Saturday, July 8, 2017

Of Mice and Humans

"New Research Describes the Differences Between Mice and Humans" screams a headline of an article in Eurekalert. 

Golly. I guess I'm ahead of my time because I've known the differences between mice and humans for decades. The mice are the furry ones with long tails, and the humans are the larger ones who fight and kill each other because they don't agree on politics or religion.

But once you get past the headline on Eurekalert, you find that researchers are finally accepting that mouse research often doesn't translate into human treatments. Mice have been cured of diabetes hundreds of time, but the drugs the researchers used just don't seem to work when they try them on humans. 

The problem is that it would be unethical to try new drugs on humans without some evidence that they might do something beneficial. Mice are relatively cheap to maintain, and we already know a lot about them. If we used only larger animals like pigs or dogs or monkeys, the cost of research would be even higher than it is now, and animal rights groups would protest. Very few people object to mistreating rodents.

Now researchers are beginning to find out why mouse research doesn't always translate into human cures. These researchers looked into a class of receptors found on beta cells in both mice and humans. They are called G-protein-coupled receptors (GPCRs), but the names don't matter.

What they found was that some of these receptors are found in both mice and humans, but others are not. Some are found only in mice, and others are found only in humans. If they know which ones are found in both mice and humans, future researchers can limit their research to those receptors. There's no point in spending millions of dollars on some drug that affects a receptor found only in mice! That money could instead be used to study drugs that affect both species.

Of course not all drugs target GPCRs. But a large number do. Let's hope these findings channel research into fruitful drugs, and not duds.

Thursday, July 6, 2017

Hunger

I know what ravenous hunger is.

More than 20  years before I was Dx'd with type 2 diabetes, I used to get reactive hypoglycemia, although I didn't realize that's what it was. At the time, I was working at a daily newspaper, and I occasionally did the wire desk, which mean I had to arrive at work at 7 a.m.

I normally didn't eat breakfast, and I wasn't especially hungry for lunch. But because I was a night owl and hated getting up early enough to get to work by 7, I'd reward myself with a chocolate doughnut, in addition to the strong black coffee I usually had.

Then, almost exactly 4 hours later, I'd get the shakes and a feeling that if I didn't eat something immediately, I was going to die. So I'd rush to the candy machine and get a candy bar, and that got rid of the shakes and the feelings of doom.

Now if I go low, which doesn't happen often but it does happen, I have that same feeling that if I don't eat I'm a goner. And because I want to get rid of that feeling that I'm doomed, I sometimes overtreat and then go high for hours.

Of course the official recommendation is to eat 15 grams of carbs, wait 15 minutes and retest, then eat a little more if you're still low. But one thing I really miss on my low-carb diet is fruit. When I was a kid I remember telling my mother, "What I really like is meat and fruit." So I keep canned sugarfree peaches in the cupboard to eat if I go low. They have about 6 grams of carbs in a cup, which is often just right when I'm not very low, and I wolf them down.

So I was wondering if this same 15/15 approach would work not just for lows but for weight loss.

I suspect that many people who have weight problems have something wrong with their appetite controls. When everyone else is feeling just hungry before a meal, they may feel ravenous. And when you're ravenous you tend to wolf down whatever you can reach. It takes about 20 minutes before your body lets you know you've had enough, and if you eat fast, by that time you've eaten a lot more than you need.

It's not enough to tell people to eat slowly. What exactly does that mean? Would it work better to measure out a small amount of food, eat it, and then wait 15 minutes? If you were still hungry, you could eat a second small amount of food. You'd keep doing this until you were no longer hungry.

Of course, if you have only 30 minutes for lunch, this would be difficult. Even with an hour it might be hard if it took four small portions and until you felt full. If so, you could increase the portions until you found an amount that filled you up with one or two servings.

So would this work? I really don't know. I'd try it myself but I no longer get ravenously hungry except when I'm very low, and that doesn't happen very often. I've always had a big appetite. One time a waiter at a Chinese restaurant remembered me two years later. He said they'd all been talking about me, "Because we'd never seen anyone so small eat so much." (This was in the days before they let you take extra food home and I hated to waste food, so I ate my whole meal, including the rice, and then finished what my brother couldn't eat.)

But as I get older my appetite seems to have abated, and "normal" portions now seem dauntingly large. So I no longer have that urge to stuff myself. I sometimes even stop eating when there's still food on my plate and heat it up and eat it at the next meal. So my weight has been steady for a long time.

It's nice to have a normal appetite after all these years, but I do understand what it's like to feel ravenous. I wish we could figure out how to fix that.

Sunday, June 11, 2017

Is Blood Glucose Testing Worthwhile?

Here we go again: Another study  claiming that self-monitoring of blood glucose levels (SMBG) doesn't help patients with type 2 diabetes. You can see the full text here.

Some previous studies have claimed the same thing, and some even claimed harm from SMBG, namely increased rates of depression or decreased "quality of life," although others claimed benefit.  Most informed patients agree that in order to be effective, patients must be trained in how to interpret the results and take action as a result. If you eat doughnuts and see a high number on your meter after a couple of hours, don't eat doughnuts. Just measuring without using the results to take some kind of action is, most agree, pretty useless and a waste of money.

The authors of the recent study agree: ". . . for SMBG to be an effective self-management tool in non–insulin-treated T2DM, the patient and physician must actively engage in performing, interpreting, and acting on the SMBG values."

In this study, patients were randomly assigned to one of three groups: no testing, testing, or testing with feedback. In the latter group, the feedback was computer-generated, not actual conversations with a human being. Here are examples of the feedback:

Sample Messages for Blood Glucose Values at Goal

• You are right on target. Remember to check your blood sugar tomorrow morning.”
• “Keep up the good work.”
• “Outstanding!”
• “Way to go. Keep checking every morning before breakfast!”
• “Your blood glucose goal is between 70-130 in the morning before you eat. You are doing marvelously.”

Sample Messages for Blood Glucose Values that are Mildly Elevated
 
• “Keeping track of the foods you are eating and the physical activity you are doing may help you pinpoint reasons why your blood sugars are running high.”
• “This number is a bit off target. Remember to check again tomorrow morning before eating.”
• “Your target in the morning before eating is 70-130.”
• “Staying on track with your diabetes can be tough at times. You can do this! Aim for a target fasting blood glucose value in the morning between 70-130.”

Sample Messages for Blood Glucose Values that are Very Elevated
 
• “Please discuss with your health care provider to talk about ways to get your blood sugars down to a more healthy range.”
• “Please consider making an appointment with your doctor. Your blood sugars have been too high lately. Your target before breakfast is 70-130.”
• “Time to check in with your primary care provider about these blood sugar numbers. They have been running too high.”

This is certainly better than nothing, but the messages are too general to be of much use and focus on fasting levels. I don't see anything like "Oops. Your numbers were high after this meal. See if you can figure out what it was in the meal that made your numbers go too high."

In fact, I couldn't find in the paper or even supplementary material anything about when patients were told to test, so I asked the corresponding author, Katrina Donahue. It turns out it was not simple. She said,

"The testing was based on once daily testing, but would vary depending on the patient’s blood sugar levels. First, they were instructed to test a.m. fasting blood sugars. When at goal, they were instructed to test a.m. fasting 3-4 times per week and pre bed 3-4 times per week. If still at goal, they were instructed to test a.m. fasting 1-2 times per week and 2 hour post prandial 5-6 times per week."

So only those patients who reached their fasting goals (7-130 mg/dL) were told to test after meals, and it's testing after meals that really tells you how different foods affect your blood sugar numbers, although your fasting levels may give a general idea of your overall control.


One interesting thing in this paper is the graphs showing hemoglobin A1c levels with time and the proportion of patients actually testing when assigned to the testing group. The A1c levels over 12 months are very similar to the results we usually see in diet studies. Initially the intervention is successful, but then, usually after about 6 months, the results slowly revert to baseline.

A similar pattern was seen with the proportion of patients told to test who were actually testing: High compliance at first dropping to about 60% by the end of the year.

I think these graphs show something important. People who are diagnosed with diabetes are at first really upset and are willing to follow some lifestyle change, be it eating less, eating fewer carbohydrates, exercising more, taking expensive drugs, or whatever. But then, with time, the enthusiasm for major changes begins to pall. Temptations seem greater.

The same is often seen with people who diet simply for weight loss. Each new diet promises that they'll look like movie stars, so they're very compliant at first, but then the cheesecake seems more important than fitting into smaller clothing and gradually they revert to former habits and then try some other diet that has the same unrealistic promises.

So the really important question is: How can we deal with this loss of enthusiasm for a new, healthier lifestyle? I don't think getting text messages from faceless health care people will have a tremendous impact long term, although as a non-texter maybe I'm wrong.

I think we need intensive education with real human beings and contact with other people who have diabetes. We don't need individual instruction; classes should work and also let people meet fellow patients they can keep in touch with. Of course, diabetes classes already exist, but too many people have complained that they were pretty useless and focussed on cutting out fat.

We need to study what kind of diabetes education works best. We need to teach people that it's not enough to "watch your diet." As patients, we have to accept that our diet must change in major ways, and that these changes are not short term but for the rest of our lives. I think accepting that is one of the most difficult aspects of having diabetes. Years ago, when I went on a diet to lose weight, I thought that when I reached my goal weight I could then eat like everyone else. Of course if one has a tendency to gain weight, one can't.

In order for dietary changes to  have a major impact, we must accept that we can no longer revert to eating the huge amounts of food usually served at restaurants, and we can no longer eat a lot of cake and cookies. Even "healthy" fruit makes my blood glucose go too high, although I do eat limited amounts of berries. Yes, it's inconvenient, but so is losing your feet or going blind.

We need to teach people that that for most (there are always exceptions) fingerpricks really don't hurt very much. I always laugh when I read popular press articles about some new treatment that they claim will eliminate "painful insulin injections." Insulin injections are even less painful than fingersticks because you inject into areas that aren't very sensitive. The popular press probably doesn't realize that neuropathy is a lot more painful than insulin injections or fingersticks.

The key is real education. Maybe not in the first weeks or so, when most patients are still in shock, but as soon as possible. With real education, we can live a long time with this disease, maybe even longer than we would have lived had we maintained our old habits.

So the health care system should figure out how to teach patients how to test productively rather than just testing. Productive testing is a lot cheaper than treating complications.

With time, the frequency of testing can decrease as we learn what we can eat and what we should avoid. I've had type 2 for more than 20 years, and I had a continuous glucose monitor for about a year (thanks to a generous friend), so I have a pretty good idea of what works and what doesn't and now do only spot checks to make sure my control hasn't deteriorated. Without all this information I might now have serious complications that would be expensive to treat.

Testing works when done correctly. Let's find out the best way to teach it.

Friday, June 9, 2017

Can Beta Cells Be Restored to Normal Function?

Is type 2 diabetes caused, in part, by beta cells that are dedifferentiated?

I say "in part" because type 2 is a complex disease and many things may contribute a little to its cause. Today more than 80 genes or parts of genes have been associated with type 2 risk. Each one may contribute only a little to that risk, but the additive effect of all those small effects can finally add up to a large effect that precipitates full-blown diabetes.

A recent article suggests that type 2 diabetes results in dedifferentiated beta cells that are like immature cells before they differentiate into their mature insulin-producing form. (You can see the full text of the article here.) Because they are immature, they don't produce insulin, and hence the number of insulin-producing beta cells in the pancreas is reduced and you have difficulty producing enough to keep blood glucose levels from rising, especially with a large carbohydrate load.

Most interesting, however, is that the researchers at the Sahlgrenska Academy in Sweden found that the product of a gene called SOX5 controls this process. When the researchers decreased the activity of SOX5, the cells become less mature and less insulin was produced. Conversely, increasing SOX5 increased the activity of 168 genes and the production of insulin was normalized.

The researchers say that eating "unhealthy foods" and exercising too little can decrease levels of SOX5. Of course different people have different ideas about what foods are healthy, but we probably all agree that a diet of potato chips and soda is not healthy.

The researchers also found that the drug valproic acid, which is used to treat epilepsy and bipolar disease, increases levels of SOX5. It is known that people given valproic acid sometimes develop hyperinsulinemia, but the drug has not been studied as a diabetes treatment. Like all drugs, valproic acid has side effects, sometimes serious, and only more study would determine if the benefits for type 2 diabetes exceed the risks .

This new discovery is not likely to lead to a cure for type 2 diabetes in the near future, but it's encouraging that the defective (dedifferentiated) beta cells can be restored to normal function and can produce normal amounts of insulin again. Wouldn't that be nice.





Friday, May 26, 2017

Genes and Health

One thing that we see a lot on the internet is the person who lost a ton of weight with some diet and saw their blood glucose levels revert to normal. Then they write about their diet and imply that it will work for everyone.

But it won't. We need to find the diet that works for us.

I remember long ago, when I thought I was fat because I weighed 110 pounds (I'm small, and in college I weighed between 100 and 105), so I went on the Weight Watchers diet, which at that time was low-carb. A Hungarian colleague who saw that I was dieting said to me, "I hate to tell you this, but you don't have to diet to lose weight." I asked what you had to do. "Just give up sour cream," she said. I told her I didn't eat sour cream. She was aghast, as she put sour cream on almost everything she ate.

But that's typical of the "It works for me, so it must work for you" attitude. But we can have different genes that affect how we react to different diets.

Here is an article about a population in a remote part of Greece who eat a very high animal fat diet but have low levels of triglycerides and LDL. Now, low-carb diets reduce triglyceride levels, but they don't usually reduce LDL and sometimes make it go up. And as this wasn't a diet study, they didn't describe the participants' diets, but most Greeks don't follow low-carb diets.

So people from this area of Greece could tell others that their diet (whatever it is) reduced LDL so it should work for everyone. But it's apparently their genes, not their diet, that is important. Anyone who wishes to read the full text of the article can see it here.

Another recent article, this one in the New York Times, describes a similar situation, but in an American woman: very low levels of LDL and triglycerides. Both the woman and some of her siblings were found to have a rare gene that caused a lack of plaque in their arteries. One sibling with the gene had been a heavy smoker and had high blood pressure and type 2 diabetes but still lacked plaque in his arteries.

Again, it was no particular lifestyle that resulted in low levels of some lipids. It was their genes.

So if some diet or some exercise program or some drug makes your blood glucose return to normal, of course that's wonderful. But before proselytizing on the internet, remember that our genes may affect how we respond to any regimen. By all means, let people know the wonderful results that you got. But don't expect the same regimen to work for everyone.


Nutrition Label Errors

Nutrition labels are good for knowing how much carbohydrate is in the processed food you eat, if you eat any. Unfortunately whole foods don't come with nutritional labels.

But I've always considered the labels as approximations rather than exact numbers. They'll tell you, for example, that there's more protein than fat or whatever in some food, but they won't really tell you the exact amounts.

There are several reasons for this. First, they round the numbers off. So 3.49 grams would be listed as 3 grams and 3.5 grams would be listed as 4.

Second, they don't have to include anything with less than 5 calories or 0.5 grams. And this pertains to the serving size. So if you ate 4 servings, you could have a lot more of something than you thought.

Third, the manufacturers don't analyze every package they sell. One estimate was $750 per analysis in 1997, a lot for a loaf of bread, although they can also us nutritional tables to estimate the totals.

Finally, the nutritional content of the ingredients used to make the product can change from batch to batch and the manufacturer can't control that.

So overall, the labels are useful but not exact.

I recently came across a label that was just plain wrong. It was a sausage product and listed the ingredients as pork, water, wheat rusk, and salt and spices. So pork was the first ingredient (manufacturers are required to list ingredients according to amounts) but the label said it had no protein, as well as no carbohydrate. Huh? Pork is mostly protein and fat and rusk is mostly carbohydrate.

I telephoned the company and asked if maybe they just used pork fat and was told yes. Then I went back to the label and saw that it said one link had 150 calories, of which 50 calories were from fat. So what were the other 100 calories from. The water?

I called the company back, and now they admitted that the label was wrong. The sausage contained 4 g of carbohydrate and 19 g of protein. That totaled 146 calories, or 150 rounded up.

But what if someone used the carbohydrate and protein content to calculate bolus insulin. The calculated insulin would be incorrect, and they'd go higher than expected.

So that's yet-another reason it's so difficult for people who inject bolus insulin to keep their blood glucose levels level. I wonder how many other labels contain similar errors.

What this means is if you see a label that seems odd, don't assume it's correct. First check the numbers. Multiply grams of carbohydrate and protein by 4 and grams of fat by 9 to get calories. If they don't add up, call the company to find out. In someone without diabetes, thinking you were eating a little less carbohydrate and protein would not cause much harm. But when you're injecting bolus insulin, it could.

And because of rounding off, always take labels with a grain of salt.

Furthermore, remember that you can't always believe what someone who answers the telephone tells you. They could know about the issue, or they might not. In a large company, it sometimes pays to call twice to see if two different people have the same response.

Good control requires constant vigilance, but it's worth it in the long run.




Friday, May 12, 2017

Honoring David Mendosa

Diabetes writer David Mendosa died on May 8, only about a month after he was diagnosed with angiosarcoma in the liver. The diabetes community is mourning, with tributes at all the major diabetes sites in the United States and Europe as well as personal blogs.

David didn't want any kind of services. I was thinking of a fitting memorial for him, and I thought of this. He told me that he hoped his legacy would be his promotion of low-carbohydrate diets. He had been following one since 2007, with excellent results.

So one way to honor David would be to follow a low-carb diet for a month, or a couple of weeks, or just a week, if you haven't already been doing so. If you're already on a low-carb diet, you could make sure you're strict with the diet for a period of time to honor David. Let's face it, most of us do fall off the wagon from time to time.

Then, if you find the low-carb diet works for you, if you have better blood glucose levels and you discover that a low-carb diet doesn't mean deprivation, tell your diabetic friends. Ask them to tell their friends. Wouldn't it be wonderful if we could see an explosion in the number of diabetic people following low-carb diets in honor of David Mendosa?

A couple of caveats: if  you go suddenly from a high-carb to a low-carb diet, a period of adaptation is needed as your body builds up the enzymes needed to metabolize fat, and some people lack energy for a week or two. It's called the low-carb flu. If that happens to you, don't despair. It's temporary. Also, low-carb diets act like diuretics, so make sure you eat enough salt to retain some water.

Of course not everyone may be able to honor David in this way. For those who would prefer some other kind of donation, Caring Bridge, on which David, and then his friends and relatives, posted about his final journey is accepting donations in his memory, as is Tru Hospice Care Center, the hospice where he spent his final days.