Tuesday, October 8, 2019

Changing Dietary Habits

I've had type 2 diabetes for 23 years now. When I was diagnosed, the only treatments available were sulfonylureas, metformin (which had only been approved here the year before), or insulin. And the cutoff for a diagnosis of diabetes was a fasting blood glucose (BG) level of 140 mg/dL.

Since then, myriad drugs have come on the market, including the glitazones, glutides, gliptins,  gliflozins, and meglitinides. A real tongue-twister.

Examples of these newer drugs are Actos (glitazone, or thiazolidinedione); Victoza (glutide; GLP-1 agonist); Januvia (gliptin; DPP-4 inhibitor), Invokana; (gliflozin; SGLT-2 inhibitor), and Starlix (meglitinide; long-acting sulfonylurea). Some of them are available as combinations with other diabetes drugs. Some are injectable and others are pills. Some last a week and others just a day or less.

You can find a more complete list here.

Some of these drugs can cause weight gain and others can contribute to weight loss. Some are supposed to protect the heart and some seem to increase rates of heart disease. Some increase rates of pancreatitis. Other side effects include nausea, urinary tract infections, ketoacidosis, and even lower-limb amputation.

Clearly, deciding which medications are best for you depends on many factors, and different physicians have different preferences. However, today most agree that metformin is the best drug to start with unless you can't tolerate it because of GI side effects.

But despite all the new drugs, one treatment remains the same as when I was diagnosed: diet and exercise. At first, this treatment is the most difficult of all.

We'd all like to be able to take a pill and continue eating what we've always eaten, including, in almost all cases, more food than our body needs. This is not entirely our fault. Portions at restaurants are often huge, and tempting treats are offered everywhere. We've usually been raised to clean our plates and not waste food. But if we want to be healthy, we need a major brain reshuffle to reject old ideas and acquire new ones.

What works for me is a low-carb diet, and I think that's the best one to start with. If for some reason, it doesn't work for you, then you can try to find another diet that works for you. But controlling our food intake, no matter how, is essential. Exercise is good for the heart but usually has less effect on blood glucose levels than diet does.

The most difficult thing facing you when diagnosed, I think, is accepting the fact that you're going to have to revamp your eating habits, usually in a major way. You have diabetes, and it's not going to go away. It can be controlled, but not cured, at least not today. It's difficult to accept this at first, but it's necessary if you want to live a long and healthy life.

That's bad news, but here's some good news. One study showed that people with diabetes who take metformin actually live longer, on average, than people who don't have diabetes. This doesn't mean you can take metformin and not change your dietary habits. But it is consistent with the saying that the best way to stay healthy is to develop a chronic disease that forces you to take care of yourself.

So instead of raging against our fate, we should be grateful that fate has given us a second chance. Let's use it to stay healthy for many more years to come.

Tuesday, October 1, 2019

The Glimins

There's a new class of diabetes medications on the horizen, not yet approved by the FDA. They're called glimins, and the one that has had the most research is imeglimin. Results of Phase 3 trials in Japan were reported at the European Association for the Study of Diabetes annual meeting in Barcelona in September.

Phase 1 trials test the safety of a new drug in a small number of healthy volunteers. Phase 2 trials test the efficacy of the drug in more people. Phase 3 trials test even more people in what are usually blinded studies (meaning neither the patient nor the physicians know which patients got the drug and which got a placebo). Once a drug has passed Phase 3, the company can apply for FDA approval.

One problem with the glimin class is that there's already a generic drug on the market called Glimin. It seems to be a sulfonylurea or a sulfonylurea plus metformin. It's marketed in Asia, and perhaps the term glimin is used there to mean diabetes drug as there seem to be different formulations. As far as I know, none of these products are available in the United States. But there could still be confusion.

The drug imeglimin is reported to work via the mitochondria to affect several systems important for glucose control: decrease the release of glucose by the liver, increase the uptake of glucose by muscle, increase insulin secretion, and decrease the destruction of beta cells by apoptosis (a way the body gets rid of cells it thinks it doesn't need). It may also mobilize fat in the liver.

The exact mechanism by which imeglimin works is not yet known, but metformin was used for years before it was known how it worked, and the mechanism is still not completely understood.

The reports of imeglimin sound wonderful, but there's very little information about the new drug available yet. And side effects of new medications often don't emerge until thousands of people have taken the drugs. So this information doesn't have much immediate practical use. There were reports on its benefits in 2012 and it's still not on the market. However, knowing a little about it means that if there are news stories about it, you can understand their relevance.

Friday, September 27, 2019

Drunk Without Drinking

NAFLD, or nonacoholic fatty liver disease, is common in people with type 2 diabetes, especially when blood glucose levels aren't controlled. More than 50% may develop it.

And of course a high intake of alcohol can produce fatty liver disease.

Now researchers have discovered that more than half of patients with NAFLD have gut bacteria that produce alcohol from the sugar the people eat. There's apparently a specific bacterial strain of  Klebsiella pneumoniae that produces more alcohol than usual, and this strain was found in 61% of people with NAFLD, but only 6% of controls.

Mice fed these strains of K. pneumoniae developed signs of liver damage. When these mice got an antibiotic that killed K. pneumoniae, their condition was reversed.

One man studied had severe liver damage and a condition with the name Autobrewery Syndrome. It's normally caused by alcohol-producing yeast, but this man  had no signs of yeast infection. When tested on an alcohol-free high-carbohydrate diet, he had a very high blood alcohol concentration of 400 mg/L, or .04%. Legal intoxication is usually .08%.

Now, most people wouldn't produce as much alcohol as this man did on a high-carbohydrate diet. But the production of a smaller amount over a long period of time could damage the liver of a person who never drank alcohol.

This is another reason to avoid high carbohydrate diets. The bacteria seem to produce alcohol only when fed a lot of carbohydrates that can be broken down into glucose.

You can read the full study here.

They point out that endogenous alcohol production by particular bacteria is not the only cause of NAFLD: "It would be worth emphasizing that it has become clearer that NAFLD is a very heterogeneous disease and the findings here likely represent just one type of etiology."

But it's a fascinating finding and makes one wonder how many other unanticipated products of gut microbes contribute to disease.

Wednesday, September 25, 2019


Here's a study confirming what most of us already know: YMMV, or Your Mileage May Vary. Some people prefer YDMV, or Your Diabetes May Vary.

Different people may have different reasons for getting diabetes. Some may have a lot of insulin resistance. Others may be pretty insulin sensitive but they just don't produce enough insulin. They do produce some, so unlike people with type 1, they can often get along without added insulin. And others may have a combination of these deficits.

In this study,  two groups were studied: Pima Indians from the Southwestern United States and Asian Indians from Chennai, India. They found that the Pima Indians tended to have a lot of insulin resistance (three times as much as the Asian Indians), but the Asian Indians, who were also older and thinner, tended to have defects in insulin secretion (three times less).

Unfortunately, when you're diagnosed, it's not common to have a lot of tests to find out exactly what is causing your diabetes. Most doctors tell you it doesn't matter, because they'd treat the disease the same way regardless of the cause. And a bunch of extra tests would be expensive.

However, if you come from an ethnic group that tends to have insulin resistance, that would probably be your major problem and you should focus on things like exercise and weight loss that can reduce insulin resistance. If you come from a group that tends to secrete too little insulin, it would make sense to focus on eating foods that don't require a lot of insulin, in other words, trying a low-carb diet.

Of course, many of us in the United States have a mixed heritage, so such studies would be less useful. Nevertheless, they might give hints about what kind of treatment to focus on.

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.