Fourth Thursday Update

September 25, 2014

 


Looking for Patterns

Pareidolia is the human tendency to identify patterns in random visual information, so that we perceive familiar images (especially faces) in the clouds...

...and in vegetables...

...and in rocks...

...and in icebergs:

NASA is constantly dealing with public over-reaction to geologic formations on Mars which look like people or animals, at least from certain angles:

That was the famous "Face on Mars", a hill which had a certain Sphinx-like appearance in the first low-resolution photo that captured it with a low sun-angle. Years later, a higher-resolution photo taken with the sun higher in the sky clarified matters somewhat:

It's a damned hill, people.

I enjoy pareidolia as much anyone, or at least I used to as a child: I was very adept at finding pictures in clouds, in the texture of a plastered wall, and in the stains on a driveway. Being less excited by it now, I am less good at it now, but I see the fun of it.

I also see the danger in it, as people sometimes read too much significance into a "pattern" that means nothing. Pareidolia doesn't always lead us to an accurate understanding of how things work. In science, the identification of any sort of pattern in data is often taken as an excuse to speculate very freely about what it means.

I don't know whether that is what's happening in the case of some recent research coming out of Massachusetts, but I'm a little suspicious that it might be. The paper I read on the subject is called "Dynamical glucometry: Use of multiscale entropy analysis in diabetes" and it is published by the American Institute of Physics (not an outfit normally associated with diabetes research). The researchers looked at data gathered by means of Continuous Glucose Monitoring (CGM), a procedure in which someone's blood glucose level is monitored by testing at five-minute intervals over an extended period. They did some very serious number-crunching on CGM data gathered on 18 diabetic and 12 non-diabetic elderly people.

The data showed, unsurprisingly, higher blood glucose on average in the diabetes patients, and higher spikes. But the data also showed differences between diabetic and non-diabetic subjects which were more subtle and required more careful analysis to uncover.

For example, although both diabetic and non-diabetic subjects showed a lot of short-term fluctuation in glucose levels, in the case of non-diabetic subjects the fluctuations were more rapid (and smaller) -- for them there was a constant small-scale jitter, as opposed to the larger, slower fluctuations seen in diabetic subjects. In the graph below, the fluctuations of a non-diabetic subject are shown at the top (with a closeup inserted to reveal the rapid-fire jitter), and the bigger but more lumbering fluctuations of a diabetic subject are shown below:

The small, jittery fluctuations of non-diabetic subjects have been known about for some time, and most researchers assumed they represented "random noise" -- inevitable inaccuracies introduced by the measurement process. But the researchers suspected that this was not random -- there was some kind of pattern to it. The researchers performed an elaborate statistical analysis on these jittery fluctuations, including such mathematical tricks as comparing the actual jitter (in terms of how much one data point differed from the one before it) with an artificial jitter pattern created by shuffling the order of the data points. In the graph below, the top graph shows the size of fluctuations in their actual order, and the bottom graph shows the size of shuffled fluctuations:

Perhaps, like me, you're thinking that the bottom graph looks different, but not a way which seems striking or meaningful. Well, the number-crunchers have ways of analyzing such differences and finding a pattern in them. They performed an "entropic analysis" on all these real and reshuffled sequences of data points, and concluded that the "controls" (non-diabetic subjects) showed jittery fluctuations that were exceptionally "entropic" (disordered), especially in comparison with the diabetic subjects:

Okay, having found this pattern, what are they claiming it means?

Here's where things get just a bit vague and confusing. Certainly they think it's important. They think that glucose levels in non-diabetic people are more jittery because a healthy glucose-control mechanism is complex and has many factors active at a time; a diseased glucose-control mechanism is less jittery because the relevant factors are not all active, or not in equilibrium.

A summary from the authors: "Current therapeutic strategies focus almost exclusively on glucose lowering by searching for molecular 'targets' involved in increasing sensitivity to insulin or insulin release by the pancreas. Our findings support extending the conventional notion of a discrete (pathway or signaling) therapeutic target to include the overall control 'system as target.' For example, two interventions may reduce blood glucose to a similar extent; however, one may do so by restoring healthy multiscale dynamics, the other may fail to do so. We anticipate that the former would be preferable to the latter. Furthermore, we suggest that dynamical glucometry, defined here as the application of an ensemble of computational tools, including multiscale entropy, to the analysis of serum glucose time series will help uncover hidden information of basic and clinical value."

Well, okay. No doubt that seems more clear and specific to them than it does to me. When I read a thing like that,I suspect that what it really means is "Please give us more money to spend doing this kind of research, and maybe we'll eventually discover something useful in the process". Am I being harsh? Possibly so, but come on: what does it mean to say that a diabetes therapy should be aimed at "restoring healthy multiscale dynamics"?

What it might mean is "get some exercise". If it does, then I'm willing to play along with them.

However, I can't help suspecting that the number-crunchers stared at their data for a long time, and ultimately decided that they had, at long last, found the face in it.

 


Third Thursday Update

September 18, 2014

This was a very rough day for me. I spent all of it trying desperately to meet an all-but-impossible deadline. I was creating several huge online-help files for a new product that was going to begin its final software build this evening. The help files had countless broken hyperlinks in them which had to be repaired -- but a series of hardware and software problems were preventing me from making the necessary repairs. I was running around the office all day, frantically enlisting various people's help in solving these problems so that I could complete the files before the final build started.

In the end, I completed all the help files, six minutes before my deadline. So, no drama or anything.

My blood pressure is surprisingly low -- now that I have met the deadline, and just got back from the gym and settled down in front of my computer (and fell asleep for a few minutes, actually). However, I would hate to have measured my blood pressure at any time during the day before I met my deadline.

A cardiologist once told me that the only thing it takes to get people to start generating harmful levels of stress hormones is to give them a task and a limited time in which to finish it. I think I proved that today.

There is something fundamentally unhealthy about modern living. Control of infectious disease (through sanitation and vaccination) has disguised this fact; we think we're healthy because most of us don't die before age nine anymore. Yeah, modern living is a much better deal for children than ancient living was. But for adults? That's where modern living falls short. We really haven't got this figured out, people!

 


The Asian Diabetes Dilemma

Diabetes prevalence is rising everywhere, but it's rising especially sharply in Asian countries. It's become a huge problem in China, where diabetes accounted for only 2% of healthcare spending in 1983, but shot up to 18% in 2007. Currently, one in ten people in that country have diabetes -- and five in ten have "prediabetes". What might be the explanation for this?

Not only is Type 2 diabetes becoming increasingly common in Asian populations, it is occurring at lower levels of obesity than would be the case in the USA or Europe. Apparently, if you are Asian, the amount of weight you can gain without greatly increasing your risk of diabetes is a lot less than what other people could get away with.

I would have assumed that the Asian diet, with its heavy reliance on rice and noodles, was the obvious culprit here: take in that much starch and of course your blood sugar is going to get out of control. But this reasoning fails to account for the fact that the Asian diabetes crisis is a recent phenomenon. Rice and noodles are not newcomers to the Asian diet, so it's hard to see how they could be what's causing diabetes prevalence to rise in Asia.

Some new research suggests that the diabetes surge in Asia may be caused not by the traditional Asian diet, but by the modern abandonment of it.

In recent years Asians have adopted a more Westernized diet -- with less carbohydrate and less fiber, but with more fat and more animal protein. A new study finds that Asian-Americans who return to a more traditional Asian diet tend to have much less insulin resistance (and also tend to lose weight) as compared to those who stick to an American diet.

This is exactly what I hoped the researchers would not find, because it presents me with a difficult dilemma.

My own experience seems to show that a high-carb, high-fiber, low-fat, low-meat diet is, indeed, effective for weight loss -- but not so effective for glucose control.

Do I go on an "Asian" diet to lose weight, even though it makes my blood sugar go up in the short term, because researchers are claiming it will pay off for me in the long run?

It's hard to have the nerve to do that. It's hard for me to dive into a plate of rice, or a bowl of noodles, and not worry about what my post-prandial test result is going to be like.

It may be that the traditional Asian diet is good for preventing obesity and diabetes -- but not so good for managing diabetes once you're got it. In other words, this could be an approach that's right for a lot of people -- but in my case it's too late to take advantage of it.

But it's also possible that I'm missing a good bet here, if I don't give the Asian approach a try.

Decisions, decisions...

 


The Trouble with Artificial Sweeteners

Artificial sweeteners have been linked to all sorts of problems, including abdominal obesity and diabetes. It hasn't been clear how they could be causing such problems, however.

Researchers in Israel have come up with a possible explanation: artificial sweeteners have an influence on gut bacteria, which in turn have an influence on human metabolism. Consuming artificial sweeteners seemingly leads, indirectly, to glucose intolerance.

Maybe this means that, if I give up Diet Pepsi, I can improve my glucose profile without adopting an Asian diet...

 


Second Thursday Update

September 11, 2014

I expected a lower fasting test today, but I'm going through a stressful period at work (a big software release deadline is coming up, and I lost the contractor I was counting on to help me finish it on time). Maybe my anxiety level contributed.

At least my after-lunch test was good!

 


Does "diabetes" mean anything now?

English is a weird language. It has an almost bizarrely large vocabulary; often a single concept is represented by a long list of synonyms. English dictionaries need to include usage notes explaining the fine shades of meaning that distinguish "fast" from quick, swift, rapid, fleet, brisk, hasty, and hurried. In fact, we have so many synonyms that we need a thesaurus to keep track of them -- a type of book for which, in many other languages, there is no need.

And yet, despite our record-breaking oversupply of words, we nevertheless like to burden a given word with a multitude of possible meanings. The word "pass", for example, can mean almost anything related (perhaps metaphorically) to a transition or a path of movement. You can pass a test, make a pass at someone, get dizzy and pass out, throw a forward pass, pass along a rumor, or pass from adolescence to adulthood. If you're a smooth talker, you can pass for an expert. While driving, you can pass another car, but if you do it while driving over a mountain pass, there's a risk that you will pass away in the process. If you have a pass to the local cinema, you can go see a movie there, or else give it a pass. However, let me mention (in passing) that if you do go see the movie, you can then pass judgment on it, complaining that this is what passes for entertainment these days. In short, "pass" means almost anything someone wants it to mean.

We might expect the language of medicine to be above this kind of linguistic sloppiness. Medicine is a science, after all (isn't it?). We expect scientific language to be precise and unambiguous. We expect a diagnostic term such as "diabetes" to have one clearly understood meaning.

Perhaps that could have happened, if diabetes had been a modern discovery. But diabetes is among the earliest diseases to be identified and named; the word has been around for many centuries, and it has acquired layer upon layer of metaphorical meaning. "Diabetes" is about as specific a word as "pass", at this point. It means whatever the person using it has in mind.

I am reminded of this confusing situation by a recent article from the University of Manchester, with the eye-catching title, "Is Type 2 Diabetes 'diabetes' as currently understood?". I will get to the article in a moment, but first, some thoughts on various things "diabetes" can mean.

"Diabetes" comes from a Greek verb which means, you guessed it, "pass" (specifically in the sense of water passing through the body and out of the bladder). You were said to have diabetes is you were "passing" (producing urine) at an elevated rate.

Diabetes in this sense is a symptom, not a disease -- more than one disease can cause excess urination. As a diagnosis, "diabetes" needs a qualifier. What we usually call "diabetes" is an abbreviated form of "diabetes mellitus". Mellitus, meaning "honeyed", specifies that the excess urine is sweet in this case. If you have "diabetes insipidus" (a pituitary disorder, unconnected to blood-sugar problems), then the urine you are producing so abundantly is, sad to say, insipid (not flavorful).

Diabetes mellitus was, unfortunately, named during a primitive era, when no clinical technology existed, and the old taste-test was what doctors had to rely on. We have better measurement methods than that now, but not alas, better terminology. Whenever we use the word "diabetes" we are referring back to a time when being a doctor meant tasting your patients' urine. As if that's not reason enough to discard the term, it's misleading, now that we think of the disease as a problem in the bloodstream rather than the urine stream. We still say "diabetes mellitus", but what we mean by it is that the blood, not the urine, is abnormally sugary.

Defining what "abnormally high" blood glucose is can be surprisingly difficult. The glucose level in the blood fluctuates considerably, whether you have diabetes or not, over the course of a day, so simply measuring glucose at one arbitrary moment and calling it "high" or "low" can be misleading. Digesting a meal adds glucose to the bloodstream; physical activity subtracts it. Everyone's glucose shoots up after meals, but there's supposed to a limit to how high it goes, and how long it stays high. Diabetes mellitus can be defined only in terms of the glucose level under specified circumstances (after a 12-hour fast, for example, or two hours after consuming a standardized dose of oral glucose), or else in terms of the average glucose level over time (as indicated, indirectly, by the result of a hemoglobin A1c test).

But, no matter how you define abnormally elevated glucose, you are really defining a symptom, not a disease! There's more than one way for blood glucose to become abnormally elevated.

The old terms "juvenile" and "geriatric" diabetes mellitus referred (respectively) to an auto-immune disorder which typically manifests early in life and a less-understood, but more common, disorder which typically manifests later in life. These two kinds of diabetes mellitus came to be called Type 1 and Type 2 (I'm not sure which doctor chose those richly meaningful terms, but Dr. Seuss is the most likely suspect.)

Type 1 at least has a comparatively clear cause: the patient's immune system goes a little crazy (why this happens is not certain) and attacks a specific type of cell within the body as if it were an invading microbe. The type of cell attacked, in the case of Type 1, is the beta cells in the pancreas which produce the patient's insulin supply. If you have Type 1, you produce no insulin, or very little of it, and have to inject insulin to survive.

Type 2, on the other hand, is much harder to get specific about. People with Type 2 can produce insulin (sometimes in abnormally large amounts) but it doesn't work as well as it should, because the patients's cells have become insensitive to it. This "insulin resistance" can apparently be triggered by a lot of different problems, but it is especially associated with obesity and inflammatory conditions.

However, some Type 2 patients do not necessarily have much of a problem with "insulin resistance" -- they instead have a problem with declining production of insulin (not as severely curtailed as in the case of Type 1, but bad enough to cause blood glucose to get out of control).

These differences among Type 2 patients obviously raise the possibility that "Type 2 diabetes mellitus" is not a specific disease -- it's a category of diseases. Maybe it doesn't mean anything other than "diabetes mellitus that isn't Type 1"

The article I read tonight takes the uncertainty even further. Is Type 2 diabetes actually diabetes at all, in the sense that the term is most commonly understood?

The researchers at Manchester University studied patients who were thought to be "at risk for" Type 2, but were not considered to have it yet because their blood glucose was not yet elevated, or at least not elevated enough to meet the diagnostic criteria for the disease. The researchers wanted to find out if anything else of a troublesome nature goes on in the bloodstream of such patients, during the period before glucose rises above the normal range.

It turns out, unfortunately, that troublesome things are indeed going on in such patients before the diabetes diagnosis. Abnormalities develop in lipids (fat-related compounds in the blood), and these changes can be harmful to the circulatory system. In other words, the harm that diabetes can do begins before, under current definitions, the patient can even be diagnosed as diabetic.

Another way of putting it is that, just as sugary urine turned out to be merely a consequence of excess sugar in the blood, the excess sugar in the blood may turn out to be merely a consequence of other problems in the bloodstream which are harder to spot.

J. Kennedy Cruikshank, the lead author of the research paper which the article summarizes, is quoted as follows: "We found that several groups of fat metabolites, also linked to body fat, were changed in the blood, as were others including some amino acids and to some extent vitamin D, before glucose levels increased. Blood vessels become damaged as part of the condition, but problems in the vessels arise before high blood sugar sets in during a ‘pre-diabetes’ period. The current method of categorising type-2 diabetes solely by a patient’s glucose level means that many will already have suffered blood vessel damage and will experience poorer outcomes. Our study overall adds weight to the argument that type-2 diabetes should not be classified as ‘diabetes’ as we currently understand it from just measuring blood glucose.”

Well, it's easy to say "call it something else, and define it differently", but the researchers are going to have to come up with a pretty specific plan to replace what doctors are doing now. First of all, they're going to have to come up with a more comprehensive description of what these lipid abnormalities are, and what is causing them. Second, they're going to have to come up with good clinical tests which identify those abnormalities. Finally, they're going to have to say what doctors and patients should do about this renamed syndrome once they realize it has developed.

I don't think I can help the researchers define the syndrome, or develop tests for it, or even choose a name for it (though they certainly should come to me first -- it's clear by now that they shouldn't be trusted to name anything on their own). Where I might be able to help them is in the what-to-do-about-it department. My exercise program has improved my lipids test results at least as much as it has improved my glucose test results. I have no proof that these improvements in lipids go hand-in-hand with an improvement in the particular "fat metabolites" which the researchers were investigating, but I think it's a reasonable inference.

 


First Thursday Update

September 4, 2014

The opportunity to have a trail-run in the state park after work is a summertime luxury for me. Come September, as the sun sets earlier and earlier, it becomes more and more difficult to squeeze in a run of any significant length before it gets dark (and in my opinion those trails are no place to be after dark). By the end of this month it will probably be impractical to do any evening runs there, so tonight I decided to take the opportunity while I still had it.

Plenty of other people were there doing the same thing, hiking and running and cycling and horseback riding in the fading orange sunlight. I felt an odd sense of community with them. It was as if we were all thinking, but not saying, "Summer may be dying, but we're not!"

 


Bad, bad molecules!

Scientists keep discovering new molecular villains to take the blame for causing diabetes, or for causing the health problems associated with diabetes. The newest bad-boy molecule to join this rogue's gallery is methylglyoxal, known as MG to its friends (of whom it has but few). Why is MG bad? Because MG is, or at least so we are told, the culprit in the case of "who killed HDL?".

HDL cholesterol is the so-called "good cholesterol" -- the form of cholesterol which is supposed to clear away the dangerous deposits on arterial walls which are left there by LDL ("bad") cholesterol. An abnormally high ratio of LDL to HDL on your lab results is considered a danger sign, because if you have too much LDL and not enough HDL, it means that your bad cholesterol is depositing plaques on your arteries faster than your good cholesterol can remove them.

People with Type 2 diabetes typically have abnormally low levels of HDL cholesterol, which means the bad/good ratio is unusually high in them, and the risk of arterial disease is heightened. But what, exactly, is causing people with Type 2 to have abnormally low levels of HDL?

That's where the villainous molecule known as MG comes in. According to researchers at the University of Warwick in the UK, MG is a highly reactive molecule that is formed from glucose in the body. It has a propensity to damage HDL cholesterol molecules, so that they become unstable and are soon cleared out of the body. This results in a reduced level of HDL in the blood.

The body produces a good-guy molecule to counteract this bad-guy MG molecule. The good-guy molecule is known as glyoxalase 1 (known as Glo 1 to its friends, of which it has, or will soon have, many). Glo 1 converts MG to harmless substances. But, wouldn't you know it, the body's production of Glo 1 is often insufficient, due to the effects of aging, inflammation, and stress. In people with diabetes, there is too much MG produced (because the body has too much glucose to make it from) and not enough Glo 1 to neutralize it (because people with Type 2 tend to have various sources of inflammatory stress going on).

So, if excessive MG combined with insufficient Glo 1 is the reason Type 2 patients tend to have insufficient good cholesterol, what can be done about the problem? And how can somebody get rich off it?

The researchers are suggesting that we can either develop drugs which reduce the level of MG, or else develop supplements which cause the body to produce more Glo 1 -- so that the Glo 1 can do the job of reducing MG for us.

Of course, another possible solution would be to exercise a lot. My own problem with low HDL went away after I had been exercising regularly for a few years, and it hasn't come back since. But nobody's going to get rich telling diabetes patients to work out.

It's not hard to see what lies behind this endless quest for molecular villains: each one becomes a "drug target", which sounds so much nicer than "cash cow" but means the same thing. If there are a hundred molecules which can be shown to be more abundant in people with diabetes, then there are a hundred opportunities for somebody to invent a chemical which targets and destroys one of those molecules, and perhaps create the next billion-dollar pill.

But what if these molecular villains are not causes but effects? We're told that they are causing trouble, but it seems pretty obvious that trouble is causing them.

Too much MG is produced in Type 2 patients because it's made from glucose and Type 2 patients have too much of that. Not enough Glo 1 is produced in Type 2 patients because production of it is inhibited by inflammatory stress and Type 2 patients have too much of that. Improving your overall health as a Type 2 patient will seemingly address both of those "causes" of further trouble. Targeting MG and Glo 1 specifically seems more like a plan to hide the problem than to solve it. If you solved the real problem, secondary problems with MG and Glo 1 probably would not arise!

 



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