Wednesday, October 5, 2016

Quantum Leap in Diabetes Treatment

 I recently attended a talk on diabetes at Harvard, led by Doug Melton of the Harvard Stem Cell Institute. It was inspiring because they were talking about a cure, not just about some new drug or some new type of pump.

Melton has two children with type 1 diabetes, and after the talk, when I went up to thank him for his work, he said he's really driven to find a cure because of his kids.

The talk was titled A Quantum Leap in Diabetes Treatment, and Melton described how they can now take induced pluripotent stem cells (iPSCs) and transform them into beta cells. They use iPSCs instead of regular stem cells isolated from aborted embryos because President Bush restricted funding for stem cell research in 2001. One speaker said that move set back the research by about 10 years.

However, in the long run it turns out that using iPSCs instead of cells from aborted embryos has the advantage that you can use cells from your own body, which would be less likely to be destroyed by your immune system, although autoimunity can destroy your own tissues.

Melton said it's taken about 10 years to work out how to make beta cells from the iPSCs. First you have to tell the cells to differentiate into gut cells. Then into pancreatic cells. Then into hormone-producing pancreas cells. Then into beta cells. Each step in the process requires different chemicals, some small molecules and some proteins. Complex thought it is, they can now quickly make a lot of functioning beta cells in a test tube. Well, actually in flasks.

You can see the process here. Semma Therapeutics, which this links to, is named for Melton's two children Sam and Emma.

One thing emphasized at the talk was that this type of research requires cooperation among different specialists. Melton and his lab do the basic research, but they're not physicians and require the help of transplant surgeons like Sayeed Malek, of Harvard Medical School and Brigham & Women's Hospital. They also need engineers to scale up production of beta cells and pharmaceutical companies to produce large amounts of the substances used to transform the stem cells. They said that only in the Boston area can one find so many different specialists, so the cure is likely to be found there.

The first patients to get the new beta cells will be those who have had a pancreatectomy and who have very labile diabetes as a result, they said. This is because such people lack the autoimmune attack that is part of type 1 diabetes, so they can investigate one half of the puzzle without the other. This will be done next year, with only 10 patients.

The next step will involve patients who are already taking immune-suppression drugs, for example those who have had a kidney transplant.

Finally, patients with type 1 will get the cells, and eventually even those with type 2 whose beta cells can't produce enough insulin to overcome their insulin resistance. Clearly the cure will take time, but Melton said he's really optimistic about it.

Others who spoke and answered questions were Gordon Weir of the Joslin Diabetes Center, who was a teacher and mentor of Melton, Robert Millman of Semma Therapeutics, and Peter Amenta of the Joslin Diabetes Center.

Weir said this field is really accelerating. They're starting trials for spinal transplants and retinitis pigmentosa.

Someone said that cancer cells resist immune attack, and they're trying to find out how they do it, so this could be used with autoimmune diseases.

They're also trying to find a universal donor cell that would lack the triggers for autoimmune attack.

They said it will cost $1 million per patient to do the stem cell implants, so until they reduce the cost, they're probably not going to implant many patients.  However, they also noted that T1 is also very expensive, and will get even more so, and if you spent $1 million on a 6-year-old, you might recoup the cost through the kid's lifetime.

They noted that beta cells replicate very slowly, like brain cells. So each beta cell normally divides only 5 or 10 times in a lifetime, or 1/10,000 cells dividing per day. So just eliminating the autoimmune attack without beefing up the replication wouldn't help.
Again, I found it inspiring to hear people who know what they're talking about instead of the opinionated views one hears on the internet and the paranoid idea that big pharma will never contribute to a cure because producing the relevant drugs is so profitable. These people really want to find a cure.

I want that too.

Tuesday, August 16, 2016

Diet and Cholesterol

Most of us with type 2 diabetes also have problems with lipid levels, both cholesterol and triglycerides. So the following blogposts about diet and lipid levels, written by a nondiabetic/prediabetic software engineer, are relevant to us.

Because the author, Dave Feldman, is a software engineer,  his blog is a bit geeky (understatement of the year), and it will probably tell some of you more about diet and cholesterol than you wanted to know. But he's done an incredible number of N=1 experiments on himself, and the results are fascinating.

He's on a low-carb diet, and in a nutshell, he's shown that at least in his case:

1. Cholesterol levels change quickly, in about 3 days, not very slowly as most people will tell you.
2. Counterintuitively, the more fat he eats, the lower his total cholesterol levels go. Also lower triglycerides, LDL cholesterol, and LDL particle number, which some people think is a better marker of cardiovascular risk than LDL cholesterol. HDL levels increase.
3. It's his diet in the 3 days preceding the test that affect the cholesterol levels. Diet on other days doesn't seem to matter.

Note that some people argue that cholesterol levels don't matter. Whether they do or don't, it's interesting to see how quickly they change with the fat content of the diet, which suggests that unless you eat the same thing every day, the lipid values you get with standard testing don't mean a lot.

After testing himself rigorously, Feldman also tested his sister. He says he's a "hyper-responder" to a low-carb ketogenic diet, meaning that when he went low-carb, his cholesterol levels skyrocketed. Although most people see cholesterol levels fall when they go low-carb, Atkins Diet author Robert Atkins had noted that in about 25% of people, cholesterol levels do go up on such a diet.

Feldman's sister, also on a low-carb ketogenic diet, is not a hyper-responder, and he wanted to see if she'd react the same way he did, so they both ate the exact same food at the exact same time of day for a few days. It turned out that although her cholesterol levels were lower, they followed the same pattern: more fat in the three days preceding the test resulted in lower cholesterol levels.

If you want the details, you can find them here:

Part I
Part II
Part III
Part IV
Part V
with more undoubtedly to come.

Feldman says he's planning to write something for the nonengineer. 

In the meantime, this suggests that if you're concerned about cholesterol levels that have changed from your last test, it might be worthwhile to see what you were eating in the three days before each of the tests, to see if that could have been a factor.

Monday, August 1, 2016

Self-Monitoring of Blood Glucose

Several years ago, some British studies claimed that there was no benefit to self-monitoring of blood glucose (BG) levels (SMBG) in people with type 2 diabetes. I blogged about the studies here, pointing out that of course the testing they studied had no benefit because they didn't also teach the patients what to do with the resulting data.

Some more paranoid patients said the studies were probably funded by the National Health Service so they wouldn't have to pay for glucose testing strips.

One study mentioned in my blogpost did find a small, but statistical, benefit to self-monitoring, and recommended that patients be taught how to use the data they got.

Now, UK researchers have published a study showing that, in fact, self-monitoring improves control when patients are guided in how to respond. The free full text of the study is available here.

The researchers used telemonitoring to guide 160 patients with hemoglobin A1c levels greater than 7.5%. The patients submitted their BG readings to a website where a physician or a nurse analyzed the data and made recommendation on appropriate lifestyle changes. Another 160 were given usual care.

Even though the participants in the treatment arm of the study submitted morning and evening BG levels only twice a week (those on insulin tested more often), their average A1c after 9 months was 7.9% and the patients in the control group had an average A1c of 8.4%. Baseline A1cs were 8.8 and 8.9% in control and treatment groups, respectively. Often just being in a study causes patients to improve their control.

An A1c of 7.9% is still too high, but the difference of 0.51% between groups is approximately the same as the reductions found with drugs like metformin. Interesting that the patients in the control group reduced their A1c by 0.5 from baseline.

Going on a low-carb diet likely would have reduced the A1cs even more, but a little improvement is better than no improvement.

Blood pressure was also lower in the group that received the self-monitoring and advice, but there were no differences in weight between the two groups.

What this study shows is that if you give patients help with interpreting their BG readings, you can improve their A1c levels in a clinically significant way. It also showed that just being in a study makes people more careful about their way of living. If you think someone is watching you,  you're more careful, even if you're not communicating with them every week.

The online method used was certainly less expensive than weekly visits to a health care person, and as we keep saying, strips are cheaper than complications.

Saturday, June 11, 2016

Idiotic Headline

I recently came across a press release (the kind that all the science sites use) with the headline "Plant-based sweeteners may help individuals control their blood glucose levels."

 I thought that was odd, because table sugar comes from sugarcane or beets, and last I heard those were plants. So I went to the article. It said, "A new study shows that it is possible to reduce the level of sugar in muffins without affecting their textural properties by replacing half of the sugar content with stevianna or inulin, which are plant-based sweeteners."

Well, yes, stevianna and inulin are plant-based sweeteners. But so are sucrose and fructose. Even the evil high-fructose corn syrup is plant-based. The only non-plant-based natural sweetener I know of is lactose, or milk sugar.

I think the reason for this idiotic headline is that "plant-based" has become a buzzword for "healthy," like "fruitsnvegetables." Popular science journalists thrive on buzzwords, like "artery-clogging fats," just as Greek poets thrived on buzzwords like "rosy-fingered dawn."

The problem is that the average reader won't take the time to think about the articles they read. In fact, they may not even read them. They'll just see the headlines, or hear someone read them on TV and think, "Oh good. Plant-based sweeteners will cure my diabetes."

I suppose there's nothing much we can do about this. Journalists are always looking for snappy headlines that will entice people to read their articles. In this case, it worked with me.

Well, enough. Time to go make a cup of plant-based caffeine drink.

Saturday, May 28, 2016

Fire, Water, and Gold

I'm a little bit absent-minded. Well, OK, I'm very absent-minded. That means that sometimes when I plan to take something with me when I go to get groceries, I forget. I live in a rural area, where the closest supermarket is about 20 miles away, so it's a big time waster if I have to go back and get the library book I went to the library to return.

The worst was when I drove to Boston without my purse. That was scary. What would happen if I ran out of gas or had an accident? Luckily, the reason I forgot the purse was that I was delivering a box of lamb to a friend, and when you have one thing in your arms you tend to forget others. The friend paid for the lamb with cash. Phew.

But when you have diabetes, you have to remember more things than library books, and when you're traveling far from home, forgetting medications or testing supplies can cause big problems. These are more serious if you have type 1 diabetes or insulin-dependent type 2. If you're out of the country it can be difficult to get replacements.

I once went to Vancouver and was so focussed on packing insulin so it would stay cool and get through customs that I forgot all my oral drugs. Obviously, my control wasn't as good as usual, but unlike someone with type 1 who forgot insulin, I didn't end up in the ER with diabetic ketoacidosis. Still, it was not a good experience.

I mentioned my absent-mindedness to a friend who had been a pilot in the RAF, and  he suggested that I do what pilots do: run through a list of things to check before I leave the house. Good idea.

So I came up with Fire, Water, and Gold. Fire means to check the woodstove to make sure I haven't left the damper open. I also make sure I haven't left a pot on the stove. In the summer I substitue Ice for Fire, which means to put ice in a cooler I keep in the car in case I buy frozen food. Water means to make sure the water isn't running. My water collects up the hill and runs down by gravity, and if it runs too long, it drains the holding tank, which loses the siphon, and I have to pump it back up the hill to get the siphon going again. Gold is my purse.

With time I found I was sometimes forgetting to take my meds before leaving for something that took the whole day, so I changed to Fire, Water, and Gold Pills. Then I added "Plus 2" to remind me to disconnect two computers if there was any chance of a thunderstorm. Fire, Water, and Gold Pills Plus 2. At one point there was also a Plus New and Plus Blue but they weren't essential and now I can't even remember what they were.

This mantra is so simple that even I can remember it, and it's saved me many a time. My list obviously wouldn't work for everyone,  but if you're also a tad absent-minded and you have medications or testing supplies you really shouldn't be without when leaving home, for a trip or just for a daylong expedition,
you can come up with your own mantra. Besides, choosing something memorable is fun.

Friday, May 20, 2016

New Hormone Involved in Blood Glucose Control Discovered

New hormones are always being discovered, and the latest, called asprosin, is related to blood glucose control and insulin levels.

When blood glucose (BG) levels fall, for instance during the night, white adipose tissue (fat) releases asprosin, which increases BG levels. The increased BG levels then trigger the release of insulin, so BG levels don't get too high. That's how it's supposed to work.

But people with a rare disease called neonatal progeroid syndrome (NPS) that means they can't store fat can't produce asprosin because they have no fat. They can't use fat as an energy source between meals, because they don't have any, and hence they have to eat carbohydrates all day and even wake up during the night to eat to make sure their BG levels don't go too low. Without fat they don't have this trigger to keep BG levels up when they're not eating.

NPS patients can eat all the carbs they want without gaining weight, which might sound wonderful to anyone with a weight problem. It's not.  The woman in this article has never weighed more than 64 pounds, and cruel people make fun of her appearance. She says she has to eat constantly to keep her energy levels up.

Scientists discovered asprosin (which got its name from the Greek word for "white" because it's produced in white fat) by studying two people with NPS. Trying to find out what caused the disorder, the researchers did DNA sequencing of the NPS patients and discovered the new hormone.Then they figured out what it did.

Lipodystrophy (loss of fat tissue) is often associated with insulin resistance, so the researchers expected that the NPS patients would have elevated insulin levels. But they found that the NPS patients had two-fold lower insulin levels than normal. That's because they couldn't produce asprosin, which increases BG levels, which increases insulin levels.

Then they found that asprosin levels were doubled in obese insulin resistant men. Thus they wondered if blocking the action of asprosin could help control metabolic syndrome and type 2 diabetes. Indeed, in mice, an antibody against asprosin does reduce both glucose and insulin levels.

Of course we all know that what works in mice doesn't always work in humans. So only time will tell if this discovery has practical application. But it does sound promising. It also shows how complex the regulation of BG and insulin levels are, and different people with metabolic syndrome or type 2 diabetes may have defects in different systems. Thus it's not surprising that there's no one-size-all solution to these disorders.

Saturday, May 7, 2016

Maintaining Weight

Many of us gain weight as we age, but some people seem to stay at the same weight for most of their adult lives. How do they do it?

A pound of fat contains 3500 calories, and dietitians and are fond of telling us that if we eat an extra 3500 calories a year, we’ll gain 1 pound a year, so we’ll gain 10 pounds a decade and 50 pounds between high school and retirement age and that this partly explains the “obesity epidemic.” The idea is that just overeating by a tiny bit will result in significant weight gain in the long run.

But that 1 pound a year works out to about an extra 10 calories a day.

Now, we all know that the body/brain does miraculous things, but it’s never made any sense to me that our bodies, and especially our brains, would be able to control our food intake so closely that we would eat within 10 calories of what we needed. A stick of chewing gum contains about 10 calories.

So I was interested to read a recent article about male Barbary macaques. It seems that these monkeys regulate the amount of thyroid hormone they produce during mating season, when they need extra energy to fight with other males as well as mating with as many females as they can.

Some monkeys actually double their levels of thyroid hormone at the peak of the mating season. Extra thyroid hormone would speed up their metabolism, burning more food instead of storing it, which would provide more energy during this stressful season. Conversely, when food is scarce, they produce less thyroid, slowing their metabolism down. This is analogous to what some humans find when they eat a lot less in order to lose weight.

Of course, this might make one think that if you're overweight, all you have to do is take a little thyroid hormone and your weight will melt away. Unfortunately, that doesn't work unless you start out deficient in thyroid hormone, and too much can be dangerous.

However, it suggests to me that the body could compensate for a little overeating or a little undereating by simply increasing or decreasing the amount of active thyroid hormone in the bloodstream to keep our weight constant. Massive overeating or undereating would still have massive consequences for weight. But that extra stick of gum every day would not make us obese.