Wednesday, November 30, 2016

Restoring Insulin Secretion

Can nonfunctioning beta cells be rejuvenated? Researchers from Florida State University think they can.

In a paper published in PLOS Computational Biology, the researchers, led by Richard Bertram, postulate that it's oscillating pulses of glucose that cause the oscillating pulses of insulin that are seen in healthy people. In nondiabetics, insulin isn't secreted continuously but in pulses, and it's been known for some time that this pulsatile insulin release is lost in people with type 2 diabetes. But no one knew why.

These researchers used sophisticated technology and mathematical modeling to come up with a new model, a Dual Oscillator Model (this type of model has been used in other research, for example, in understanding circadian rhythms here and here). They first put beta cells from mice in a high-glucose environment and found that they lost the pulsatile insulin secretion. Then by using their techniques to manipulate the glucose levels in ways suggested by the mathematical modeling, they were able to resuscitate the beta cells so that they produced insulin again in a healthy pulsatile way.

This technique is nowhere near the stage at which it could be used clinically to cure type 2 diabetes. But it's exciting because it suggests that a type 2 cure is possible, at least in those with viable beta cells. Those cells apparently aren't dead; they're just not functioning properly.

The authors' model is described in detail in their paper, the full text of which is free online. It's fairly dense and mathematical. They found that in response to glucose, some beta cells produce electrically driven fast oscillations in calcium levels, and other produce metabolically driven slow oscillations. They suggest that these two types of cells cooperate to produce pulsatile insulin secretion.

Clearly, creating conditions in vivo that would replicate the results found in their "microfluidic device" would not be simple. But the more we understand about how beta cells operate, the better. And their finding that continuously high glucose levels caused the beta cells to lose their oscillating insulin pulses is another indication that the standard Western lifestyle with too many calories as well as too many carbohydrate foods is not a good idea. Many close relatives of people with type 2 diabetes lack oscillating insulin pulses, suggesting a high risk of progressing to full-blown diabetes.

Maybe this new way of looking things will help us to find at-risk people in the very early stages, when their condition can be truly reversed.

Monday, November 28, 2016

Adolescent weight gain

An interesting study has shown that resting energy expenditure in adolescents is lower than in older or younger people. This means that they'll burn fewer calories when resting, leaving more available for growth and weight gain.

I found this fascinating because I was a normal-weight child but became "chubby" at about 11 or 12 and then lost weight with no change in lifestyle when I was about 16. Other family members showed the same pattern.

I'm always interested in why something happens, and in this case the authors hypothesize that because growth requires a lot of energy, the body tackles the problem of rapid growth in adolescence by making adolescents be more energy efficient, so they get more calories from the same amount of food.  In a society in which food was scarce, this would be the only way those rapidly growing bodies could get enough calories to build the new tissues they needed.

When growth is complete, the body stops being so efficient with its digestion as the extra calories are no longer needed, and the metabolism increases again. 

However, in our world, where food is usually easily available, turning down the metabolism during adolescence may lead to obesity that doesn't reverse when growth is complete.

This pattern of decreased metabolism only during adolescence is obviously not universal. Some people were chubby children and others don't slim down in their late teens when growth is complete.

However, it's an example of the fact that weight gain and loss are not always a result of voluntary food choices. Sometimes Mother Nature is nudging us in one direction or the other.

Wednesday, November 9, 2016

Trump and Diabetes

One of Donald Trump's goals as President is to repeal the Affordable Care Act, often referred to as "Obamacare."

I can understand why many are upset about the fact that it's expensive. Good health care is expensive, and Medicare isn't free either.

But one of the mandates in Obamacare is that insurers can't penalize people for having preexisting conditions. Before that, it was almost impossible for people without health insurance who had already been diagnosed with diabetes to get any health insurance at all.

If Obamacare is repealed, does this mean millions of people with diabetes will suddenly find themselves with no insurance and no possibility of getting replacement insurance?

It's a scary thought.

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.