Wildly Fluctuating by Gretchen Becker
20 June 2019A diabetes blog with wildly fluctuating topics ranging from humor to serious stuff to miscellaneous musings on the diabetes news of the week by a type 2 diabetes patient/expert and author of The First Year: Type 2 Diabetes
Two recent research reports concern helping beta cells produce more insulin. Interestingly, they both involve inhibiting something rather than trying to stimulate the beta cells, as the sulfonylurea drugs do.
People think of type 2 diabetes as being caused by insulin resistance and some wonder why you would want to produce more insulin if you have type 2. But in fact, type 2 is often caused by insulin deficiency. That is, you're producing insulin, often more than normal, but it's not enough to overcome your insulin resistance. So more insulin can help.
The first studyinvolves deleting senescent, or old, beta cells from the pancreas. When the Joslin Diabetes Center researchers did this in mice, they found that the remaining beta cells were rejuvenated and started producing enough insulin to keep blood glucose (BG) levels in the normal range.
How did they do this? One approach was genetic modification, which is fine in mice but unlikely to be practical in humans. The other approach was with senolytic drugs, drugs that remove senescent cells. Although you can buy drugs claiming to be senolytics from companies that market supplements, this field is relatively new and large-scale controlled trials have not yet been done. Pilot studiesshow promise.
The authors of this paper think that diabetes is caused by stress: in type 2 the stress of insulin resistance and in type 1 the stress of an autoimmune attack. Of course this doesn't explain what causes insulin resistance or an autoimmune attack, and these are the underlying problems.
The second study involved removing two signaling molecules that dampen the insulin response. This is the opposite of most approaches, which try to stimulate the insulin response directly instead of inhibiting inhibitors. The sulfonylureas stimulate insulin release, even when a person is not eating carbohydrate, which means your blood glucose can go low when you're not eating.
These studies were done in mice, and oddly, removing the inhibitors worked only when the mice were on a high-fat diet. The reason for this is not yet known.
The inhibitors are TLR2 and TLR4. TLR stands for toll-like receptor,and normally, TLR2 and TLR4 stimulate the immune system when they detect invadors. But they also work together to block beta cell proliferation, so when you remove them, the beta cells multiply like mad, so much that they can be seen with the naked eye.
There are in fact drugs that inhibit TLR2 and TLR4, but inhibiting them would not only stimulate beta cell growth, but it would inhibit the immune system and make a person susceptible to infection.
Nevertheless these new approaches are interesting and may result in methods to rejuvenate beta cells in people with both types of diabetes (most people with type 1 do have a few beta cells remaining despite the autoimmune attack). How wonderful that would be.
Is type 2 diabetes as well as type 1 diabetes autoimmune?
The classic description of type 1 diabetes is that it's an autoimmune disease. Normally, control mechanisms make sure that the body doesn't attack itself, but in type 1 diabetes, something has gone wrong with this process and the immune system does attack the beta cells, eventually almost totally wiping them out, so people have to inject insulin.
Type 2 diabetes, on the other hand, is described as a disease of insulin resistance. The beta cells can still produce insulin, but not enough to overcome the insulin resistance, and as time goes on and the beta cells deteriorate, type 2 patients may need insulin as well.
But researchers at the Stanford University School of Medicine and the University of Toronto say their research suggests that type 2 diabetes is also an autoimmune disease.
This makes sense to me. I've always felt that the two types of diabetes have a similar underlying cause and secondary effects that modulate this response. Also, studies show that people with type 1 diabetes can have some insulin resistance but not usually as much as in people with type 2, and people with type 2 diabetes can produce some autoantibodies but not usually as much as people with type 1.
In other words, there may not be a sharp line between the two versions of the disease but a continuum, with some people having more of one type of defect and others more of another.
But because of the classic understanding of the two types of diabetes, doctors don't usually test for antibodies in patients with typical signs of type 2, those who are overweight and don't get much exercise, and they don't test for insulin resistance in thin patients who have autoimmune antibodies.
Of course, this new theory wouldn't mean that classic approaches to type 2 diabetes such as weight loss and increased exercise wouldn't help. When such approaches reduce insulin resistance enough, then the defective beta cells may be able to produce enough insulin to keep blood glucose normal, depending on how damaged the beta cells are by the time of diagnosis.
But if these new ideas are confirmed with more research, it would open the door to new treatments for patients with type 2, focussing on the autoimmune aspects of the disease.
The researchers say that immune cells cause inflammation in fat when the fat cells are growing so fast that new blood vessels to support the fat cells can't keep up. Some of the fat cells die as a result and spill their contents into the fat, causing inflammation. This is seen in mice on a high-fat, high-calorie diet and in humans with type 2 diabetes.
The inflammation then causes insulin resistance, according to the researchers. And mice genetically engineered so they didn't produce antibody-producing B cells did not become insulin restant when they became fat. Injecting such mice with B cells or antibodies from obese insulin-resistant mice made the mice insulin resistant. So the immune system clearly plays a role in this.
In humans, “We were able to show that people with insulin resistance make antibodies to a select group of their own proteins,” said Edgar Engleman, senior author of the paper. “In contrast, equally overweight people who are not insulin-resistant do not express these antibodies.”
This line of investigation is in early stages, but it suggests new avenues of research. And new ways of looking at a problem often lead to new solutions.
I've written beforeabout the egg trampoline: stories saying eggs are good and then eggs are bad, seeming to bounce from one extreme to the other.
But part of the problem is not the research but the way the popular press deals with that research, writing sensational headlines to capture the interest of the public.
Most popular science sites like Eurekalert and Science Daily don't research stories they post to their sites but simply print press releases sent out by the public relations departments of the universities and research centers where the research was done, including the headlines. The goal of the PR people is to call attention to their institutions, so, as often occurs these days, if the research was done at several different instutions, each one may send out press releases with a slightly different spin.
You might see one saying "X University Scientists Discover New Hormone" and another saying "Y Institute Researchers Find Hormone to Cure Halitosis." Same research, different slant. But both tend to inflate the impact of the hormone that was discovered and the importance of the researchers at their institution.
The problem is that the average reader won't track down the original research to see if it did, indeed, cure halitosis. They'll just remember the headlines.
Two examples related to eggs are "UBC Researchers Say Eggs for Breakfast Benefits Those With Diabetes, and "Bad News For Egg Lovers."
I won't critique these stories because frankly I'm tired of this egg controversy and I'm especially tired of observational studies that don't really show much of anything. And then I came across a blogpost that analyzes the problem with nutritional studies. It's worth reading if you read or listen to news stories about nutrition. Enjoy.
Are thin people thin because they have incredible self-control whereas overweight people have very little? Or could their genetics play a large role?
A story in the New York Timessuggests the latter. They describe people with a version of a particular gene, MCR4, who are simply almost never hungry. Self-control has little to do with it. Conversely, people with another version of the gene are constantly hungry. In other words, it's appetite that controls how much people eat in an environment in which food is plentiful, and some people are hungrier than others.
Overweight people often think that, but no one believes them and people tell them (or at least believe) they have no self-control.
I've always thought genes play a large role in controlling appetite. A good example is in my book The First Year: Type 2 Diabetes:
"Having diabetes genes may affect the appetite. Alex E. described the time someone brought some scrumptious pastries to work. A thin person walked in, looked at the pastries, and said, "Oh my, those look good. I wish I were hungry so I could try one." Alex was flabbergasted. He was hungry all the time and thought everyone else was too."
Of course, genes are not the only factors affecting appetite. Hormones such as leptin and ghrelin and fluctuating blood glucose levels can affect hunger, as can habit, for example always eating lunch at a certain time. If you always have lunch at noon, you're likely to get hungry around noon. Other psychological triggers can affect appetite too. And one can change habits. But genes are important.
The researchers note that the MCR4 genes don't affect metabolism but affect appetite. In other words, if a thin person and an obese person eat the same meal, they'll burn about the same number of calories, but the thin person often eats less of the meal.
Researchers have found at least 300 mutations in the MCR4, and it's likely that mutations in different parts of the gene would have slightly different effects. It had been shown previously that mutations in the MCR4 gene increase the risk of obesity, but the recent studywas the first time it has been shown that other mutations in the MCR4 make people feel full even when they haven't eaten.
Unfortunately efforts to develop drugs to increase activity of the MCR4 gene to decrease appetite were halted when the drugs were found to decrease appetite but also to increase blood pressure. Other efforts produced other unacceptable side effects. Clearly, tweaking this gene is possible but not easy. But as more is learned about the gene's effects, useful drugs without side effects might be developed.
And it's important to understand that it's unlikely that dealing with just one gene that affects obesity is unlikely to solve the growing problem of obesity. Many genes are involved, as illustrated by this study.
As the authors note: "Finally, a clear understanding of the genetic predisposition to obesity may help to destigmatize obesity among patients, their health care providers, and the general public."
So how does this all affect you? Well, if you're very overweight and feeling guilty about it, understand that it may not be your fault. It could be your genes.
However, that doesn't mean you shouldn't try to do something about it if the excess weight is contributing to other problems like high blood pressure or type 2 diabetes. The fact that weight loss will be more difficult for you than for some other people doesn't mean it's impossible. Dump the guilt and get to work.
You can succeed.
Tagatose is a sugar with a glycemic index of 3, and it's also 92% as sweet as sucrose (table sugar). Like sucrose, it's crystalline, and you can pretty much substitute it for sucrose tablespoon for tablespoon. Also, it browns like sugar.
I wrote more about tagatose and a related sugar called allulose hereand here.
Thus tagatose has many appealing characteristics except that it's expensive. When it first became available in the early 2000s, mostly in Europe, I was thrilled. But the availability didn't last, and in 2006, the only company making it decided it wasn't economically feasible.
Now researchers have reported that they could engineer yeast to produce tagatose with much greater efficiency than the traditional methods. Chemists might enjoy the original article, which has more details.
"For example, rare sugars such as tagatose and allulose are currently produced by enzymatic reactions followed by complicated separation processes. As a result, the production costs of rare sugars are significantly higher than HFCS, which does not require additional separation. Due to this high production cost, introduction of rare sugars into foods and beverages has been hampered in spite of potential benefits of rare sugars."
It will be interesting to see if this new method makes it into commercial production.