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.






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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.

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.



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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.


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hboxed macaroni and cheese.

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.

Can Viruses Cause Obesity?

Is it possible that viruses can cause obesity? I'm not talking here about what we consider common viruses like the cold virus or HIV virus that attack humans directly, but bacteriophages, which attack bacteria and can kill them.

In fact, some people are using bacteriophages, often called just phages, to treat antibiotic-resistant bacterial infections. Phages were discovered in 1915 by FW Twort in England and then in 1917 by the Canadian Félix d’Herelle but haven't been studied a lot since then in terms of human disease.

Now there is some evidence that phages in the gut can contribute to obesity.

The idea that the gut microbiome can contribute to obesity is not new. Numerous studies have shown that transferring a sample of gut bacteria from fat animals into the guts of animals raised in sterile environments will produce fat animals, and transferring bacteria from thin animals will produce thin animals.

So it was not a surprise when University of Iowa scientists showed that the weight gain that often results from use of the drug risperidone, used for psychiatric disorders, was related to the gut microbiome of mice. What is interesting is that the researchers were able to cause the weight gain not just by transferring samples of the gut microbiota, but also by transferring the gut phages alone. When they gave the mice samples of isolated phages, the mice had decreased energy expenditure and a significant increase in weight, just as they had with the drug risperidone.

The usual caveat applies. Humans don't always react like mice. For one thing, humans don't set up  housekeeping in my walls. But our physiology is also somewhat different.

Nevertheless, the idea that bacteriophages could be affecting our weight is intriguing, and further research could lead to new approaches to keeping us all thin.

Spinning the News

I recently posted a blogpost about how the popular press often simply regurgitates press releases publicity people at various institutions send them.

And now come two "stories" that are such blatant attempts to trump up business for a certain food -- pears -- that it's laughable. One says pear consumers weigh less than non-pear-eaters, and the other says pears are healthy.

One study was sponsored by USA Pears, the other by the Pear Bureau Northwest, which is, in their words, "a nonprofit marketing organization to promote the fresh pears grown in Oregon and Washington."

Then one paper says, and this is the shocking part, "While the body of evidence connecting pear intake and health outcomes is still limited, USA Pears has been contributing to research efforts by commissioning independent studies to learn and affirm the heath attributes of pears."

Hold on! USA Pears has commissioned research aimed at proving that pears are healthy? Presumably if the research shows that pears cause warts, they won't publish that. But that's not scientific research. Scientific research tries to ascertain the truth, not support some preconceived conclusion. So OK, in fact this ideal is often not reached. But at least you should pretend you have an open mind.

The other study concludes that "intervention studies with pears that show positive health outcomes, most likely improvements in gut health, are urgently needed." In other words, research that shows negative outcomes is not needed.

What bothers me is that this kind of "research" and the ensuing press releases do, in fact, work. Most people seeing headlines like this or hearing them read out on the evening news will only remember, "Gosh. Pears are healthy and if I eat pears I'll lose weight." In fact, when you don't have diabetes, most fruits are healthy in moderation. Each fruit is higher or lower in some nutrient, but they all contain healthy nutrients as well as sugars.

I keep those 100-calorie sugarfree canned fruits on hand to use when my blood glucose goes too low, and they do a good job of raising my blood glucose and taste good as well. But I don't expect to be a lot healthier or to weigh less as a result.

At this point, except for occasional rants like this one, whenever I see a story promoting the health benefits of a single food, I look to see who funded the study. If it's some growers' organization like USA Pears, I don't even bother reading the story. There's enough real science research to read about without wasting time on this sort of thing.