the predisposing girth.

This put ethnopharmacologists and nutritionists on the trail. What was it about those French people who drank a lot of red wine (despite a diet high in butter, and both saturated and unsaturated fats) that made them better off? And what about those  tea drinkers (sometimes black or green tea and sometimes herbal blends)?  And eating blueberries seemed to help in some way for some people. Was the apparent reduction in having the consequences of  having a belly fat body caused by these additions to their diet, or was it just a coincidence?

 This research community then began to try to isolate just what specific chemicals might be in that wine, those teas, or in the blueberries, that seemed to confer that protection.

And it was not long before promising substances like the antioxidants called polyphenols  (which are found in tea and in a number of fruits and vegetables) and resveratrol and procyanidin(s) (found in red wine) were tested for their possible association with reductions in the incidence and severity of metabolic-complex-related diseases.

They were found in some cases to work well with rats but not so well with humans, or in some cases, to work well with humans, but more so, for some humans, but not others. 

These paradoxes did not stop pharmacological research, but they did cause pharmacologists to question  if there was a common underlying mechanism that made these compounds effective for some people or lab animals that had certain genetic markers and protein-producing patterns, but not for people with other markers or patterns. It was time for a chat with the molecular biologists.

A Clinical Reconceptualization: Belly Fat Behaves Like an Endocrine Organ

It took less than a decade after the grand idea that all these disparate diseases might well be part of a common syndrome, for a key idea to emerge: just as the pancreas that produces insulin is an endocrine organ, and when it functions poorly diabetes results, it was entirely possible that the accumulated belly fat became an endocrine organ of its own, secreting some combination of chemicals or blood factors that caused insulin resistance, which in turn caused the strongly associated adult diabetes, which in turn was strongly associated with heart disease, and strokes, if not necessarily certain cancers.

But endocrine organs can secrete more than one substance that affects the body in a single way. They can secrete more than one variant or conformer of a hormone, or secrete a hormone that  can have more than one possible effect, depending where it docks within the body. This is particularly likely when a kind of heterogeneous , almost accidental organ made up of belly fat and random tissue  is involved.

This led to a hunt for other substances that could be caused by the errant belly fat endocrine organ, and a number of them turned up. Belly fat was associated with high levels of Cardiac Reactive Protein (associated with heart attacks), Tumor Necrosis Factor (associated with cell death), and certain kinds of  white blood cells which produced elevated  levels of lab proteins associated with a number of the differing component diseases within the metabolic syndrome.

The clinicians then had to talk with the biochemical and drug communities to help figure out what some of the commonalities were among these disparate but abnormal levels of substances and numbers of cells.

Inflammation as a Working Unifying Concept

What became clear was that many of these substances were the result of inflammation in the body. In some cases, some initial presence  of these substances caused even more damage over time, which caused the production and release of even more inflammatory responses, in a kind of vicious cycle that had to broken for the patient to get better.

The clinical  approach became more focused for diagnosis and the measurement of the success of any proposed medical treatment on  how well  the medicine or the procedure was working to reduce the signs of inflammation. As a corollary clinicians asked pharmacologists (and vice-versa) would some anti-inflammatory drugs used for other causes, work in metabolic syndrome related diseases?

Pharmacologists  turned around and asked their molecular biology friends what appeared to be the connections between the genes of people who showed high levels of inflammation and those that had had one or more of the component diseases of the metabolic syndrome. Furthermore, they wanted to know what were the genetics of those people who seemed to respond to given drugs or had a protective effect from some antioxidants like the polyphenols. The ideal goal at this molecular level was to see if drugs could be made for people who did not enjoy that protective effect, but that worked as well.

Some State Of The Art Papers Today

Right now we are seeing the ongoing exchange of ideas across disciplines and levels of biological organization. No one group has all the answers, but this does not keep the clinicians from compiling data on the commonalties signs, symptoms and diseases among their  patients , nor  restrain the pharmacologists from finding out what is the  key  compound and its most active site, when sorting out  some heterogeneous natural product that has hundreds of components,  nor does  it undercut the love of molecular biologists to explain diseases at the cellular level.

Rather, they all take whatever they’ve heard lately  at that traffic intersection of  different specialties, and see if it makes sense for their working explanations of what is going on with patients with metabolic syndrome, and its related diseases like adult-onset diabetes, and see if they can get a better diagnostic test, treatment, or preventive medical practice out of it.

Tony Stankus, FSLA, tstankus@uark.edu, Professor, Life Sciences Librarian & Science Coordinator

University of Arkansas Libraries MULN  223 E

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Comments

[protein shake]

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[abercrombie fitch]

I wonder how you got so good. This is really a fascinating blog, lots of stuff that I can get into. One thing I just want to say is that your Blog is so perfect!

[Heather Worthington]

Great post and extermely interesting although a bit technical for me - you guys are way ahead of us. Metabolic syndrome is a concept not widely known about or discussed in the UK like it is in the USA. Yet the UK is second to the USA in terms of obesity and the follow on health issues that obesity causes. Metabolic syndrome is something that can be diagnosed almost with the naked eye - waist size - yet we ignore it. We try to promote awareness of it in the UK as part of our website http://www.checkmybody.co.uk/MetabolicSyndrome.htm.

[CD]

Great post! I found it very helpful and inspiring.

[Tommy T]

This is a very good post; one that I believe all could benefit from reading.

[blowtorchbellyfat]

very interesting information. cant wait to tell my clients

[xocoslimreview]

Finally some information based on expert research.This an article written by someone who knows his stuff.Valuable,thanks

[Nopalea]

I find it astounding that so many disorders can be attributed to inflammation. Have you read Time Magazine's article on it? I believe it was a cover story back in 2004- "Inflammation- The Secret Killer". I didn't notice it cited in your research listings, but it certainly backs up everything you posted here.

[diabetes and heart disease]

This is an interesting study. Its a known fact that some diseases occur together and compound together to cause serious health problems.

[ben king]

Yes there is some good info here. It is a bit technical but then so is the body, so i suppose it fits

[diabet diet]

interesting info