Glucose Outside and Inside Cells

When we speak of glucose levels, we're usually referring to the levels of glucose in the blood, or blood glucose (BG). And this level is important, because the glucose in the blood travels throughout the body to provide nourishment for our cells. It can also react chemically with tissues that are exposed to blood, for instance the endothelial cells that line the blood vessels, and damage them, especially when BG levels are high.

However, BG isn't the whole story. The level of glucose inside cells is also important. Outside of research studies, we don't measure this. But because too much glucose within the cells could cause damage, many types of cells won't take up glucose unless they have insulin to facilitate its transport across the cell membrane.

This is where insulin resistance comes in. Insulin resistance can be protective, keeping too much glucose from getting in some cells when it's not needed. In 2015, I blogged about the benefits of insulin resistance in the heart.

Insulin resistance can also function as a way to get glucose to tissues that need it. For example, when you have an infection or trauma, or when you're starving, or when you're in late pregnancy, your muscles become insulin resistant. This means the muscles won't grab all the glucose, thus making more glucose available for the cells that really need it, such as the site of infection or trauma, or the brain when you're starving. In late pregnancy, it ensures that the mother doesn't grab all the glucose and leave the developing baby with too little.

In other words, insulin resistance is a mechanism to select which tissues get glucose. If you're starving, you want to make sure the brain has enough glucose, because even though the brain can function on mostly ketones, derived from the breakdown of fat, it still needs a little bit of glucose. No point in wasting it on muscles.

However, if you're starving you still want to be able to hunt and gather, so the body overrides the insulin resistance in working muscle so  you can run after that impala and get a decent meal.

When it comes to obesity, the basic dogma goes like this: For some reason, maybe genetic, you have more insulin resistance than normal. The insulin resistance means you have to produce more insulin than normal. And the high insulin levels make you gain weight. The increased weight makes you even more insulin resistant. So you have a vicious cycle going.

This means that in terms of obesity, insulin resistance is bad and you should do whatever you can to reduce it.

But there's some evidence that maybe we have it backward. Maybe it's insulin sensitivity that makes you gain weight and the ensuing insulin resistance is the body's effort to control this weight gain.

Grizzly bears are very insulin sensitive in the late summer and fall when they're packing on the pounds. Then when they're snoozing in their dens, they become insulin resistant and lose weight by burning their stored fat.

There's some indication that a similar effect, minus the winterlong snoozing, can occur in humans. One study in 1991 showed that among the Pima Indians, known for their high diabetes rates in modern times, the ones with the most insulin resistance put on the least weight (other studies showed exceptions to this concept in some ethnic groups).

This all makes sense. If you're insulin sensitive, your cells will take up more glucose, and with more glucose in the cells, the body can make and store more fat. You might have less insulin in the blood, but that insulin will be effective in keeping the stored fat in place.

So what do we really need for health?

What we really need is for our cells to not only take up glucose from the blood, reducing BG, but to burn that glucose in the cells, so the internal glucose levels don't get too high. We can burn all the glucose that gets taken up by not eating more than necessary, and by working our muscles to burn a little extra. Exercise is good but less effective than diet when it comes to controlling weight.

This sounds a lot like "diet and exercise," and for eons that has been the standard treatment for type 2 diabetes. Of course, we'd all like a pill that would allow us to overeat as most Americans do while simultaneously making us slim and muscular. But so far, no such pills have emerged.

So all this blather about insulin resistance has no practical application. But it should give you a new perspective on the issue of insulin resistance.

Could Salt Cause Obesity?

Could a high-salt diet lead to obesity?

Intuitively it makes sense. Most populations still eating traditional diets do eat salt, but often not as much as is found in Western diets, and such populations have low rates of diabetes. When they move from rural to urban environments and are exposed to salty Western food, they tend to gain weight.

(I did once read about an isolated group somewhere in South America, maybe the Yanomami, that didn't use salt; instead they burned a plant to get a calcium compound and used the ashes to flavor their food. When the anthropologists offered them some salty food, they said yuch and threw it away. But by the next day they'd changed their mind and were soon begging for more. I can't find the article I read, and perhaps the writer was exaggerating, but it does suggest that salt is addictive.)

If you don't think salt is addictive, try to eat just one potato chip.

It's been found that salt increases appetite, and now there's some scientific evidence that salt could lead to obesity through increasing leptin resistance. Leptin turns down your appetite when your fat stores are sufficient for your needs, and if you have leptin resistance, you have a big appetite even though your body is already storing plenty of fat.

For those interested in the mechanism, it seems that salt increases to aldose reductase pathway in the liver and hypothalamus. (The aldose reductase pathway is also involved in some diabetes complications.)

This pathway results in the production of fructose, which then causes insulin resistance. And blocking fructose metabolism blocks the effects of a high-salt diet.

In humans, a high-salt diet causes insulin resistance after only 5 days, and this study showed that in Japan, salt and calorie intake were correlated. In mice, a high-salt diet makes the mice eat more than usual. In the Japanese study in humans, the researchers showed that salt intake can be shown to be correlated with BMI, and high salt intake predicted diabetes and nonalcoholic fatty liver disease.

Could it be that too much salt, rather than too much fat or too much carbohydrate, is the real reason for the rise in obesity in America? Most Americans eat a lot of their meals away from home. And restaurant food and street food tend to be salty as well as sweet and fatty. If the salt makes you eat more, then you get more sugar and fat and calories, and you put on weight.

We all know that correlation does not mean causation, but when there's some proof of a mechanism, it becomes more likely.

Wouldn't it be ironic if it turns out that it's salt that is driving the increase in obesity? Of course you need calories to gain weight, but if the salt makes you eat more calories, then we can blame the salt.

And the fix is obvious.

Does Amyloid Clog Beta Cells?

When the beta cells produce insulin, they also produce a protein called IAPP. This stands for islet amyloid polypeptide, and the IAPP is secreted along with the insulin. IAPP is also known as amylin.

Amyloids are proteins that tend to clump when present in excess, and various amyloids contribute to diseases such as Parkinson's (alpha-synuclein clumps) and Alzheimer's (beta-amyloid clumps). The IAPP also clumps, and this causes the beta cells to decline and eventually die, resulting in diabetes.

Now researchers have found where the clumping occurs. It seems be in the tubes that let newly synthesized proteins leave the site of their synthesis (the endoplasmic reticulum) and emerge into the cytoplasm. When these tubes are clogged, insulin can't be released and the whole system gets gummed up.

One interesting thing is that the clumping of amyloids occurs more often when the proteins are present in excess. This means that if you're producing a lot of insulin, you're also producing a lot of IAPP, and the probability of amyloid clumping increases.

"What happens is that as demand for insulin increases, you get more and more IAPP production, and the more you make, the more likely it is to aggregate,” says the lead author of the cited paper Can Kayatekin. “So, the idea is that as you make more IAPP, it starts poisoning the very cells that are producing it.”

Now, what makes you produce a lot of insulin? Eating a lot of carbohydrate, of course. So this could be one way in which high-carbohydrate diets can increase the risk of diabetes.

However, ascertaining where the clogging occurs wasn't the only thing these researchers found. They also found an unclogger called STE24 in yeast and ZMPSTE24 in humans that snips off the clogging IAPP and opens up the channel again. This article has a nice illustration of the declogger.

This research like so much, alas, has no immediate application except to confirm the idea that a very high carbohydrate diet is probably not good for anyone. Sometimes it's the basic research that eventually leads to real advances in treatment, and further research could lead to methods of getting  unclogging enzymes to beta cells so insulin production could go on as it should.

Right Before Our Eyes?

I sometimes don't see something that is right in front of me.

For instance, this morning I was looking for some zhoug, a spicy Yemenite sauce that I like on top of cheese. I usually keep sauces in the back of the fridge, so that's where I looked. It wasn't there. Had I taken it out already? Nope. Had thieves broken into the house to steal my zhoug? Not likely.

I finally found it in the front of the fridge, right before my eyes.

Another time I spent hours looking for a book. I knew what part of the bookcase it should be in and looked and looked and couldn't find it. Did the thieves I thought took my zhoug also take Richard Feinman's book? Not likely.

I finally found it right where I'd been looking. I'd remembered that it had a white cover, but in fact it had a blue cover.

Well, what does all this have to do with diabetes? It made me wonder how many other things we think are missing are right before our eyes. Could we be looking in all the wrong places for the cause of type 2 diabetes? Is the real cause staring us in the face but we don't see it because we're expecting something else?

For decades we've been told that type 2 is caused by obesity, so the focus is there. But what if the real cause is something else, something that causes both obesity and diabetes (so they are related) but we're not seeing it because we're so focussed on weight?

I'm not sure how this concept will help the average patient; I just hope that some creative soul deciphers the puzzle so we can end this scourge before the prevalence is 100%.

Idiotic Guidelines

A group called the American College of Physicians (ACP) has released new guidelines for the treatment of type 2 diabetes in nonpregnant adults. These guidelines are insane.

They want patients with hemoglobin A1c levels under 6.5% to reduce their treatments so their A1c levels rise to 7% to 8% (8% is an average blood glucose [BG] level of about 183). This is despite the fact that numerous studies have shown that mortality rates are increased with higher BG levels, even in people who are not considered diabetic.

Here is a good illustration of this. Scroll down to the graphs.

Why are they recommending this idiotic approach? Jack Ende, president of the ACP, told Medscape, "For most people with type 2 diabetes, achieving an HbA_1c between 7% and 8% will best balance long-term benefits with harms such as low blood sugar, medication burden, and costs.”

Well, I don't know about Dr. Ende, but me, I'd rather incur higher costs and have a medication burden than expire or have my legs cut off.

As for the possible low blood sugar, seriously low BG levels aren't common among people with type 2 diabetes, but physicians worry about them. According to Dr. Richard Bernstein, he has been told something like this by many physicians. "I like to keep the BG levels a little high, because if my patient dies from hypoglycemia, I can be sued. But if the patient goes blind or has legs amputated because of high BG levels, people will say, 'Well, that's what happens when you have diabetes."

In other words, some doctors care more about themselves than they do about their patients.

The authors of this paper write, "Metformin is not associated with hypoglycemia and is generally well-tolerated and low cost, but it is associated with other known adverse effects and results in use of additional medication with little to no benefit at HbA_1c levels below 7%." They don't specify what the adverse effects are, but common ones are gastrointestinal like nausea and diarrhea. I'd rather have a little diarrhea than drop dead from heart disease.

What is the ACP anyway? It turns out it's an organization if internists, not endocrinologists. And two other organizations, the American Diabetes Association and the American Association of Clinical Endocrinologists, disagree with the ACP. Medscape has outlined the controversy, but you may have to register with Medscape to read it.

Most organizations recommend individualizing A1c goals according to the patient's characteristics. Both groups support less stringent goals in people with limited life expectancy or who are incapacitated and unable to manage medications well and hence apt to make mistakes and have serious hypoglycemia. But to recommend such goals to everyone is idiotic.

And of course the authors don't suggest that for most people, a low-carb diet can have as much effect on A1c as multiple medications without the risks of the medications. 

What I find scary about this article is that it can be used for CME (continuing medical education) credit, which implies it's generally accepted knowledge. Let's hope that more groups with experience treating patients with type 2 diabetes will protest against the ACPs guidelines.

Early Diagnosis of Diabetes Risk

Last summer, I blogged about a proposal to make the 1-hour instead of the 2-hour postprandial blood glucose (BG) level the standard measurement to diagnose impaired glucose tolerance. Now a second researcher has made a similar proposal.

The first author, Michael Bergman, kindly sent me the full text of the article, which has 12 authors from 6 countries: USA, Belgium, Denmark, Sweden, Portugal, and Israel. With such widespread support, it may be that other researchers and clinicians will begin to see the wisdom of this approach.

These researchers say that after a 75-gram oral glucose tolerance test, a 1-hour value of 155 or greater identifies people with reduced beta cell function, and such values are a stronger predictor of type 2 diabetes than the standard 2-hour result. They found this to be true in East Indian, Japanese, Israeli, and Nordic populations, suggesting, but not proving, that it's universal.

There's more and more evidence that complications such as neuropathy and vascular disease can occur at BG levels that aren't currently considered diabetic. And this article documents studies showing beta cell deterioration at similar levels.

So the earlier a patient realizes there's a problem, the earlier something can be done about it.

One problem is how much patients would cooperate with treating a condition that is mostly predictive. Increasing the risk of something doesn't guarantee that the event will occur, and patients tend to think it won't happen to them, like the smokers who keep smoking despite excellent evidence that smoking causes lung cancer.

Not too long ago, well, OK, about 20 years ago, but it seems like yesterday, the cutoff for diagnosing type 2 diabetes was a fasting level of 140 mg/dL, higher than the 126 mg/dL used today. But some physicians argued against diagnosing patients even at that level because they said once labeled as diabetic, the patients would face discrimination, especially from the insurance agencies. That's no longer permitted, at least in theory, but some discrimination probably still exists. Given a choice between a healthy applicant and a diabetic applicant with the same qualifications, one can guess which one would be hired.

The other problem would be how long patients diagnosed with pre-prediabetes would keep to healthier lifestyles or would want to take drugs like metformin that might help keep their BG levels down. Even patients with overt diabetes have difficulty sticking to their diets.

Despite these challenges, however, I think it would be useful for patients to know that they were at risk so at least some of them could take measures to stave off diabetes, or even prediabetes. There was recently a fascinating story about a genetics researcher, Michael Snyder, who, when his own DNA was sequenced, discovered he was headed for type 2 diabetes. With this proof, he subsequently altered his diet and exercise routine substantially and his numbers returned to normal.

Snyder is an example that shows that early diagnosis can result in preventing chronic diabetes. So even if the average patient wouldn't take pre-prediabetes seriously, some would, and that means it makes sense to change screening standards to the 1-hour measurement.