Friday, November 27, 2020

New Satiety Hormone Described

I've often felt that people who have always had problems with weight have something wrong with their appetite control, so after a meal that would make most people feel full, they're still hungry. And if food is available, it's difficult not to eat it when you're hungy.

I gave an example of this in my book The First Year: Type 2 Diabetes. Someone described a time when a coworker brought some pastries into work and offered them to everyone. A thin person said, "Oh my those look good. I wish I were hungry so I could eat one." The overweight man said he was flabbergasted. He was hungry all the time and just assumed everyone else was too.

Now a new satiety hormone that decreases appetite after eating has been described. The interesting thing about this hormone, called lipocalin-2, is that it seems to work in people who are obese but not in those who are normal weight.

In mice, giving lipocalin-2 long term reduces their food intake and prevents weight gain, without leading to the slowdown in metabolism that is often seen when people try to lose weight by eating less. Studies to see if the mouse results could be replicated in humans showed that normal weight subjects showed an increase in lipocalin-2 after eating, and this coincided with how satisfied they felt after eating.

But in people who were obese, lipocalin-2 levels did not increase after a meal and in fact decreased. It's not clear if they became obese because of a defect in producing lipocalin-2, if they had lipocalin resistance, or if they became obese for other reasons and the obesity caused the defect in lipocalin-2 production. But those who lost weight after gastric bypass surgery (and presumably those who lost weight in other ways) had their lipocalin-2 levels restored to the levels seen in normal weight people, suggesting that the obesity came first.

This sounds like a miracle hormone, but we don't yet know a lot about it. The authors say "the hormone can curb appetite with negligible toxicity," but like most hormones, it does have other effects. For example, it sequesters iron and increases inflammation. and it also plays a role in the central nervous system.

This is not the only hormone that affects appetite; the incretin GLP-1 does the same about the same amount. The GLP-1 agonists like  Byetta and Victoza act in part by reducing appetite.

Time will tell if lipocalin-2 drugs, not yet available, have more benefits than drawbacks. You can read a little more about lipocalin here

Sunday, November 1, 2020

EMFs and Diabetes

 "Remote control of blood sugar: Electromagnetic fields (EMFs) treat diabetes in animal models" When I saw that headline, I thought, "Oh wow! Remote control of blood sugar. My doctor could sit in her office and dial up a good blood sugar level and send it, and I'd be cured."

Unfortunately, that's not what the story is about.

Rather, exposing diabetic mice to a combination of static electric and magnetic fields for a few hours per day normalizes blood sugar and insulin resistance. The fields used were approximately 100 times that of the Earth, and the researchers said they reversed the diabetes within three days of treatment.

Note that the study was done in mice, and human studies often don't replicate rodent studies. However, the researchers also treated human liver cells with EMFs for six hours and showed that a surrogate marker for insulin sensitivity improved significantly. So the EMFs might also work in humans.

Here is a link to the full article, which notes that "attempts to investigate the potential effects of EMFs on glucose metabolism have yielded conflicting findings with some studies demonstrating that EMFs raise fasting blood glucose and others suggesting that EMFs have no effect." But the authors criticize the methods of the earlier studies.

One researcher, Magda Havas, thinks that EMFs from electrical wiring (dirty electricity) may may elevate blood glucose and contribute to "brittle" diabetes.

Clearly, we have a lot to learn about EMFs and diabetes, but the current study is certainly interesting. Stay tuned for more developments.

Thursday, October 29, 2020

Potatoes: Another Stupid Study

"People with type 2 diabetes need not avoid eating potatoes based on glycemic index" is the title of a recent Eurekalert news release about potatoes. Now, most people seeing that would think "I don't need to avoid potatoes" and wouldn't read the rest of the story.

Note that the study was funded by the Alliance for Potato Research and Education (APRE), and although they say APRE had no role in designing or carrying out the study, one tends to be biased toward any group that is sponsoring one's work. APRE "is a not-for-profit organization 100% dedicated to expanding and translating scientific research into evidence-based policy and education initiatives that recognize the role of all forms of the potato—a nutritious vegetable—in promoting health for all age groups." That certainly doesn't sound unbiased.

However, even more important that the funder for this study is what they actually showed. They showed that participants had a better 'nocturnal' glycemic response when they ate a mixed meal with skinless white potatoes compared to an isoenergetic and macronutrient-matched mixed meal that included a low glycemic index carbohydrate food -- basmati rice. 

Note that they didn't compare potatoes with a no-starch meal, say substituting broccoli or spinach for the potatoes. They just say potatoes aren't worse than basmati rice. But I suspect some people, even dieticians, will remember "People with type 2 diabetes need not avoid eating potatoes" and eat baked potatoes or even french fries when they would have much better control if they ate green vegetables instead. 

Participants ate about 50 grams of carbohydrate per meal, the same amount that is used to measure glycemic index.

 I agree with the authors that the glycemic index alone isn't enough to predict the glycemic impact of a mixed meal. And even with the exact same meal, different people will have different responses. Even one person may have a different response on a different day. We have to test ourselves, preferably with a continuous glucose monitor, to find out how various foods and mixed meals affect us.

However, no one with type 2 diabetes should be eating 50 grams of carbohydrate per meal. Unless money is really tight and we need to fill up on cheap starches, when potatoes would be better than cake and cookies, I think the potatoes should remain at the grocery store. And people who write research press releases should be clearer about exactly what their research shows.

The full text of the study can be found here.

Tuesday, October 20, 2020

Short and Long-Term Effects

While looking for something or other, I recently came across this article saying that arginine has no long-term effect on heart health. Arginine is one source of nitric oxide, which dilates blood vessels. Nitroglycerin, used by heart patients for angina, also produces nitric oxide.

 The cited article was published in 2007 and took me back. At the time, arginine was hot stuff among some people concerned with heart disease. Author and blogger David Mendosa wrote about it in 2006, and it was strongly recommended by his endocrinologist, Dr. Joe Prendergast. Sadly, both David and Dr. Joe have since died. Here is a more recent article. 

I won't discuss here the merits of arginine or the arginine-containing Heart Bars (discontinued) that Dr. Joe was so enthusiastic about. What is interesting is the fact that according to the first article, arginine does improve heart health in the short term, but just not in the long term. 

This is true for other treatments and supplements as well. One good example is caffeine. Caffeine binds to a receptor for adenosine and blocks the adenosine from binding. When you need sleep, your levels of adenosine are high, and binding to that receptor makes you sleepy. When caffeine blocks the adenosine you're less sleepy.

Sounds great if you need to stay awake past your usual bedtime, but there's one problem. When you ingest caffeine on a regular basis, your body compensates by making more adenosine receptors. So now you need even more caffeine, and more, just to stay awake during the day. You're addicted.

Thus when you try anything new, you should be aware of the possibility that the short-term benefits, or side effects, may be different from the long-term effects. Metformin is a good example of the difference in negative effects. Many people can't tolerate metformin if they start it at the full dose, because of gastrointestinal problems like diarrhea. But if they start it slowly, it's fine. The body, which is generally smarter than we are, has figured out how to adapt.

I have personal experience with metformin side effects. I'd taken it for about 20 years with no problem, when it occurred to me that instead of taking 500 mg extended release (ER) twice a day, it would be easier to take 1000 mg once a day. My endocrinologist prescribed the 1000 mg without mentioning that it wasn't ER; the 1000 mg doesn't come in ER. I didn't notice that the bottle didn't mention ER, and because the pills were so large, I just assumed that's what it was. Dumb mistake.

After a while I started getting diarrhea. As my water supply isn't perfect (a spring with some surface water), I wondered if it was Giardia. We did tests and more tests. No clues. Finally, it occurred to me that it could just be the metformin, and sure enough, when I stopped taking it, the diarrhea went away.

A dosage that worked when spread out over the day didn't work without side effects when given at one time. I then returned to the 500 mg twice a day, introduced slowly, and had no more problems. 

Sometimes, especially if you find that a drug or supplement that worked wonderfully when you started taking it seems to have lost its oomph, it might make sense to take a vacation from it for a short time. Obviously this wouldn't be a good idea for a life-saving drug like insulin or medication for high blood pressure. But it might work for less essential supplements.

We don't know a lot more than we do know about how the body works, so any treatment is a work in progress. Stay alert to the effects of the drugs and supplements (and food) that you do take. Let your doctor know if prescription drugs seem to be working differently than when they were first prescribed. Maybe, like arginine, the differences are not in your imagination.


Sunday, August 16, 2020

CGM for Newbies

When I was diagnosed with type 2 diabetes in 1996, I lusted for affordable access to more test strips so I could learn more about which foods made my blood glucose (BG) levels go up.

My insurance would pay for only 3 strips a day, so if I wanted to do a detailed study of something, with a graph, I had to not test at all for several days or a week and stockpile the strips. I suppose I shouldn't complain. Previous generations didn't have BG meters at all; they had to test urine, which showed only what their glucose levels had been several hours earlier.

But now there are so many ways one can see what one's BG levels are, including continuous glucose monitors (CGMs), which measure BG every 5 minutes or so and even show the results as graphs.
But these gizmos aren't cheap. Most insurance plans will cover the CGMs for people with type 1 diabetes, but not for type 2 until your beta cells have degenerated to the point that your C-peptide levels indicate that you're producing almost no insulin.

 But it's now being discussed whether CGMs should be supported for type 2s. Some people think it's not cost-effective. But I've always thought people with type 2 should be given CGMs soon after diagnosis, as most people have no real understanding of what types of food make BGs go up. In fact, many don't even know what a carbohydrate is. Perhaps right away wouldn't make sense, as getting a diagnosis of type 2 is usually a shock, the patient's head is spinning, and learning to deal with a CGM might just be a burden. At first it might be better just to follow whatever the doctor or nurse or dietician suggests.

But after a few weeks, the patient should be ready to learn more. For example, the patient might learn that the "healthy" breakfast of cereal and skim milk suggested by a dietician still supporting low-fat diets for people with diabetes made the BG soar. Then the patient could try various other foods to look for something that kept BG steadier and was also tasty and satisfying for that patient.

Because of the cost, the CGM might not need to be a permanent part of the patient's regimen. As the patient learned what worked, finger-stick tests could be used to confirm what the patient had already learned.

One program, United Health Group's Level2, is offering CGMs to patients enrolled in a United Health insurance. They say that "Level2 is provided at no additional cost to eligible members as part of their covered health insurance plan." The program also includes personal coaching and a Fitbit to track activity. But you have to have been diagosed in the previous 24 months to be eligible. There are also some other restrictions.

I would have killed (well, maybe not literally) for a program like that when I was diagnosed.

Other diabetes programs offer not CGMs but unlimited test strips along with coaching. Examples are Virta Health, which promotes low-carb diets, OneDrop, and Livongo. They all charge monthly fees, sometimes considerable, but employers or health insurance will sometimes pay those fees. Other sites like MySugr and Dario offer unlimited strips with or without coaching.

Today, on Medicare I don't qualify for a free CGM because I don't use mealtime insulin, and I no longer lust after unlimited strips. I test fasting BG just to make sure I'm not totally out of control, but otherwise I test only if I have a new food or some unusual exercise or get sick. But I occasionally buy a Libre CGM for $63 for two weeks as a spot check in case some food I thought was fine and so didn't think to test actually sends me way up, or if there's something I want to test.

The technology has certainly improved since I was diagnosed, and I'm pleased that newbies have a lot of support if they know where to get it. I hope they do get this support. Good control from the beginning reduces the probability of complications, and that reduces the overall cost of treatment. A CGM is a lot cheaper than new legs or a kidney transplant.

I wonder what's next.

Thursday, July 30, 2020

New Type of Diabetes Medication

 A new type of diabetes medication is being developed, and it sounds great. However, although it works in rodents, human cells, and dogs, there has not yet been a clinical trial of the drug, so it won't be available for some time.

The drug has the decidedly unmemorable name SRI-37330, and it works in part by decreasing glucose output from the liver. Glucose levels are controlled primarily by two hormones: insulin, which lowers blood glucose (BG) levels, and glucagon, which raises them. When you have type 2 diabetes, you not only don't produce enough insulin, but you produce too much glucagon. The glucagon stimulates the liver to produce glucose (gluconeogenesis) and release it into the bloodstream, even if your BG level isn't low.

SRI-37330 inhibits glucagon secretion and function, reduces glucose production in the liver, lowers serum triglyceride levels, and also reduces fatty liver. It does this by inhibiting a protein called TXNIP (thioredoxin-inhibiting protein), which has been shown to be elevated in people with diabetes and to have detrimental effects on islet function. The islets in the pancreas are where the beta cells produce insulin.

The drug has no effect on insulin secretion or function. It has no effect on glucose uptake by muscle or white adipose tissue. It has no effect on the secretion of glucose in urine.

SRI-37330 has no effect on glucagon secretion when BG levels are low, which reduces the chance that it could cause hypoglycemia. And it has no effect on body weight. But in obese, diabetic mice, it reduced BG levels significantly within 3 days, and they eventually returned to normal.

All these effects sound wonderful, and even if they don't turn out to be as dramatic in humans as in animals, it would be nice to have another drug with a different mechanism of action, as we're all different, and a drug that works wonderfully for one person might not be so great for another.

The lead author of this paper, Anath Salev, kindly sent me a copy of the full text. An interview with her can be seen here.

Saturday, July 18, 2020

Metformin and Energy

If you're trying to lose weight, there's a good chance that medical people will tell you that the important factor is that energy coming in is less than energy going out.

This is true.

But most people equate "energy out" with exercise. If you want to lose weight, they suggest that you exercise more. One problem with this advice is that for a lot of people, exercising just increases their appetite and makes them eat more, and so "energy in" goes up along with "energy out" and there's no loss of weight.

But exercise isn't the only part of "energy out." Any physiological process that wastes energy and converts it to heat will mean less energy is available to create fat. One example of this is the so-called biochemical futile cycles in which a chemical reaction converts A to B but then the body just converts B back to A. Because no reaction in the body is 100% efficient, each time the cycle occurs, a little bit of energy is lost as heat.

There are substances called uncoupling agents that increase the wasting of energy, and they were used by patients some years ago. The only problem is that one side effect of these compounds is death, so they weren't very popular.

Another part of "energy out" is any food lost in feces.  For example, if you eat a food that is poorly digested, much of the energy in the food is lost. An example of this is fiber. There's energy in fiber, and some microorganisms can digest it and convert it to useful substances. Humans can't. But sometimes bacteria in the lower bowel digest the fiber and produce substances like butyrate that we can digest.

So just measuring what you eat isn't enough. You need to know how much of what you eat is digested. In animal nutrition this is known as TDN, or total digestible nutrients.

Recently, research has shown that the diabetes drug metformin can increase the amount of sugar that is secreted in feces. This would both lower blood glucose levels and mean fewer calories were metabolized so they couldn't contribute to weight. (In animal nutrition, the goal is usually to get the animal to put on weight as quickly as possible, but the principles are the same.)

When I was diagnosed with type 2 in 1996, no one knew how metformin worked, but I was told it was better than the sulfonylureas (they didn't say why), which were the only other oral drugs available at the time, so I chose it and have been taking it ever since.

Eventually they discovered that metformin causes an increase in a molecule called AMPK, which is an energy sensor, and the recently discovered increased glucose excretion is a second mechanism. I suspect there are others that haven't yet been discovered.

The increased secretion of glucose into stool is analogous to the increased secretion of glucose into urine caused by the drugs called SGLT-2 inhibitors, for example, Invokana and Jardiance. In both cases, you're wasting calories by excreting them rather than converting them to heat.

There's still a lot we don't know about how metformin works, but we do know that it helps a lot of people with type 2 diabetes, and it's relatively inexpensive. On some drug plans, it's free.

Recently, the slow-release form of metformin was shown to contain a substance that increases rates of cancer. So far, only some brands have found this contaminant, but it's possible more will be added to the list when they are tested. If you want to see if your metformin is on the list, you can check here. This list was compiled on July 15, and there might be others added later.