Wednesday, March 28, 2018

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.

Thursday, March 22, 2018

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.

Monday, March 19, 2018

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.

Friday, March 9, 2018

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%.

Tuesday, March 6, 2018

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 HbA1c 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 HbA1c 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.

Friday, March 2, 2018

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.

Tuesday, February 27, 2018

Why You Are Hungry After Losing Weight

Everyone knows it's difficult to lose weight; but it's possible. What's really difficult is keeping that weight off after you've lost it. Most people regain the weight they've lost, and then some.

Now researchers have a clue to why this is true.

A small Norwegian study of people with "severe obesity" (average 275  pounds, BMI 42.5 plus or minus 5) showed that everyone in their study was hungrier than they had been before the weight loss, which averaged 24 pounds.

The reason seemed to be that their hunger hormones were increased.

One hormone that was affected by the weight loss was ghrelin, which is produced by the stomach when it's empty and tells you it's time to eat again. After you've eaten, the levels of ghrelin decrease. One might expect that after a long time at a lower weight, the body would adapt and ghrelin levels would be reduced to normal. But this didn't happen, at least for two years.

What this means is that if you've lost weight, you can't expect things to go back to what they were like before you gained the weight. You'll always be hungrier than other people.

It's good to know this, because forewarned means forearmed. If you know ahead of time that increased hunger will be a problem, you will have time to figure out how to deal with it. If your health care people know that increased hunger will continue, they can try to help you figure out how to deal with it.

I think most overweight people think that if they could just lose weight, they'd be thin people, and they could eat like thin people. I certainly thought so when I was young and went on a diet because I weighed 105 pounds. Well, in college I had weighed 100.

I was going on a vacation in Puerto Rico and wanted to be able to eat whatever I wanted, so I lost those 5 pounds on a Weight Watchers diet, which in those days was a low-carb diet. Once in Puerto Rico, I cleaned my plate at restaurants and ate desserts and promptly regained all the weight I'd lost. Clearly I hadn't been transformed into a thin person who could eat everything in sight without gaining weight.

Again, being forewarned that your hunger will increase as you lose weight should help. If your health care people understand how difficult it is to maintain weight lost through dieting, they should be more empathetic about what you're going through and better able to help you to cope.

Many people, including me, find that low-carb diets reduce hunger, and the diet used for the weight loss was 50% carbohydrate. So this study provides no evidence about ghrelin levels if the dieters had restricted carbohydrates. Let's hope so. For me, at least, a lifetime without cookies would be better than a lifetime with hunger.

Friday, February 23, 2018

Can Viruses Produce Insulin?

Scientists at the Joslin Diabetes Center have found four viruses they say produce insulin-like proteins (viral insulin-like peptides, or VILPs)

The VILPs bound to human insulin receptors and stimulated all the signaling pathways that are stimulated by insulin.

The VILPs also bound to receptors for insulin-like growth factor 1, an insulin-like hormone that affects growth.

Mice injected with the peptides (peptides, like proteins, are chains of amino acids, but they're shorter) had lower blood glucose (BG) levels, indicating that the VILPs can have some of the actions of insulin.

So would these viruses affect BG levels under ordinary circumstances? It's known that they can infect fish and amphibians. And analyses showed that humans are exposed to these viruses in the intestine, possibly as a result of eating fish.

But do the viruses get into human cells? No one knows yet. The mice with lower BG levels were injected with the VILPs rather than getting the viruses from eating infected food.

Because this is such a new finding there's not yet much information about viral hormones that could affect humans, but because scientists think there are more than 300,000 viruses that can infect or be carried in mammals, there are certainly a lot of possibilities.

This finding has no practical application yet, but it opens up a whole new way of looking at hormones, and new approaches often lead to major breakthroughs.

Stay tuned.

Sunday, February 4, 2018

Do Our Bones Control Our Weight?

It is well known that sitting for a long time is unhealthy and contributes to, among other things, the risk of obesity. But no one has explained how this happens.

An obvious explanation is that if you're sitting, you're not exercising, but studies have shown that this is not the answer. Sitting and the amount of exercise are independently associated with risk.

Now a group of researchers has come up with a new idea. They propose that our bones, specifically the osteocytes in the long bones, can sense our weight, and when the weight goes up they signal to the brain that we should eat less. They call this a gravitostat.

The researchers show that this weight control is independent of leptin, the hormone produced by fat cells that tells us to eat less when we get fat enough. People who are overweight often have what is called leptin resistance, meaning the leptin system isn't working well.

The researchers used mice and rats to demonstrate their theory, loading the animals with weights and following their effect on body weight. They found that as they added weights in capsules, the animals' body weight (obviously less the weight of the capsules) decreased steadily. And this weight loss was not due to increased energy expenditure, but to decreased food intake.

In addition to the weight loss, insulin resistance decreased.

Not long ago, scientists thought that fat was an inert substance used only for storing energy. Now they know that fat cells are actually endocrine organs that secrete hormones, for example, leptin, that affect other organs.

Then they thought bones were inert structures that mainly functioned to support our weight. Now they're finding that the bones too seem to be endocrine organs.

What's next? Fingernails?

Whatever, the concept of a gravitostat has a possible practical application, unlike so much of today's diabetes and obesity research, which is one reason I don't report on much of it. Most patients can't use information about some new transcription factor or biochemical pathway to affect their diabetes control.

But if weighting mice with capsules made them lose weight, would weighting humans with increased loads help them lose weight? Would it make your diet work better if instead of just walking, you walked while carrying a 10-or 25-pound load in a knapsack? The rodents were loaded with 15% of their initial body weight.

For a long time I've felt that when people lose a lot of weight, one reason they stall is that they're no longer moving such a big load as before. They start with muscles capable of carrying a large load, but as they lose the weight, those muscles aren't working as hard. So I thought it would make sense to add weights to the body as the weight was lost to avoid losing muscle along with the fat.

In fact, I had grandiose plans to develop weight-carrying vests to which you could add weights as you lost. If you lost significant weight, you would be amazed to find how heavy the vests had become. I planned to get rich on my scheme. Unfortunately,  a little research discovered that such vests already exist, so I had to cancel my plans for a villa on the Riviera.

So using existing vests and weights, would they help humans, like the rodents, lose weight? Remember that rodent research doesn't always translate into human results.

But what's to lose other than a few bucks? Unlike experimental drugs, weights shouldn't have side effects, unless you dropped them on your toes.

Sunday, January 28, 2018

Another Misleading Headline, Sigh

Here we go again. A study is reported with a headline that implies something other than what the study shows.

The headline is "New research finds drinking 100 percent fruit juice does not affect blood sugar levels." Hogwash! Everyone with diabetes knows that drinking fruit juice of any kind makes blood glucose (G) levels go up, usually a lot.

It turns out what they meant was that drinking fruit juice doesn't make the next day's fasting levels increase a lot. My what a surprise! I have a glass of orange juice for breakfast and my BG levels skyrocket, but by the next morning they're down to where they usually are.

But that's not what the headline said.

Furthermore, saying that 100% fruit juice is innocent  implies that fruit drinks with added sugar are not. No, they didn't say that, but most people would think that.

The study did find that those who drank the fruit juice had higher insulin resistance. Did that go into the headline? Of course not.

Then there's the problem that this was a meta-analysis, in which researchers combine results from many studies in order to get statistically significant results, which depend on the size of studies. Such studies have many problems, including how they select the studies for the meta-analysis.

A similar study was sponsored by Juice Products Association, which suggests even less credibility.

But the worst sin is implying that fruit juice has no effect on BG levels, whether the studies were similar or not. We all know they do.

Friday, January 26, 2018

Misleading Headlines

A recent headline read, "Study links low carbohydrate intake to increased risk of birth defects."

Now, if you read that headline and didn't read the following story carefully, what would you think? You'd probably think that a lack of carbohydrate causes birth defects and hence low-carb diets should be avoided if you're planning to get pregnant.

But why would eating less carbohydrate cause birth defects? One explanation, and I think a good one, is that folic acid supplementation tends to prevent neural-tube birth defects, and for this reason the government mandated adding folic acid to enriched bread and other cereal products. Because people on LC diets don't eat much, if any, cereal products, they wouldn't be getting this protective folic acid.

Folic acid is also in liver and leafy greens like spinach, but some people may not like spinach and leafy greens, which is one reason bread and some cereals are supplemented.They assume everyone eats bread and cereal.

Many people don't read whole articles. They just read the headlines and assume they're accurate summations of the essence of the story. So why didn't the headline in this case say, "People on low-carb diets may need to supplement with folic acid if they could get pregnant." 

Another factor proposed to explain birth defects is any kind of dieting before conception or early in prenancy. One study showed that weight-loss dieting during the first trimester doubled the risk of neural-tube defects. This makes sense, as restricting calories could result in various deficiencies, including folic acid.

There's a lot of this type of spinning research studies. People have preconceived notions and analyze the research and write headlines from their point of view. Not long ago, the popular meme was low fat. That's now out and "more fruits and vegetables" is in. "Plant-based" is another popular meme.

I wonder what it will be 50 years from now?

BTW, a similar report came out in 2007. Why they're revisiting it is not clear.

Wednesday, January 17, 2018

The Most Important Thing

People sometimes ask me, "What's the most important thing to do if you're diagnosed with type 2 diabetes?'


Well, actually, I don't usually shout, but I sometimes want to. If you're reading this, then I think you're taking this disease seriously, trying to learn as much as you can about it so you can control it.

But too many people don't. They want the doctor to give them a pill so they can go on exactly as they have in the past, eating too much, especially foods that make their blood glucose (BG) go up, and getting no exercise.

One problem in type 2 control is that the results of not controlling well aren't immediate. You won't break out in blue spots if you a big piece of chocolate cake with ice cream. Your hair won't turn pink if you eat a huge pile of mashed potatoes and gravy with Texas toast on the side. Some people feel bad when they have high BG levels. Others don't.

I was diagnosed with fasting levels in the 300s, and I went into the 400s after meals. But I felt fine.

No, the effects of high BG levels are insidious. The glucose gloms on to various substances in your body and eventually causes complications. The damage from the glucose can result in cataracts, retinopathy that can lead to blindness, neuropathy that can make your feet hurt all the time, vascular problems that lead to heart attacks, amputations, and impotence, kidney disease, and more.

None of these complications are pleasant. But if you take this disease seriously and control your BG to normal or near-normal levels, the chances that you'll get complications are low.

It's not easy.Watching your friends pig out at an ice cream stand while you drink a cup of black coffee, no sugar, isn't fun. Different people have different ways of dealing with this. Some can eat just a couple of spoonfuls of some treat and leave the rest. Others find it works best to avoid the treats altogether. I'm in the latter group. If I ate a couple of spoonfuls of some treat, I'd crave it all. When I haven't eaten bread, cake, and ice cream for years, I no longer want them, even if all around me are eating them.

This situation of not wanting the treats isn't instantaneous. It takes a while before you can deal with these situations easily. But persistence pays off.

Well, I'd rant on and on, but right now I'm craving a lamb chop with broccoli and butter, so I'd better go.