5th Thursday Update

January 29, 2015


This disease is too complicated!

Most writing, and even most medical research, on the subject of Type 2 diabetes seems to have an unstated goal of making the disease less complex than it is known to be. If we can just identify the gene, the hormone, the protein, the foodstuff that is ultimately responsible for the whole complicated mess, then we will know what to do about the problem. And every week or two, somebody thinks he has found that one thing that counts. Most reports of scientific breakthroughs in the study of this disease seem to be cries of "Eureka!". Every university research team thinks it has finally isolated and identified the one factor that truly matters in terms of disease causation. It's odd, then, that every university research team seems to stumble on a different smoking gun. How can so many unrelated factors be the factor?

The research teams that look for dietary causes of diabetes tend to look at dietary differences from country to country, plotting their data to show that eating more of this or that type of food correlates with higher diabetes rates. I have seen graphs suggesting that diabetes correlates with eating more meat, more fat, more refined flour, or (as in the case illustrated below) more refined sugar.

The data points seem to be all over the place, but that helpful diagonal line, pointing up and to the right, tells us that the overall trend is for more sugar consumption to correlate with more diabetes. Okay, but the data points are not exactly gripping that line for dear life, are they? The correlation would be more persuasive if the pattern looked more like this:

It doesn't, though -- I faked that. The actual data includes enough variability to suggest, at least to me, that increased sugar consumption is only one factor affecting diabetes prevalence. Some other factor or factors must be involved, if the five highest diabetes rates are in locations where sugar consumption is down rather than up!

I'm not questioning the idea that increased consumption of carbohydrates in general is probably an important contributor to the increase in diabetes prevalence in recent decades. But maybe refined starches play at least as big a role as refined sugars do. And maybe other lifestyle changes have played important roles as well.

My own preference is to resist the impulse to oversimplify diabetes. I have tried, in this blog, to discuss the disease as if my readers are educated grownups and are not going to be scared off by descriptions that go into more detail than usual about the nuts and bolts of diabetes. Still, even I have to draw the line somewhere. I read an article today about research uncovering the reason why diabetes sometimes interferes with wound-healing. The answer, roughly paraphrased, is that diabetes can cause a gene which normally promotes wound-healing to prevent wound-healing instead, because diabetes interferes with the way that gene regulates other signalling molecules. If you're feeling brave, you can take a plunge into the abstract here:

"Surprisingly little is known about the impact of diabetes on the molecular events of mucosal healing. We examined the role of the transcription factor forkhead box O1 (Foxo1) in oral wounds of diabetic and normoglycemic mice with keratinocyte-specific Foxo1 deletion. Diabetic mucosal wounds had significantly delayed healing with reduced cell migration and proliferation. Foxo1 deletion rescued the negative impact of diabetes on healing but had the opposite effect in normoglycemic mice. Diabetes in vivo and in high glucose conditions in vitro enhanced expression of chemokine (C-C motif) ligand 20 (CCL20) and interleukin-36gamma (IL-36gamma) in a Foxo1-dependent manner. High glucose–stimulated Foxo1 binding to CCL20 and IL-36gamma promoters and CCL20 and IL-36gamma significantly inhibited migration of these cells in high glucose conditions. In normal healing, Foxo1 was needed for transforming growth factor-beta1 (TGF-beta1) expression, and in standard glucose conditions, TGF-beta1 rescued the negative effect of Foxo1 silencing on migration in vitro. We propose that Foxo1 under diabetic or high glucose conditions impairs healing by promoting high levels of CCL20 and IL-36gamma expression but under normal conditions, enhances it by inducing TGF-beta1. This finding provides mechanistic insight into how Foxo1 mediates the impact of diabetes on mucosal wound healing."

Is that clear? No, probably not. Like I said, this disease is too complicated. However, that doesn't mean I think we should just pretend it's simple.



It worries me that so many of the Google searches that yield a reference to my site have to do with diabetes killing people, including some pretty direct questions about how, and in what circumstances, diabetes could be expected to kill someone.

Typical examples this month include "does hypoglycemia kill faster than diabetes", "how can low blood sugar kill you", and "how low is your blood sugar when it kills you".

But today's search results yielded one that bothers me even more: "how to kill a diabetic person". Looking on the bright side, this question might have been posed by a mystery writer researching possible murder methods for a whodunit. I guess I would advise them to read up on the real-life Claus von Bulow case, if only to warn them that any would-be murderer who relies upon diabetes to operate predictably is headed for big trouble.

There is no simple formula that says "if you're diabetic and this happens to you, you die". There is no agreed-upon blood sugar level which is fatal if you're below it and safe if you're above it (or the other way around). Even for extreme lows, the concern is more about long-term harm to the brain and heart than about a risk of immediate death. Acute lows don't actually kill people as often as you might imagine -- but frequent lows on a chronic basis can certainly trigger health problems which will shorten your life.

The trouble with diabetes as a murder method is that, as I said above, the disease is too complicated. Murderers need to use things that work in predictable ways.


About "data"

I have occasionally been corrected by people who tell me that "data" is a plural, and that one should write "the data are", not "the data is".

I am perfectly ready to concede that "data" was a plural, in classical Latin. If we spoke that dead language today, I would have no choice but to treat "data" as a plural.

However, in modern English (a language spoken by living people), "data" is almost always used as a mass noun (grammatically identical to "information"). Most people never use the singular form "datum", or even know of its existence. "Datum" appears only in the most rarefied scholarly writing, by the sort of people who can refer to topics as "topoi" without blushing. Because the rest of us don't use "datum", we can't really use "data" as a plural. If people occasionally need the singular form, they say "data point". That is, living people say that. What dead people say is not my concern.


4th Thursday Update

January 22, 2015


Taking a seat

Evidence is accumulating that I am in my late 50s, and I'm having more and more difficulty overlooking that fact. Not that I really feel that old, in most respects.

Most of us don't feel that we really are the age indicated by our birth certificates, and the approach of a "milestone" birthday can seem like a surprising and inexplicable development. In April of 2017 I will turn 60, a fact which, at this point, seems a little puzzling. How did this happen, especially to somebody who feels as if he hasn't entirely put adolescence behind him? Apparently, if you hang around long enough, aging just happens.

I haven't had anything dramatic happen to me (no new health problems), but I have noticed a certain degree of slowing down. I'm still doing the same kind of exercise as before (six days a week, usually a run of 4 to 5.5 miles, with a longer trail run on the weekend), but I'm doing it more slowly than I used to. And I'm typically feeling a little more stiff and sore than before. Some of the yoga poses that used to be pretty easy for me are challenging now (which is a pretty good indication that I need to be doing them more often).

But the biggest indication of aging is that I'm more sedentary -- not in the sense that I don't work out, but that, during all those hours of the day when I'm not working out, I'm spending more and more time sitting down.

I'm not claiming that I wasn't spending too much time sitting in front of a computer in years past, but I'm doing more of it now than I used to. And I'm no longer under the misapprehension that this doesn't matter so long as I keep working out.

Researchers are finding more and more evidence that prolonged sitting is hazardous to your health -- and that this is true even for people who exercise.

To be sure, working out does ameliorate the health impact of sitting to a degree -- it seems to reduce that impact by about 30%. But, of course, that means that 70% of the health impact of sitting is not ameliorated by a daily workout.

It has long been known that prolonged sitting is bad for cardiovascular health. One study from the 1950s compared the health of bus drivers (who worked in a sitting position) and bus conductors (who worked in a standing position). It turned out that the drivers had a much higher risk of a heart attack.

The latest study shows that prolonged sitting increases all-cause mortality by 24%. Cardiovascular disease mortality is increased by 18%, cancer mortality by 17%, diabetes incidence by a whopping 91%.

I repeat, working out ameliorates these impacts of prolonged sitting, but only to a degree. Apparently, working out is not enough. We need to find a way to be less sedentary during those long stretches of the day and night when we are not exercising.

It seems that dramatic increases of activity are not required to address this problem. Getting up and wandering around periodically may be enough. The trick is remembering to do it.

Since it is the computer that usually leads me to spend too much time sitting, I have decided to install a PC application which interrupts me periodically to tell me to take a break. The one I'm experimenting with now is called Workrave, and it's a free download. I haven't been using it long enough to be sure I can recommend it, but so far, so good.

Because there is a running display which warns me of upcoming "micro-breaks", more extended "rest breaks", and ultimately "turn this thing off and go to bed" breaks, I think I will be able to work with it reasonably well. (The last application of this kind that I tried gave me no advance warning of upcoming breaks, and tended to hijack my computer at very inconvenient moments, such as when I was half-way through logging into something.)

I realize that, to some degree, slowing down as we get older is a natural and unsurprising development. But, when we notice that it is having the effect of exacerbating our bad habits, we can at least try to do something about the bad habits.


Those darned carbs

It sometimes seems as if the world is conspiring to make me eat more carbohydrate. To a degree that is literally true, given the way the US government subsidizes grain production. At any rate, foods tend to be prepared for us in such a way as to magnify their carbohydrate payload. Various ethnic foods are served to us on pillow-sized mounds of rice or noodles. Bagels have doubled in size. The cafeteria where I work used to have a do-it-yourself sandwich bar, with low-carb sandwich thins as one of the available breads; now you have to let them make the sandwich for you, and the bread choices are all hulking specimens of ciabatta or baguette.

Back in the day when low-carb diets were popular as weight-loss schemes, it was a lot easier to find convenience foods that weren't starch-bombs. Those days are gone, unfortunately.

So, right now, I am increasingly relying on what I think of as inconvenience foods. That is, the kind that you make yourself, and require effort. I'm not a great fan of effort, when it comes to food, but I guess I've got to do what I've got to do.

Lately I've been having some success with slow-cooker recipes; it's often possible to make something in a slow cooker that's low-carb and actually tastes good. I wish that were true of zero-effort cuisine!


3rd Thursday Update

January 15, 2015


Find Your Greenspace!

Outdoor exercise has some important advantages over gym exercise. Here are some of them:

But perhaps the greatest advantage of all is that, once you commit yourself to exercising in the great outdoors, you're probably going to spend a lot more time on it than you would on a gym workout. Instead of half an hour on the stair climber, you'll probably spend at least an hour hiking, running, or cycling -- largely because exercising outdoors feels pleasant (as compared to exercising in the gym, which feels like jury duty).

Of course, it's easy for me to recommend outdoor exercise, even at this time of year, because I live in coastal California and the January weather is quite mild. Not everyone has it so easy; I spoke to my boss in Scotland this morning; he said he was calling me from home because the Forth Bridge was closed due to 100 mph winds. So, if you're dealing with a cruel winter where you live, pretend I'm writing this in May.

Anyway, I recommend finding out about good outdoor exercise locations in your area. Often there are "greenspace" or "openspace" areas that most people overlook -- minimally-maintained parks with trails suitable for hiking, running, or mountain-biking.

Recently (on New Year's Eve, to be precise) I hiked at a greenspace that was walking distance from my sister's residential neighborhood, but seemed a world away once you got onto the trails. I had never been there, even though I used to live in the same neighborhood. I had been completely unaware of its existence until my sister introduced me to the place.

Odd as it seems, this is the greenest time of year in these parts. There was a lot of rain in the week before Christmas, and grass was sprouting everywhere.

Of course, one thing you have to contend with in greenspaces is steep slopes. The reason these places are undeveloped, even if they are surrounded by areas of high-density housing, is that they're too steep to be built on. On this kind of terrain, even walking is a true workout.

I just don't see how that's not a huge improvement over the elliptical trainer at the health club.

So, my advice is: find your local greenspace. If you can find someone to go there with you, so much the better. But get out there!


Inactivity and premature death

A large (>330,000 participants!) European study of the health effects of physical inactivity found good news and bad news about the subject.

The bad news first: inactivity is strongly associated with premature death. In fact, it causes twice as many premature deaths as obesity does.

The good news, however, is that even a small amount of exercise helps. (And more exercise helps more.)

One of the researchers: "This is a simple message: just a small amount of physical activity each day could have substantial health benefits for people who are physically inactive. Although we found that just 20 minutes would make a difference, we should really be looking to do more than this -- physical activity has many proven health benefits and should be an important part of our daily life."

Another researcher suggested that doctors should perhaps concentrate on encouraging patients to exercise, rather than on encouraging them to lose weight, because becoming more active it the easier of the two goals to achieve -- and, at least according to this study, it does more to improve the patient's health.


A drug that's full of surprises

An experimental drug known as amlexanox, which has been used as an asthma treatment, also seems to be showing promise in the treatment of obesity, diabetes, and fatty liver disease.

In studies on mice, amlexanox alters the chemical signaling which occurs between fat tissue and the liver. One effect the drug has is to increase the level of a chemical messenger known as cAMP; this in turn triggers fat cells to burn up their stored fat, resulting in loss of body weight. Also, the drug triggers the release of a hormone called interleukin-6, which causes the liver to release less glucose into the bloodstream, thus reducing the blood sugar level.

That these effects came as a surprise to researchers (the drug was supposed to treat asthma, after all, not obesity or diabetes) makes me wonder what other effects the drug might have, effects which the researchers are not expecting -- and whether those unexpected effects will turn out to be helpful or harmful. That is always the problem with drug development: a medication is created in the hope that it will have a single, very specific, very useful effect. But then researchers have to figure out what other effects it is having, and whether they are helpful or harmful to the patient.

As this drug is currently being tested on mice, I assume it is some distance from becoming available for human use. I wish the researchers well in turning it into a useful therapy -- but I'm not sure I'm going to the first person to try it!


2nd Thursday Update

January 8, 2015

I wasn't able to go running at lunchtime, so I had to put off my workout until after dark. Usually I go to the gym in that situation, but I felt the need for a nice long run, if only because my fasting glucose this morning seemed higher than it should have been.

I always have a hard time persuading myself to go outside to run after dark, because I live in a woodsy and very poorly-lit neighborhood, and because the area abounds in wildlife (mainly white-tailed deer) with a proven tendency to leap out at me out of the bushes and scare the hell out of me (since I don't know exactly what is leaping out at me). And yet, when I finally do manage to drag myself out into the night and get on with it, I always feel good about it after a while. So it proved tonight. And then I had dinner, and the diabetes gods rewarded me with a post-prandial result which was lower than my fasting result had been. (It was a rather low-carb dinner, but still.) Of course, I had the luxury of doing a night run in California. Despite the season, it was 55 degrees outside after dark. I'm not sure I would be doing night runs if it was freezing outside. If I lived in the midwest, I might be seeing more of the inside of a gym this time of year.


Toward a thinner mouse

Brown fat (the kind of fat tissue which burns fat and glucose to generate heat, instead of saving them for a rainy day) has been much discussed lately as a possible key to prevention or treatment of obesity and diabetes. If humans could turn some of their white fat tissue into brown fat tissue, they would apparently have less tendency to gain weight and become insulin-resistant.

The catch is that humans don't have very much brown fat, and our white fat has no tendency to turn into white fat -- except when we get a lot more exposure to cold than most of us are ever going to seek out. The number of people who are going to move to the south pole (or even sleep naked with the windows open in January), for the sake of weight loss and diabetes prevention, has got to be pretty small. Accordingly, researchers are concentrating instead on possible ways to induce the development of brown fat tissue in humans.

Researchers at UC Berkeley have identified a protein ("transcription factor Zfp516" they call it) which apparently stimulates the body to convert white fat into brown fat -- at least in mice. They genetically modified mice to produce more Zfp516 (and hence produce more brown fat), and what do you know? The "transgenic" mice, with their extra brown fat, maintained a higher body temperature than normal mice when exposed to cold. They also gained less weight when put on a high-calorie diet (see how much slimmer the transgenic mouse on the right is, compared to a similarly-fed normal mouse):

The point of the experiment was not to develop methods of genetically modifying humans; the point was to verify experimentally that the Zfp516 protein really does have the effect of promoting brown fat development and preventing weight gain.

Where scientists hope to take this next is to develop drugs which stimulate the body to make more of the Zfp516 protein. How practical that is, and how likely it is to produce big health benefits without side effects, is anybody's guess.

Meanwhile, in other fat-mouse news, researchers at Johns Hopkins have looking at mouse obesity from a different direction. Instead of finding out how genetic changes might determine whether or not a mouse gains weight, they have been finding out how weight gain in a mouse results in changes affecting its genes.

A lot of people have the idea stuck in their heads that our genes function as a fixed blueprint which we are stuck with forever. Well, our genes don't change with circumstances, but circumstances can affect how the genes are expressed. "Epigenetics" refers to the processes by which genes are activated and inactivated. Apparently weight gain is one of the things which can cause genes to be turned on and off -- which may partially or even entirely explain why obesity causes changes in health. The Johns Hopkins researchers compared obesity-induced epigenetic changes in mice -- and then compared them to obesity-induced epigentic changes in humans. The results turned out to be remarkably similar for the two species -- and the changes affected some genes already known to be associated with diabetes risk.

The study authors commented, "Mice and humans are separated by 50 million years of evolution, so it's interesting that obesity causes similar epigenetic changes to similar genes in both species. It's likely that when food supplies are highly variable, these epigenetic changes help our bodies adapt to temporary surges in calories. But if the high-calorie diet continues over the long term, the same epigenetic pattern raises the risk for disease."

I am pretty sure that what's driving this exploration of the epigenetics of obesity is the hope of developing the next billion-dollar-drug, but even those of us who might not be in a hurry to take that drug will probably benefit from what is learned in the process. Anything we can learn about health is useful, whether we are looking for a new drug or looking for a way not to need that new drug.


Metformin: too much or too little?

I saw two articles about metformin this week which seemed to have to come to me from two alternate universes.

One article reported on "an emerging consensus that the US Food and Drug Administration (FDA) labeling for metformin is too strict with regard to mild/moderate renal impairment." In other words, metformin isn't being prescribed enough, because of excessive alarmism about risks associated with the drug in patients with kidney disease.

The other article reported on the discovery that, because metformin is so widely used (it's the number one drug prescribed for diabetes), America's lakes and rivers are being contaminated by it. Lake Michigan has enough metformin in its water that the endocrine systems of fish are being adversely affected by it.

I realize it is possible that both articles are right in what they are saying. The fact that metformin is apparently safe for some patients who are being warned against taking it has no real bearing on whether or not it is safe for fathead minnows. (It seems that the male minnow's endocrine system mistakes metformin for a female hormone, and fertility problems result). I just couldn't help seeing a humorous contrast between two articles in one week, one saying metformin is not prescribed enough and the other saying it's prescribed too much.

If our society must choose to address only one of two problems (diabetic humans, and feminized fish), I'm pretty sure I know which of the two is going to be given priority. Mr. Minnow is going to have to man up as best he can!

1st Thursday Update

January 1, 2015


Resolution Running

After the hard rain of Christmas week, we've been experiencing the sort of chilly but brilliantly sunny weather that northern California tends to get in January -- all the better to showcase the green eruption of moss and grass that the December rains produce.


All of a sudden, this semi-desert region looks like a passable imitation of Ireland.


It's a great time for those of us who took part a little too enthusiastically in Christmas parties to get out and exercise in the fresh air. And air was never fresher! It's been very windy for the last few days, and the winds seem to have arrived straight from Alaska, with an extra dose of oxygen included.


I've been hiking and running on the local trails, trying not to let myself forget for a moment how wet and slippery the trails are.


I'm also trying not let myself forget that, despite the wind, it's only cold by California standards -- much of the country would be delighted to have non-freezing temperatures this time of year.


Plenty of other people are out there, biking and running and hiking, burning off their holiday treats.


One of the trail-joggers was, apparently, Queen Elizabeth, which was a surprise to me -- I hadn't known she was in California. Energetic for her age, isn't she?


I also ran into a fair amount of wildlife. I guess, if you're a deer, all this new grass is the equivalent of a plate of Christmas fudge. Jump on it while it lasts, Bambi! Our green season does not last very long.


Most people make New Year's resolutions to be more active than they were the previous year, and they at least make a good start. In January, especially when it's sunny and you have time off work and nothing else is competing for your workout time, it's easy enough to do a few excursions out into the fresh air. The trick, of course, is to remain active for the rest of the year, once the initial burst of New Year's energy begins to flag.

The secret of remaining on track with it, to the extent that there is a secret, is acknowledging to yourself that it's necessary. Not "a good idea" -- necessary. It's like paying the rent: you don't have to be in the mood to do it, you just have to do it.

Research results continue to show that exercise matters, in measurable ways. Researchers at the University of Missouri School of Medicine found that "reducing daily physical activity for even a few days leads to decreases in the function of the inner lining of blood vessels in the legs of young, healthy subjects causing vascular dysfunction that can have prolonged effects". Five days of inactivity in the test subjects resulted in a decline of sensitivity to insulin, resulting in poorer glycemic control. This comes as no surprise to me, but I admit I'm surprised to learn how swiftly inactivity can have an impact on cardiovascular health: "We found that skipping just five days of physical activity causes damage to blood vessels in the legs that can take a prolonged period of time to repair."

So, you see, we really do have to keep moving.


Being poor: not a good plan for diabetes management

JAMA is reporting that, when it comes to diabetes management, poverty is a bit of a handicap. "Difficulty paying for food and medications appears to be associated with poor diabetes control among patients in a study that examined the impact of economic insecurity on managing the disease and the use of health care resources".

I cannot imagine how "difficulty paying for food and medications" could not be associated with poor diabetes control. Did the researchers really think a different outcome was possible? Well, if so, they were disappointed.

The cornerstones of diabetes management (as least in the case of Type 2) are exercise and carbohydrate restriction -- neither of which is as easily available to the poor as they should be. Exercise is a lot easier to incorporate into your daily routine if you can afford a gym membership, or at least have enough free time to devote to outdoor workouts. And as for food, poverty tends to force people to rely heavily on cheap, high-carbohydrate staples such as rice.

If you have no time or money to devote to exercise, and you're counting on rice and beans to save you from starvation, and you can't afford to buy drugs to compensate for those problems, then it would be pretty surprising if you had great success in managing your diabetes.

Here's an interesting giveaway in the research report: "Health care systems are increasingly accountable for health outcomes that have roots outside of clinical care. Because of this development, strategies that increase access to health care resources might reasonably be coupled with those that address social determinants of health, including material need insecurities. In particular, food insecurity and cost-related medication underuse may be promising targets for real-world management of diabetes mellitus." So you see: economic reality should perhaps be looked into as a health issue, not because it's obviously the right thing to do, but because health care systems are starting to be judged by how well the patients are doing (and not by how many prescriptions get written per month).

Sometimes it's easy to forget that health care systems exist for the purpose of keeping people healthy, but that is indeed what the whole institution of medicine is there for. Factors which make people healthy or unhealthy are the factors that count.


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