Thursday, December 22, 2016

On Science Research

Some people wonder why we haven't come up with a cure for type 2 diabetes yet. The paranoid among us often suggest that Big Pharma knows of a cure but is keeping it secret because type 2 diabetes is so profitable for them.

I acknowledge the flaws of Big Pharma, including huge salaries for those at the top and huge increases in the prices of life-saving drugs so that many people can't afford them. But I don't think there's a big conspiracy hiding a cure.

The fact is that the biochemistry underlying type 2 diabetes is complex, and adding to the complexity is individual variation.

For example, look at this figure printed in Nature. It's from a paper on mechanisms controlling insulin secretion. The figure shows the various pathways leading to or modifying to rate of insulin secretion. Each step had to be discovered through experimentation, often complex with the potential to give false results if something wasn't done correctly, or if some assumption proved later not to be true. If one group produced results that weren't accurate, those following up on that work would be basing their analyses on false results from the first group, so their analysis might be wrong too.

The New Yorker recently ran an interesting story about some stem cell research that was later questioned, and withdrawn, resulting in the suicide of the leader of the lab in which the research was done. He may have been innocent but couldn't deal with the stress of being associated with questionable research. The article illustrates how full of pitfalls this complex research can be.

Now look at the figure again and imagine different patients with defects in different parts of the scheme.

Seems almost impossible to understand in full, doesn't it.

But nothing is impossible. Eventually we'll sort it all out. We'll do genetic studies on all patients to find out where their metabolism is faulty and hence what sort of treatment would be the best. This won't happen next week. Maybe not in this century. But it will happen if we don't wipe out life on Earth before we get a chance to cure type 2.

In the meantime, our best approach is not to accept a one-size-fits-all approach to controlling diabetes but to find what works for us, including careful attention to diet, experimenting to find out which diet works best for each of us so our need for drugs is minimal. Then we need to work with our doctors to figure out which drug is best for us. Being active also helps. I think low-carb diets are best for most people and should be where they start on diagnosis. But some patients may have better success with other approaches. The important thing is to find out what works for you. You might have a defect that is slightly different from another person's and so you might need treatment that is slightly different.

For example, a recent study showed that some patients with glioblastoma (a brain tumor) benefit from a treatment that was shown in clinical trials not to work. That's because results of clinical trials are reported as averages. Some treatment may harm some patients, help some patients, and have no effect on some patients. If the harm canceled out the benefit, then the researchers would say the treatment was ineffective. But if you were in the small group that was helped, it would be worthwhile for  you.

 Until we know everything, which is unlikely ever to happen, I think we should support, at least emotionally, the efforts of the scientists who are trying to puzzle this all out. It's true that many are more concerned with their own careers than they are with helping patients, but the world isn't perfect. And I don't think it helps to rant that all doctors are money-grubbing opportunists, all drug companies are hiding cures so they can sell us expensive drugs, and all researchers are just trying to justify their next big research grant so they can fly to conferences at scenic beach resorts.

These accusations do apply to some people.  And I think we sometimes do need to rant, especially when we've just been diagnosed and have been given bad advice, or no advice at all, by the medical people we trusted to take care of our health. Or if we're shamed by medical people who think excess weight is our fault and is easy to lose. The internet gives us a chance to share our rants with other people who can understand where we're coming from.

But the internet also gives us a chance to share our successes and the results of any N = 1 experiments we've done. For example, an engineer has done some fascinating experiments correlating his fat intake with his lipid results from standard tests. The results are not what you'd expect, and maybe they'll lead to research in formal clinical studies with lots of people. Once we've gone beyond the ranting stage, the internet gives us a chance to contribute to the knowledge base that will eventually help others control this disease.

In the meantime, we need to understand that biochemical and biomedical research is complex and open to error, but headline writers want simplistic conclusions, like "Eating Food X Prevents Diabetes," when in fact some study showed that eating Food X was associated with a tiny reduction in diabetes rates in a specific population.

So hang in there. Keep testing. Keep an open mind. Be sceptical of popular press articles about diabetes. Don't expect perfection, but control as well as you can.

And enjoy the holiday season, which involves more than just food: the music, the companionship, the beautiful lights. The days are getting longer. Soon it will be spring (well, first we have to survive February, but at least it's short). Maybe this year someone will make a type 2 diabetes breakthrough. We can always hope.

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.

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.

Monday, March 28, 2016

Same genetic factor causes both type 1 and type 2 diabetes

Type 1 and type 2 diabetes may have the same underlying cause, namely "fragile" beta cells that are easily damaged by cellular stress. This was the conclusion of research by 29 researchers in Europe, Australia, and Canada led by Adrian Liston, who kindly sent me the full text of the paper. The research was published this month in the journal Nature Genetics.

The traditional view of diabetes is that types 1 and 2 are quite different. Type 1 is an autoimmune disease in which the body's own immune system destroys the beta cells, the cells that produce insulin, and the destruction is so great that patients must inject insulin.

Type 2 is thought to occur because of insulin resistance. Insulin resistance means the body can still produce insulin, but cells don't respond properly to it, so they are unable to overcome this resistance and may eventually die from "overwork."
 The liver produces glucose when it thinks glucose is needed, and insulin is supposed to shut this process down when glucose levels are adequate. But insulin resistance in the liver means that it keeps pouring out glucose into the bloodstream even after meals when glucose levels are high.

Because being overweight increases insulin resistance, obesity and rates of type 2 diabetes are associated, and some people call type 2 diabetes a "lifestyle disease" and blame patients with type 2 diabetes for "bringing it on themselves." For this reason, some people want to change the names of the two diseases so it's clear that they are different.

But now it seems that the underlying cause of both diseases is the same: a genetic defect in the beta cells that makes them more susceptible to various kinds of stress. Without the fragile beta cells, people can tolerate insulin resistance by simply producing a lot more insulin, and they can even tolerate an autommune attack on the beta cells as well.

This idea is consistent with the saying that "genetics loads the gun and the environment pulls the trigger." In both types of diabetes the gun is loaded. In type 1 an autoimmune attack pulls the trigger. In type two it's insulin resistance, especially in the liver.

I've always felt that type 1 and type 2 diabetes must have the same underlying cause. Otherwise, why would there be families in which some people had type 1 and others had type 2? Seems unlikely if there weren't some common trigger. Now we may know what that common factor is.

This research is complex. The researchers used NOD (nonobese diabetic) mice, which are very prone to get autoimmune diabetes and are considered a model for type 1 diabetes. Then they studied various strains of mice with altered genes, some resistant to stress and some sensitive.

Although the NOD mice get autoimmune diabetes, the researchers found that they also have genetic defects in glucose control that precede the autoimmune attack and cause cell death. The researchers suggested that the dying beta cells could trigger the autoimmune attack, and later, because there are fewer beta cells, the remaining ones would have to work harder. This insulin-producing overdrive is a form of stress, to which these mice are especially susceptible.

Models of type 2  diabetes usually involve mouse strains that are bred to get fat easily on a high-fat diet (in the wild mice don't eat a lot of fat, which is one reason they're so keen on peanut butter and cheese - -  until the trap goes off - - and standard mouse chow is low in fat). In type 2, it could be that the beta cells have to go into overdrive when calories, especially carbohydrates, are in excess, requiring the synthesis of tons of insulin because of insulin resistance, and this would cause cellular stress to  fragile beta cells. Someone with robust beta cells could eat a ton of food and have a lot of insulin resistance without destroying the beta cells.

The researchers also showed that in mice, a high-fat diet could mimic the genetic effects. Liston said that certain fats, especially palmitic acid, make the beta cells more fragile, and even mice without the genetically fragile beta cells developed diabetes when given a high-fat diet. However, it should be noted that the effects of a high-fat, high-carb diet can be very different from the effects of a high-fat, low-carb diet. And high-fat mouse diets are also usually full of carbohydrate.

The researchers suggest that the increased prevalence of a high-fat "Western diet" may partly explain the increased incidence of type 1 as well as type 2 diabetes. I wonder if the increased prevalence of toxins in our increasingly polluted environment could be the stress that kills the beta cells in those whose beta cells are fragile.

Because of the complexity of this research (these researchers spent 10 years working on it), it's not likely to be replicated in the near future. Nevertheless, it gives intriguing hints about where other research should go.

It suggests that for most people, some cellular stress is OK. But those whose families include people with either type of diabetes should realize that they may have the same genes and fragile beta cells, and they should be careful not to increase cellular stress through diet.

Finally, if both type 1 and type 2 are precipitated by the same genes, we should all work together to support research that will some day solve the puzzle of this very inconvenient disease instead of bickering about which type of diabetes is worse or who is to blame for getting the disease.


Tuesday, March 15, 2016

Smarter Insulin

I don't usually wax poetic about new products in the gizmo field. So a meter has a bigger screen or holds more in memory or whatever. Big deal. It's still the same basic product.

But this gizmo has me excited, although it may be some time before it's commercially available. The idea of "smart insulin" that is only activated when blood glucose (BG) levels are elevated was reported last year. To do this, the researchers inserted insulin into microbubbles along with glucose-sensing chemicals similar to those in our meter strips. When BG increased, the microbubbles fell apart and released insulin into the bloodstream through microneedles in a patch.

What is exciting about the new research, done by the same group in North Carolina, is that instead of putting insulin in the patches, they've encapsulated beta cells, which are exquisite sensors of BG levels. The BG level in the blood increases and gets into the patch, the beta cells secrete just the right amount of insulin, as they do in the pancreas of nondiabetics, and BG levels go down.

Because the beta cells in the patch are encapsulated, they won't be rejected by the immune system, which is one of the problems with attempts at beta cell transplants.

Both types of patch were tested in mice, and it will be a long time before they're available for us, as noted in this analysis of the first device. Still, I think it's an exciting new way of looking at possible solutions to freeing people with diabetes from the burden of having to think about their BG levels 24/7.

As an aside, I always chuckle when popular-press articles always mention freeing people from "painful shots"  as if that were the biggest problem with diabetes. In fact, except for a tiny minority with real needlephobia, injecting insulin or pricking the fingers is not very painful and is not the major burden of diabetes, as Dr John Buse , a coauthor of the studies points out: "Managing diabetes is tough for patients because they have to think about it 24 hours a day, seven days a week, for the rest of their lives."

How wonderful it will be if these new patches work out.

Friday, March 11, 2016

Diabetes Research: The Twisting Path

Wouldn't it be wonderful for those of us who are pancreatically challenged if someone discovered a drug that would make our beta cells (the cells in the pancreas that produce insulin) multiply without multiplying too much (ie, cancer)?

Well, in spring 2013, a group from Harvard reported just that in mice. They called the hormone that caused beta cell replication in mouse liver and fat betatrophin (the protein was already known by other names, such as ANGPTL8 and lipasin). Probably in part because the research came from a respected research lab, it caused a lot of excitement and hope, including articles in the popular press suggesting that type 1 diabetes would soon be cured (we've all heard that one before), and other labs followed up on the Harvard research.

The saga of betatrophin is interesting in that it illustrates the pitfalls of scientific research, especially in today's world, where the research can be so complex.

In fall 2013,  another lab showed that mice in which the beta trophin gene was knocked out didn't have any changes in glucose metabolism.

And in fall 2014, a third lab reported that betatrophin did not cause beta cell proliferation.

The Harvard group then retracted their claim that betatrophin caused significant beta cell expansion, saying that further work had shown the same thing as the third lab. They said that when they used more mice, they found that some mice responded and others didn't. When they used only 7 mice they happened to have mostly responders; when they used 52 mice they found lower beta cell replication rates.

Later, an analysis of the saga asked whether a mouse system was in fact the best system in which to study human beta cell replication. And indeed another study had shown that although mouse beta cells responded dramatically to betatrophin, human beta cells were completely unresponsive.

An editorial in the journal Diabetes called this "the elephant in the room." Many studies are done in mice, and humans don't always respond like mice. They include a long list of compounds that induce robust beta cell replication in rodents but not in humans. Agreeing that despite these problems we still need to study rodents because we can more quickly get information that would be impossible in human studies, they cautioned about  not forgetting the elephant in the room.

I suspect most readers won't want to slog through all these papers. So what does this long saga offer us nonrodent patients?

I think it's a cautionary tale. We need to learn to take the results of research with a grain of salt. No one study, even a study by respected researchers in the top of their field, is definitive. It must be replicated in other labs.

This is especially true today, when research often involves dozens of different researchers, sometimes working in different labs, performing very complex techniques including manipulating genes. A mistake in just one of the myriad techniques involved could throw all the results off.

We need to be especially cautious about the popular press summaries of complex research. The popular press called the initial Harvard study a "breakthrough," and apparently physicians were overwhelmed with patients, or the parents of patients, wanting to try betatrophin.

We also need to be cautious about mouse studies. Mice aren't humans, and although they sometimes do react just like we do, other times they respond quite differently. The mouse studies just give researchers ideas that they can then try on human volunteers. Only when the human studies are done, with good safety and therapeutic results, can we begin to hope that someone will develop the compound under study.

This saga also shows how medical research isn't always a straight line from an idea to a treatment. There may be many dead ends, side trips, restarts, and disagreements. Even if several labs get the same results, there can be disagreements about the interpretion of the results.

So it's good to read reports of new research, but one must be careful about attributing too much credance to any one study. And if study A appears to show one thing and study B appears to show the opposite, we shouldn't throw up our hands and reject all scientific research. The path to the truth is twisting; we have to accept that.



Tuesday, March 1, 2016

Convenience Foods

Could the increasing use of convenience foods be triggering the increasing incidence of obesity and type 2 diabetes? By convenience foods I don't mean just junk food or fast food or highly processed foods that come in boxes or trays to be heated up in the microwave.

I mean real foods that are sold to consumers cut up or pureed or simply ground, like sausage and hamburger.

A recent study has found high levels of PAMPs, or pathogen-associated molecular patterns, in such foods, whereas fresh whole foods have none or very low levels. For example, PAMP levels in a whole onion are almost undetectable. But PAMPS in onions that you can buy prechopped are high. This makes sense to me, because chopping food greatly increases the surface area on which bacteria can grow. Even if they don't grow enough to make us sick, they could trigger a respose to the PAMPs.

What exactly are PAMPs? They are molecules released by certain bacteria that have patterns that tell our innate immune system to get rid of the bacteria through complex pathways. Some of these pathways involve inflammation. 

When the body produces an inflammatory response, it usually also activates an anti-inflammatory response that is supposed to keep the inflammation from getting out of hand. But if we're constantly triggering new inflammatory responses by snacking on PAMP-containing foods, we'd be in an almost constant state of inflammation.

People used to eat two or three times a day, mostly food freshly prepared from whole ingredients. In today's world, many people snack all day. Even if they're snacking on what are considered healthy real foods, if these foods aren't freshly prepared and contain high levels of PAMPs, the constant snacking could be triggering inflammation all day long. In other words, we would have "chronic inflammation," which has been blamed for myriad health problems.

Because people today mostly work full time and don't have a lot of extra time for chopping onions and tomatoes, the appeal of buying such food is obvious. Food "kits" with various prechopped ingredients ready for a stir fry or a stew are also appealing. The same goes for hamburger. How many people today buy a hunk of beef and grind it right before cooking?

I don't buy prechopped ingredients, but I produce them at home. If a recipe calls for a little onion, I'll slice up a whole onion and save what I don't need immediately in the fridge. I'll puree a whole cauliflower and save it, sometimes for several days. And I love sausage. My fridge is probably brimming with PAMP-containing foods.

Could the constant barrage of PAMPs in today's world be responsible for the increase in chronic conditions like obesity and diabetes?

Eating foods with low levels of PAMPs leads to lower LDL levels and weight loss. I don't think the latter is because of the calories burned chopping onions and tomatoes.

So what can we do about this? The idea that it's the PAMPs that are causing poor health is, after all, only an idea. When we work full time and then have to pick up kids and go home to make dinner, the appeal of prechopped and preground foods is clear. Very few of us have time to grind our own flour (if we eat flour at all). It's unrealistic to expect us to give up convenience completely.

The manufacturers are apparently trying to work out processing methods that would remove the PAMPs. But in the meantime, avoiding prechopped and preground foods when possible could help. So could doing less snacking to give our bodies time to resolve any inflammation triggered by the previous meal. It shouldn't be that hard to take a whole tomato for a salad and slicing it right before eating instead of mixing it all up at home.

Would such changes make a lot of difference to your health? I don't know. But they couldn't hurt.


hboxed macaroni and cheese.

Monday, February 8, 2016

Eat Like Your Grandmother?

"Eat like your grandmother" is a mantra oft repeated in nutritional blogs and on websites. But does it make sense?

My grandmother was a big fan of Crisco. That's the creamy white stuff that's full of trans fats. Unhealthy,  yes, although it sure made tasty pie crusts with half butter (for taste) and half Crisco (for texture). So should I go out and buy a huge container of Crisco?

What's silly about the statement about your grandmother's eating habits is that the eating habits of your grandmother depend on your age and how old people in your family were when they had children. I'm assuming about 25 years between generations, so if you're 20, your grandmother was probably born around 1945. That means she grew up with lots of frozen and processed food, including TV dinners, which were considered hot stuff in the 1950s.

But if you're 70, your grandmother was probably born in the 1890s, when eating habits were very different from what they were in the 1940s and 1950s. And obviously ages between 20 and 70 would have grandparents with birth dates varying to match. If generations in your family were 40 years instead of 25 and you're 70, your grandmother might have been born in the Civil War era.

That makes "Eat like your grandmother" pretty meaningless, except for the idea that her ethnicity, as well as her era, would have influenced her cooking and eating habits. I do think that if most of your ancestors ate a lot of rice, you probably have genes for processing carbohydrates, but if your ancestors ate mostly caribou, you probably have genes that mean you'd do better on a high-meat diet.

What most people mean by "Eat like your grandmother" is probably "Don't eat packaged and fast foods." But then why don't they just say so?

Maybe I'm just in a grumpy mood because I'm doing bookkeeping in preparation for taxes, but I just heard this imprecise mantra one time too many.