Tuesday, July 16, 2019

Diagnosing diabetes risk early

I've been following the saga of Michael Snyder, a geneticist at Stanford, for some time. Snyder participated in a genetic study in which his own DNA was analyzed, and in the process he discovered that he had a gene linked with increased risk of type 2 diabetes. Then a viral infection made his blood glucose (BG) levels soar high enough that he was told he had type 2 diabetes.

Snyder modified his diet and increased his exercise and slowly brought his BG levels back to normal ranges within 6 months. When I mentioned this in a blogpost, I wrote as if bringing his BG levels back to normal meant that he could escape chronic type 2 diabetes as long as he maintained his diet and exercise regimen.

I was wrong. A recent story in the New York Times states that although he was able to maintain normal BG levels for three years after the initial diagnosis, they eventually increased enough that he was again told he was diabetic. He said it seems he's slow to release insulin.

In fact, almost everyone with type 2 diabetes lacks the rapid phase 1 insulin release that knocks down BG levels quickly, but we still have the slower phase 2 insulin release. When I was in a clinical study at the Joslin Diabetes Center, I showed almost zero phase 1 insulin release. Interestingly, when I took high-dose aspirin (actually an aspirin-like drug used in the study), my phase 1 insulin response increased to almost 70% of normal.

The classic description of type 2 diabetes is that it's caused by insulin resistance, but more and more research is showing that different people get type 2 diabetes (perhaps better called non-autoimmune diabetes) for different reasons. For some, the insulin resistance may be the strongest factor, but for others, factors like poor insulin secretion may be more important. Not all people with type 2 are overweight and some overweight people are insulin sensitive.

“We learned that people are Type 2 diabetic in very different ways,” said Snyder in the New York Times article.

In one study, "nine of the cohort members developed diabetes during the study. But it appears their health followed different paths to reach that state. Two people gained weight before their diagnosis, but seven developed the condition without substantial weight gain. The subjects also showed differences in how much insulin they produced. Some made very little insulin, while others produced enough insulin, but not sufficient to lower their glucose levels and forestall diabetes."

So a treatment that is best for people with one subtype of type 2 may not be best for people with another. This is not big news, but it's always nice to see some scientific validation of what we've observed.


Snyder is still trying to control his BG levels without drugs, and he's still getting a lot of lab tests. Perhaps this intense scrutiny of the physiology of one type 2 diabetes patient will give hints about the process that will help us all.

And what Snyder's story means for you is that if your diabetes progresses even though you are doing all you can to control it, don't blame yourself. Your genes may be responsible



Sunday, June 30, 2019

On Illustrations

I don't know about other people, but I'm getting really, really, really tired of seeing popular press articles about type 2 diabetes illustrated with photos of people pricking their fingers to get blood.

I mean, I know that unless you use a continuous glucose monitor, pricking your fingers is part of having diabetes. But it's not the only part. In fact, it's a very minor part. Controlling your diet is much more important.

But the finger jabbing seems to be a cliche for type 2 diabetes.

Another cliche I hate is that of a man and a woman, usually about 40 or 50 and trim, running along a deserted  beach, intended to illustrate exercise.

I mean, I know running along a beach would be good exercise, but how many people live near a beach, especially a deserted beach like the ones always shown? And if they were just diagnosed with type 2 diabetes, how many would be slim and trim like the models? Maybe some, but not the majority.

Finally, the last cliche is the same attractive couple that was running along the beach preparing a salad in a perfectly appointed kitchen while grinning from ear to ear. "Diabetes is such fun! We can't wait to finish this delicious salad so we can go out to the beach again for some more running. If it's rainng, we can stay home and do some finger-pricking to prove we're really diabetic."

OK. I'm in a bad mood. I couldn't find a deserted beach and I ran out of salad fixings. Maybe tomorrow someone will come up with some more interesting popular-press illustrations.





Thursday, June 27, 2019

Pancreatic Islet "Leader" Cells

No one understands yet exactly what regulates the release of insulin from the beta cells in the pancreas. We just know that the process is disrupted when you have diabetes, almost completely in the case of type 1 diabetes and partially when you have type 2.

Now researchers in several countries, including Germany, Great Britain, Canada, and Italy, have discovered a new clue. It seems that certain beta cells are "leader" cells or "hub" cells, and they control the other beta cells. This is like the heart's sinoatrial node (called the "pacemaker of the heart"), which controls the beating of other heart cells. And some researchers refer to the leader cells in the pancreas as pacemakers.

The studies show that if you selectively delete the leader cells in animal models of diabetes, the response to glucose becomes disrupted. It is known that in type 2 diabetes, the normally regular pulses of insulin that occur even when fasting are lost. Could this be because the leader cells are damaged? If so, why are they damaged? Are they more sensitive to high glucose and other toxins than the other beta cells?

The researchers found that the coordination of responses controlled by the leader cells was impaired in human islets taken from subjects with diabetes.

This is all fascinating albeit early days. This new study doesn't have any practical utility yet, but it could lead to more research that would have practical application.

If the heart's pacemaker isn't working well, they can give you an artificial pacemaker. The beta cell pacemakers wouldn't be as easy to replace. But perhaps now that it's known that there are such pancreas pacemakers, someone will figure out how to rejuvenate them.




Monday, June 3, 2019

Helping Beta Cells

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 study involves 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 studies show 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.



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Monday, April 29, 2019

Is Type 2 Diabetes Autoimmune?

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.

Tuesday, April 23, 2019

On Eggs and Press Releases

I've written before about 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.

Sunday, April 21, 2019

Appetite and Genetics

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 Times suggests 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 study was 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.