Friday, February 29, 2008

Polyunsaturated Logic

I recently started reading Metabolic Regulation: A Human Perspective, by Keith Frayn, because I wanted to dig in further to the science discussed in Gary Taubes' Good Calories, Bad Calories. Not that I don't believe what Gary is saying, but it's always better to get your information from the proverbial horse's mouth. Anyway, Metabolic Regulation is turning out to be a good book, explains things reasonably well, and I'll be posting interesting tidbits in the future. The science of metabolism is mostly big words. There aren't really any hard concepts, so if you can get past the vocabulary, you can learn a lot about how your body works (or at least the current understanding at the time the book was written).

This is the second time I've gotten into an advanced book on this topic, and in both cases have noticed something very interesting. Despite going into incredible detail about metabolic processes, qualifying the conclusions appropriately (e.g. "this result holds in a test tube, but may not hold in a complete living organism), they still push certain dogmatic ideas without any comparable level of evidence. It amazes me that the authors, who otherwise present information in excruciating molecular detail, don't choke when they start preaching dogma without evidence. Weird.

The major piece of dogma is the connection between saturated fat, cholesterol, and heart disease, the so-called lipid hypothesis. It's not difficult to make arguments that these connections are not causal (e.g. saturated fat does not cause heart disease), but are rather erroneous inferences from experiments or observations of varying design quality. Malcolm Kendrick lays out a pretty solid case against the lipid hypothesis in his book The Great Cholesterol Con; you can also read about it here. When I get into the textbooks, I expect them to support the lipid hypothesis with similar detail, perhaps even greater, providing insight as to the key molecular mechanisms by which saturated fat raises serum LDL, how that LDL then exerts a direct causal effect in the development of heart disease.

But instead, I get nothing. Just recitation of the hypothesis, and no evidence beyond the usual epidemiological handwaving, really not much more than you would get from a newspaper article. Metabolic Regulation at least acknowledges the weakness of the evidence (still almost all epidemiological), though still proceeds as though the lipid hypothesis were proven, even giving a mathematical expression for the relationship between serum cholesterol and dietary fats of different saturation indices.

Given the widespread belief that saturated fatty acids (SFA) raise LDL, and that polyunsaturated fatty acids (PUFA) lower LDL, you'd think somebody would have nailed the biochemistry by now. Talk about a killer drug target: "Take Satfatium, eat all the butter and bacon you want, and keep your cholesterol normal!" They could even use Robert Jarvik as the spokesperson! Talk about a cash cow. Despite the obvious and overwhelming motivations to nail down the SFA->LDL mechanism, I haven't been able to find diddly-squat, other than some weak hypotheses having to do with SFA binding to LDL or cholesterol receptors. That seems unlikely, given the relative lack of chemical and physical similarities between SFA and cholesterol (both are lipids, but that's about as far as it goes), and the relevant parts of LDL for receptor binding are proteins, not lipids. But could it happen anyway? Possibly, but it seems like an easy thing to study in a test-tube. Scientists study all kinds of cellular receptors in vitro, why not this one? Maybe it has been studied, showed bupkus, and never got published. Most scientists are averse to publishing negative results, especially when they contradict the prevailing dogma.

It's easy to play mental games and generate hypotheses; however, that your hypothesis supports some other well-believed hypothesis doesn't make it more true than one which contradicts widely believed ideas. That's backward thinking. Scientific truth is always conditional: belief in one thing is always conditioned on the truth of other information. Thus, the degree of belief in the lipid hypothesis is conditioned on the hypothesis that SFA raises LDL and that LDL exerts a causal effect on the development of heart disease: the lipid hypothesis is only true GIVEN that SFA raises LDL AND LDL causes heart disease. If any of the conditioning statements are false, the rest of it falls apart. This sort of conditional truth is generally ignored in science, partly because of the ass-backwards way most scientists do statistics, where they actually consider the evidence that the data would have been observed GIVEN that the hypothesis were true, rather than the evidence that the hypothesis is true given the data. And no, those are not mathematically the same thing.

I'll finish this post with a little brain-bubble that occurred to me. This is total speculation, and really just shows how one can create nice-sounding hypotheses from limited information. Anyway, eating more PUFA supposedly lowers total serum cholesterol. Eating more SFA supposedly raises total serum cholesterol. I don't believe either of these statements has anywhere near unequivocal experimental proof (feel free to post evidence otherwise), as the results seem to be all over the place; but let's pretend they're true, like nearly everybody else does. Now, one hypothesis as to why PUFA lowers serum is that PUFA displaces monounsaturated fatty acids (MUFA) in cell membranes. Cell membranes contain both SFA and MUFA, along with a little PUFA. The ratios of these are thought to govern the "fluidity" of the cell membrane, because as we know, SFA can pack more closely together, and thus tend to be more solid at higher temperatures. Cholesterol plays a similar role, also promoting membrane rigidity.

Now the PUFA theory we're discussing holds that eating a lot of vegetable oil raises the PUFA content of the cell membrane. It's not good if the membrane is too fluid, so in the absense of saturated fat the body reacts by driving cholesterol into the cells to increase their rigidity, thus decreasing serum cholesterol. So maybe the opposite happens as well: eat lots of SFA, cell membranes become too rigid, so they release cholesterol into the blood, and total serum cholesterol rises. Beautiful, logically consistent, and also has the "benefit" of supporting the prevailing dogmatic belief in the lipid hypothesis.

Of course, it's all a house of cards. My hypothesis depends on the PUFA/cell membrane hypothesis, for which there is little or no proof. Unfortunately, scientists are incredibly bad at sorting out these logical relationships, for whatever reason, and hand-waving hypotheses like mine often wind up widely considered as "true". I think what happens is that people neglect that actual evidence. They look at the PUFA hypothesis, think "that seems reasonable", and follow the logical chain that "proves" the SFA hypothesis. "Seems reasonable" is not evidence, though, and that distinction is too often lost on the very people who should know better.

Thursday, February 21, 2008


I previously discussed the "surprising" negative results of the ACCORD trial, designed to test the effects of intensive blood glucose control in Type II diabetics. The media was full of statements to the effect that "don't panic, lower blood in Type II diabetics sugar is good", which seems a no-brainer. I suggested that the increased insulin dosage received by the intervention group could explain the increased mortality, due to various known effects of insulin, especially on cardiovascular health.

The ADVANCE Study is even bigger than ACCORD, but with the same essential goals. It's essentially a drug trial (really two drugs, one for blood pressure and one for blood sugar). After the ACCORD results, the ADVANCE investigators quickly trotted out a press release noting that their preliminary results saw no adverse effects in the treatment group. The difference between ACCORD and ADVANCE? ADVANCE did not treat with insulin, but rather with the drug Diamicron MR, from the class of sulfonylurea drugs. Sulfonylurea drugs work by increasing the insulin production of the pancreas, so in the coarsest sense, both ACCORD and ADVANCE are treating blood sugar by increasing insulin. But Diamicron MR has some other effects which may be protective against heart attack. We also don't know how much extra insulin was provided/created in ACCORD vs. ADVANCE. And for whatever it's worth (not much, really) Diamicron MR is helping the pancreas to fulfill it's natural function in response to blood sugar variations, so there may be some difference compared to just dumping exogenous insulin into a patient's blood. But that's hand-waving at this point.

ADVANCE has yet to publish its results, so we don't know whether the treatment was ultimately beneficial or not, only that there is currently no evidence of adverse effects of the treatment. I personally believe both ADVANCE and ACCORD are treating the wrong thing. Type II diabetes is fundamentally the result of insulin resistance. High blood sugar is a symptom. If you can reduce insulin resistance, the blood sugar will follow.

Drugs like Metformin can increase insulin sensitivity. But what causes insulin resistance in the first place? There are multiple hypotheses, but the simplest one which seems to fit the facts is consumption of refined carbohydrates. Refined carbohydrates rapidly increase blood sugar, requiring the pancreas to output large quantities of insulin. Insulin stays high in the blood well after the sugar has been forced into the cells, so insulin receptors continue to be bombarded, and this constant overstimulus likely results in down-regulation of cellular insulin receptors. Insulin performs other more powerful functions beyond blood sugar control, and it is logical to believe that cells adapt their insulin response to the ambient insulin level in order to maintain reasonable allostasis. There is considerable evidence both anecdotal and clinical that patients can restore insulin sensitivity (more or less) by simply removing the stimulus of refined carbohydrates and other "high glycemic" foods from the diet. The medical community seems to have forgotten the old chestnut:
Patient: Doctor, it hurts when I do this.
Doctor: Then don't do that.

If eating carbohydrates increases insulin and leads to insulin resistance, then don't eat carbohydrates. Now, this is easier said than done. The higher your insulin, the more deranged your metabolism, and that derangement is such that it creates major sugar cravings, because insulin resistant cells can't effectively get energy from the blood. A diabetic's cells think the body is in danger of dying from starvation. The body tends to do what it can to avoid death, like sending signals to the brain to get some sugar and get it NOW. So Type II diabetic's might require some level of drug intervention to help get their metabolism back on track, but the focus of the treatment needs to be curing the cause of the disease (insulin resistance) and not simply alleviating symptoms.

Friday, February 8, 2008

Insulin Insanity

The New York Times recently reported how a large study on the effects of lowering blood sugar in Type II diabetics had to be stopped due to ethical concerns, because a lot more people were dying in the treatment group. This was the ACCORD study run by the NHLBI and NIH, which enrolled over 10000 Type II diabetics. The treatment group received "intensive" therapy to control blood sugar, mainly in the form of insulin.

The increase in deaths seems to be a big surprise to most involved, eliciting a lot of handwaving explanations. But if you just think a little about the nature of Type II diabetes and the action of insulin in the body, I suspect the outcome makes perfect sense; worse, had anybody applied some logical thinking to well-established medical knowledge, the outcome would have seemed preordained. The problem here (which seems to be endemic in modern medicine) is that few people seem to be able to see the forest for the trees. Insulin and sugar have well-known physiological effects, and any hypothetical treatment for Type II diabetes should account for these. Of course, almost nobody does this, leading to the current mess.

Let's start by being clear on what Type II diabetes is. Diabetes is generally thought of as a condition where blood sugar is chronically too high; but is chronically high blood sugar the cause of the disease, or just a symptom? In Type I diabetics, the patient's immune system attacks the pancreas (the organ responsible for making insulin), destroying it's ability to secrete insulin. Insulin is one of the body's most powerful hormones, governing many aspects of metabolism, not least being blood sugar levels. Blood sugar is tightly regulated in the body, because sugar has several damaging toxic effects; but you need a little sugar in the blood to power certain cells, like red blood cells. So Type I diabetics, lacking insulin, suffer increasing blood sugar, and all of the attendant bad effects, on average having significantly shortened lives.

Type II diabetes is really the opposite condition: too much insulin. You still have the symptom of increased blood sugar, but now it occurs because your body's cells have a downgraded response to the insulin secreted by the pancreas. Since the cells don't respond as readily to the insulin signal, sugar tends to build up in the blood, so the pancreas cranks out more insulin, which further desensitizes the cellular insulin response, resulting in a vicious cycle where both insulin and blood glucose levels increase over time. Ultimately your pancreas reaches the limit of what it can do, blood sugar goes through the roof, and you're classified as a Type II diabetic.

Now it makes sense to treat a Type I diabetic with insulin, because they have a serious lack. Insulin does a lot of things besides regulate blood sugar, and if you don't have any, you're in big trouble. But insulin is a seriously powerful hormone. It has many effects beyond reducing blood sugar, and these are just as well-known as the effects of high blood sugar itself. There's a reason why, in the presence of a too much insulin, your cells lower their response: too much insulin is damaging. Insulin resistance is a protective mechanism, and in Type II diabetics, it's out of control. From an evolutionary standpoint, one could go so far as to argue that insulin is more toxic than high blood glucose, otherwise the mechanism for insulin resistance would not have evolved (but that's just speculation on my part).

Giving insulin to a Type II diabetic is like dumping water in a sinking boat. It just exacerbates the original problem by further increasing insulin resistance AND subjecting the body to further damaging effects of chronically elevated insulin levels.

Now, you might argue that the "experts" had more information, and that I am oversimplifying things. I probably am oversimplifying things, but not as much as the so-called experts. Check out these quotes from the NYT article:

“It’s confusing and disturbing that this happened,” said Dr. James Dove, president of the American College of Cardiology. “For 50 years, we’ve talked about getting blood sugar very low. Everything in the literature would suggest this is the right thing to do,” he added.

Dr. Irl Hirsch, a diabetes researcher at the University of Washington, said the study’s results would be hard to explain to some patients who have spent years and made an enormous effort, through diet and medication, getting and keeping their blood sugar down. They will not want to relax their vigilance, he said.

“It will be similar to what many women felt when they heard the news about estrogen,” Dr. Hirsch said. “Telling these patients to get their blood sugar up will be very difficult.”

Dr. Hirsch added that organizations like the American Diabetes Association would be in a quandary. Its guidelines call for blood sugar targets as close to normal as possible.

And some insurance companies pay doctors extra if their diabetic patients get their levels very low.

The low-blood sugar hypothesis was so entrenched that when the National Heart, Lung and Blood Institute and the National Institute of Diabetes and Digestive and Kidney Diseases proposed the study in the 1990s, they explained that it would be ethical. Even though most people assumed that lower blood sugar was better, no one had rigorously tested the idea. So the study would ask if very low blood sugar levels in people with Type 2 diabetes — the form that affects 95 percent of people with the disease — would protect against heart disease and save lives.

Not very scientific, wouldn't you say? Everybody just assumed that lowering blood sugar was "the right thing to do", come hell or high water. In a sense, that's true: high blood sugar definitely causes serious damage. The problem is that nobody gave any thought whatsoever to the potential downsides of the treatment, especially in light of the known cause and symptoms of Type II diabetes, and the known effects of high insulin. The result? Many people killed in an effort to prove the dogma, not to mention millions of dollars wasted. With even a little rational thinking based on well-established knowledge, those lives would have been spared, and those dollars put to much more productive use. And the scary thing is, they still don't get it:

Clearly, people without diabetes are different from people who have diabetes and get their blood sugar low.

It might be that patients suffered unintended consequences from taking so many drugs, which might interact in unexpected ways, said Dr. Steven E. Nissen, chairman of the department of cardiovascular medicine at the Cleveland Clinic.

"Clearly", Type II diabetics with low blood sugar are different from non-diabetics: they have high insulin. They knew that before the study, but chose to ignore it, and blindly continue to do so. Apparently most of the deaths in the study were from heart attacks. Should we be surprised? Below is an excerpt from an excellent article about insulin (go down to the section "Insulin and Cardiovascular Disease"):

But there are certain tissues that aren't becoming resistant such as your endothelium; the lining of the arteries doesn’t become resistant very readily, so all that insulin is affecting the lining of your arteries.

If you drip insulin into the femoral artery of a dog, there was a Dr. Cruz who did this in the early 70s by accident, the artery will become almost totally occluded with plaque after about three months.

The contra lateral side was totally clear, just contact of insulin in the artery caused it to fill up with plaque. That has been known since the 70s and has been repeated in chickens and in dogs; it is really a well-known fact that insulin floating around in the blood causes a plaque build-up. They didn't know why, but we know that insulin causes endothelial proliferation. This is the first step as it causes a tumor, an endothelial tumor.

Insulin also causes the blood to clot too readily and causes the conversion of macrophages into foam cells, which are the cells that accumulate the fatty deposits. Every step of the way, insulin is causing cardiovascular disease. It fills the body with plaque, it constricts the arteries, it stimulates the sympathetic nervous system, it increases platelet adhesiveness and coaguability of the blood.

Insulin is a part of any known cause of cardiovascular disease. It influences nitric oxide synthase; you produce less nitric oxide in the endothelium. We know that helps mediate vasodilatation and constriction, i.e. angina.

So it would seem that, given what is known about the effects of insulin on arteries, an increase in deaths from heart attack should have been the expected outcome.

Once again, do you want these people making decisions about your health? If you are a Type II diabetic, the outcome of this study should serve as motivation to find out for yourself what is known about the cause of the disease, and the treatment options available. Don't blindly follow the brain-dead dogma espoused by most physicians and scientists, apparently blind themselves to long-established knowledge about the effects of insulin. Get the information for yourself, and ask your doctor hard questions about WHY you should do what he/she recommends. If the best answer they can give is "because I said so", you might consider looking for another doctor.