Wednesday, September 4, 2019

Studying Rodents

Much diabetes research is done in rodents, mostly mice. But mice aren't humans, and they don't always react the same way as humans.

For example, mice have been cured of diabetes many times, but these cures don't translate into human cures. So should we abandon mouse research?

No. The mouse research makes suggestions for things that might work in humans, or in human cell cultures, and raising mice is a lot cheaper and faster than raising larger animals, so many more studies can be done.

However, more attention should be paid to how the mice are raised. Some people criticize mouse studies because they are not controlled for light intensity or electromagnetic fields, which can affect biochemical systems. Others criticize the standard mouse diets.

A recent editorial in the journal Nature discussed the problems with mouse diets. It focuses on obesity research, but obesity and type 2 diabetes are linked.

You can make mice obese pretty quickly by feeding them high-fat diets, which they love; their normal diet is relatively low in fat. Think of baiting a trap with cheese.  But the Nature editorial asks if such high-fat diets have relevance to human obesity that usually develops at much lower dietary fat levels than the mouse obesity.

The editorial also asks if the metabolism of mice raised on a very high fat diet is different from that of mice raised on more normal diets. It also points out that the very high (60%) fat diets usually used to make mice obese quickly have a lot less sucrose than a lower-fat diet would, and sugar has metabolic consequences too.

So too, the types of fatty acids in a diet can affect the metabolism, and the fatty acids in the commercial mouse diets may not be similar to those in a typical (if any diet is typical) human diet.

One thing the editorial didn't address is the fact that many of these diets use the cheapest ingredients available and often satisfy the carbohydrate goal by adding sucrose instead of some kind of healthier carbohydrate like whole grains.

This editorial obviously raises questions rather than providing answers, and at the moment it has no practical value for most people.

However, the fact that people are drawing attention to the quality of the mouse diets used in so much research is a good thing. Maybe better mouse diets will result in better research results.

Thursday, August 22, 2019

New Hypotheses

Sometimes it seems as if almost everything I was taught in school is now considered wrong. Well, OK, not everything. The letter i still usually comes before e, except after c and a ton of other exceptions including neither leisured foreigner seized the heifer on the weird heights, and no one cares about spelling today anyway.

Of course in science, no theory is permanent. New evidence requires updating of current theories, somethings reversing them completely.

I just hope no one discovers that the universe isn't expanding, but imploding toward another Big Bang! And if it is, I hope it doesn't occur in my lifetime.

But on a more mundane level, three papers came in recently that are challenging accepted dogma.

The first suggests that lactate, a product of metabolizing glucose, isn't a dead-end molecule produced only when there isn't enough oxygen to metabolize it further, but rather is an important source of energy and a way to distribute this energy from one tissue to another. George Brooks of the University of California, Berkeley, has been proposing this idea for 40 years, but no one has been paying much attention, and most biochemistry sources still show it as a sort of waste product produced only in the absence of oxygen and causing pain after heavy exercise.

But the Brooks lab found that lactate is actually a preferred source of energy in some tissues like the brain and heart. Brooks calls the production, transport, and use in various tissues the lactose shuttle.

The whole review can be seen here.  

A second paper  suggests that it's not a lack of insulin but insulin hypersecretion that causes insulin resistance and type 2 diabetes. Australian researcher Christopher Nolan is one of the authors of this paper, and I've written about some of his ideas before, namely the idea that insulin resistance is protective for some tissues.

Nolan and his coauthor support the idea that there are five subtypes of diabetes and says that the type that causes insulin hypersecretion is severe insulin-resistant diabetes (SIRD). If someone has this kind of type 2 diabetes, then he says treating it with insulin injections or sulfonylureas would be counterproductive.

People with other subtypes might benefit from such treatments.

I suspect that researchers will eventually discover even more subtypes of diabetes, with some overlap, but for now we can stick to just five. Nolan says it's "time for a conceptual framework shift" to consider the main driver of type 2 diabetes to be not insulin resistance but insulin oversecretion. It's an interesting way of looking at the disease.

Finally, the third paper says that it isn't high glucose levels but defects in mitochondria and elevations in some fat derivatives and their processing in the defective mitochondria that cause inflammation. The senior author of the paper, Barbara Nikolajczyk, kindly sent me the full text, but the research is so complex I can't evaluate it and have to accept the summaries. There are 20 authors, and you can see the summary here.

In the past, there have been studies relating high blood glucose levels and inflammation, but as we all know, correlation is not causation, and it's not always clear if the high A1cs caused the inflammation or if inflammation caused the  high A1cs, or if a third factor caused them both. One study even suggested that low blood glucose levels, but not high blood glucose levels, caused inflammation in monocytes (a type of white blood cell). The Nikolajczyk study used peripheral blood mononuclear cells, which include monocytes and a few other cell types.

New hypotheses usually stimulate new research and often result in significant advances. Maybe I should  hypothesize e before i, don't ask me why, except for most words, that are known by all nerds and maybe I'd start a spelling revolution. At least no one would be hurt in such a revolution.

Friday, August 2, 2019

Does Paleo Diet Increase Risk for Heart Disease?

A recent flurry of articles in the popular press claim that following the Paleo diet causes an increase in your risk of  heart disease, primarily because of a molecule called TMAO (trimethylamine N-oxide).

Most people agree that the bacteria in your colon convert carnitine, found in red meat, to TMAO. How dangerous this is, however, is not as clear, and several  bloggers have detailed why they don't think we should lose sleep about TMAO, so I won't repeat their analyses.

Two things I think should be emphasized: (1) resistant starch increases TMAO and (2) some fish increase TMAO.

The author of the recent study emphasized the lack of whole grains in Paleo diets, saying, "We know that whole grains are a fantastic source of resistant starch." But wait! Resistant starch increases TMAO levels.

Another study even suggests that vegetables can increase TMAO levels and increased TMAO levels are helpful in heart failure.

I think we don't know enough about the relation between TMAO and heart disease to make any dietary changes according to what increases or decreases its levels. Fish and resistant starch are supposed to be healthy but they both can increase TMAO. Some people think red meat is unhealthy, but it can increase TMAO.

I think the publicity about the Paleo diet and TMAO is an example of some people thinking that any diet that doesn't follow the recommendations of the Dietary Guidelines for Americans is a fad diet and then looking for reasons to avoid it.

I remember one nutritionist criticizing low-carb diets because "They don't provide the 60% carbohydrate content recommended by the DGA." Um, isn't that what "low-carb" means? Sometimes I wonder where such people learned to think. . . if they ever did.

So I'd say one shouldn't lose sleep over TMAO. Eat what works for you to keep your blood glucose levels as close to normal as you can, keep an eye on your blood pressure and blood lipid levels, and don't panic over every flashy headline that appears in the popular press.

Tuesday, July 16, 2019

Diagnosing diabetes risk early

I've been following the saga of Michael Snyder, a geneticist at Stanford, for some time. Snyder participated in a genetic study in which his own DNA was analyzed, and in the process he discovered that he had a gene linked with increased risk of type 2 diabetes. Then a viral infection made his blood glucose (BG) levels soar high enough that he was told he had type 2 diabetes.

Snyder modified his diet and increased his exercise and slowly brought his BG levels back to normal ranges within 6 months. When I mentioned this in a blogpost, I wrote as if bringing his BG levels back to normal meant that he could escape chronic type 2 diabetes as long as he maintained his diet and exercise regimen.

I was wrong. A recent story in the New York Times states that although he was able to maintain normal BG levels for three years after the initial diagnosis, they eventually increased enough that he was again told he was diabetic. He said it seems he's slow to release insulin.

In fact, almost everyone with type 2 diabetes lacks the rapid phase 1 insulin release that knocks down BG levels quickly, but we still have the slower phase 2 insulin release. When I was in a clinical study at the Joslin Diabetes Center, I showed almost zero phase 1 insulin release. Interestingly, when I took high-dose aspirin (actually an aspirin-like drug used in the study), my phase 1 insulin response increased to almost 70% of normal.

The classic description of type 2 diabetes is that it's caused by insulin resistance, but more and more research is showing that different people get type 2 diabetes (perhaps better called non-autoimmune diabetes) for different reasons. For some, the insulin resistance may be the strongest factor, but for others, factors like poor insulin secretion may be more important. Not all people with type 2 are overweight and some overweight people are insulin sensitive.

“We learned that people are Type 2 diabetic in very different ways,” said Snyder in the New York Times article.

In one study, "nine of the cohort members developed diabetes during the study. But it appears their health followed different paths to reach that state. Two people gained weight before their diagnosis, but seven developed the condition without substantial weight gain. The subjects also showed differences in how much insulin they produced. Some made very little insulin, while others produced enough insulin, but not sufficient to lower their glucose levels and forestall diabetes."

So a treatment that is best for people with one subtype of type 2 may not be best for people with another. This is not big news, but it's always nice to see some scientific validation of what we've observed.

Snyder is still trying to control his BG levels without drugs, and he's still getting a lot of lab tests. Perhaps this intense scrutiny of the physiology of one type 2 diabetes patient will give hints about the process that will help us all.

And what Snyder's story means for you is that if your diabetes progresses even though you are doing all you can to control it, don't blame yourself. Your genes may be responsible

Sunday, June 30, 2019

On Illustrations

I don't know about other people, but I'm getting really, really, really tired of seeing popular press articles about type 2 diabetes illustrated with photos of people pricking their fingers to get blood.

I mean, I know that unless you use a continuous glucose monitor, pricking your fingers is part of having diabetes. But it's not the only part. In fact, it's a very minor part. Controlling your diet is much more important.

But the finger jabbing seems to be a cliche for type 2 diabetes.

Another cliche I hate is that of a man and a woman, usually about 40 or 50 and trim, running along a deserted  beach, intended to illustrate exercise.

I mean, I know running along a beach would be good exercise, but how many people live near a beach, especially a deserted beach like the ones always shown? And if they were just diagnosed with type 2 diabetes, how many would be slim and trim like the models? Maybe some, but not the majority.

Finally, the last cliche is the same attractive couple that was running along the beach preparing a salad in a perfectly appointed kitchen while grinning from ear to ear. "Diabetes is such fun! We can't wait to finish this delicious salad so we can go out to the beach again for some more running. If it's rainng, we can stay home and do some finger-pricking to prove we're really diabetic."

OK. I'm in a bad mood. I couldn't find a deserted beach and I ran out of salad fixings. Maybe tomorrow someone will come up with some more interesting popular-press illustrations.

Thursday, June 27, 2019

Pancreatic Islet "Leader" Cells

No one understands yet exactly what regulates the release of insulin from the beta cells in the pancreas. We just know that the process is disrupted when you have diabetes, almost completely in the case of type 1 diabetes and partially when you have type 2.

Now researchers in several countries, including Germany, Great Britain, Canada, and Italy, have discovered a new clue. It seems that certain beta cells are "leader" cells or "hub" cells, and they control the other beta cells. This is like the heart's sinoatrial node (called the "pacemaker of the heart"), which controls the beating of other heart cells. And some researchers refer to the leader cells in the pancreas as pacemakers.

The studies show that if you selectively delete the leader cells in animal models of diabetes, the response to glucose becomes disrupted. It is known that in type 2 diabetes, the normally regular pulses of insulin that occur even when fasting are lost. Could this be because the leader cells are damaged? If so, why are they damaged? Are they more sensitive to high glucose and other toxins than the other beta cells?

The researchers found that the coordination of responses controlled by the leader cells was impaired in human islets taken from subjects with diabetes.

This is all fascinating albeit early days. This new study doesn't have any practical utility yet, but it could lead to more research that would have practical application.

If the heart's pacemaker isn't working well, they can give you an artificial pacemaker. The beta cell pacemakers wouldn't be as easy to replace. But perhaps now that it's known that there are such pancreas pacemakers, someone will figure out how to rejuvenate them.

Monday, June 3, 2019

Helping Beta Cells

Two recent research reports concern helping beta cells produce more insulin. Interestingly, they both involve inhibiting something rather than trying to stimulate the beta cells, as the sulfonylurea drugs do.

People think of type 2 diabetes as being caused by insulin resistance and some wonder why you would want to produce more insulin if you have type 2. But in fact, type 2 is often caused by insulin deficiency. That is, you're producing insulin, often more than normal, but it's not enough to overcome your insulin resistance. So more insulin can help.

The first study involves deleting senescent, or old, beta cells from the pancreas. When the Joslin Diabetes Center researchers did this in mice, they found that the remaining beta cells were rejuvenated and started producing enough insulin to keep blood glucose (BG) levels in the normal range.

How did they do this? One approach was genetic modification, which is fine in mice but unlikely to be practical in humans. The other approach was with senolytic drugs, drugs that remove senescent cells. Although you can buy drugs claiming to be senolytics from companies that market supplements, this field is relatively new and large-scale controlled trials have not yet been done. Pilot studies show promise.

The authors of this paper think that diabetes is caused by stress: in type 2 the stress of insulin resistance and in type 1 the stress of an autoimmune attack. Of course this doesn't explain what causes insulin resistance or an autoimmune attack, and these are the underlying problems.

The second study involved removing two signaling molecules that dampen the insulin response. This is the opposite of most approaches, which try to stimulate the insulin response directly instead of inhibiting  inhibitors. The sulfonylureas stimulate insulin release, even when a person is not eating carbohydrate, which means your blood glucose can go low when you're not eating.

These studies were done in mice, and oddly, removing the inhibitors worked only when the mice were on a high-fat diet. The reason for this is not yet known.

The inhibitors are TLR2 and TLR4. TLR stands for toll-like receptor, and normally, TLR2 and TLR4 stimulate the immune system when they detect invadors. But they also work together to block beta cell proliferation, so when you remove them, the beta cells multiply like mad, so much that they can be seen with the naked eye.

There are in fact drugs that inhibit TLR2 and TLR4, but inhibiting them would not only stimulate beta cell growth, but it would inhibit the immune system and make a person susceptible to infection.

Nevertheless these new approaches are interesting and may result in methods to rejuvenate beta cells in people with both types of diabetes (most people with type 1 do have a few beta cells remaining despite the autoimmune attack). How wonderful that would be.