Saturday, April 18, 2009

Hidden Clues

I get my mail in a rural mailbox by the side of the road. Earlier this year, in the middle of winter, I found that the red flag that tells the mail carrier I have mail to be picked up had disappeared.

It was not an item that anyone would bother to steal. So I figured it had been knocked off and then a plow had buried it under one of the huge mounds of snow nearby. It would turn up in the spring, I thought.

Well, spring came, sort of, and most of the mounds of snow melted (there was still a small pile of snow on April 29, after 2 days of 80-degree weather!), but there was still no sign of the red flag. As I stood looking at the largest mound, still about 6 feet high, it occurred to me that the red flag I was sure was buried there somewhere might be analogous to the cure for type 2 diabetes.

It's there somewhere, I'm sure. But maybe it's buried under a huge mound of information that is leading people to look in the wrong places. Some day we'll find it. No one knows when. Maybe in 10 years, maybe in 10 decades. It's a complex puzzle. But I know we'll find it some day, just as I was certain my red flag would turn up.

And sure enough, a week or so later, when I went down the hill to get my mail, I saw that the huge mound of snow was only 3 feet high, and then I spotted something red. It was the flag!

The key to the diabetes puzzle hasn't been lost for lack of trying. The amount of research being done on the problem is tremendous. But what if everyone is looking in all the wrong places?

For example, we know that the body needs insulin. Insulin saves lives. Before the discovery and therapeutic use of insulin, people who got type 1 diabetes died. Now they can live long and relatively healthy lives.

But there's another hormone that is also important. That hormone is glucagon. Insulin is produced by the beta cells in the pancreas. Glucagon is produced by the alpha cells.

Everything glucagon does is pretty much the opposite of what insulin does. Insulin makes blood glucose (BG) levels go down; glucagon makes them go up. Insulin tells fat cells to store fat; glucagon tells them to release fat to be burned for energy.

And it's actually the ratio of insulin to glucagon that determines what will happen with your BG levels. In other words, high glucagon levels can do the same thing as low insulin levels. And most people with type 2 diabetes have higher glucagon levels than normal.

Normally, after a meal, the increased BG levels turn down the secretion of glucagon. When you have type 2 diabetes, this doesn't happen. So glucagon tells the liver to keep pumping glucose into the blood even when BG levels are already high. This is one reason we go high after meals.

Glucagon is also responsible for the increase in BG levels people with very little insulin production see after eating protein. Insulin does more than help glucose get into cells. It also helps amino acids (the building blocks of protein) get into cells. So if you eat pure protein, a normal person secretes insulin to help the protein breakdown products get into cells to be used to make more protein.

But if you don't eat carbohydrate at the same time and your insulin levels increase, your BG levels could go too low. So the body secretes some glucagon along with the insulin. In a nondiabetic person this system works very well.

But in someone producing almost no insulin, the protein meal still stimulates the secretion of glucagon, and with no insulin to balance it, the glucagon makes BG levels go up. The same is true of other stimuli, for example, exercise, that would normally trigger the secretion of both glucagon and a balancing amount of insulin. The trigger may still work, but if you can't produce much insulin, then the ratio becomes unbalanced and your BG goes up.

As their autoimmune disease progresses, people with type 1 tend to produce less and less glucagon, and because glucagon is one of the main hormones (another one is adrenaline, or epinephrine) responsible for bringing up BG levels when you go low, people with type 1 can have more serious problems with lows. Type 2s can also go low, but they usually have a bit more of a buffer with the glucagon.

People have known about glucagon and its effects for a long time, but most of the research in the field of diabetes has focused on insulin. There is one major exception, and this is the incretins, especially those that mimic or increase the levels of GLP-1. Byetta is the incretin mimic on the market today, and others are in the works.

The incretins stimulate the secretion of insulin; they also decrease the secretion of glucagon, thus giving a "double blow" to BG levels by stimulating glucose uptake in muscle and fat and decreasing glucose production by the liver.

Of course researchers are aware of glucagon and the aberrant responses of the alpha cells in people with diabetes. But most of the research today focuses on beta cells and insulin.

What if it turns out that the alpha cells and glucagon secretion are easier to control than beta cells and insulin? What if it turns out that some other hormone, maybe even one that hasn't been discovered yet, is actually more important than insulin deficiency and insulin resistance as a cause of type 2 diabetes?

I read one paper that suggested that leptin resistance (leptin is a hormone that controls hunger) is actually more important than insulin resistance as a cause of type 2 diabetes.

Thousands of research papers on diabetes are published every year. Somewhere the answers lie hidden. Like the red flag hidden under the huge mounds of snow, the buried answer to the type 2 diabetes puzzle will emerge some day, I'm sure.

When creative minds try to look at the puzzle in new ways, we may accelerate this process.


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  2. thanks Gretchen for a splendid article. It's about time too that the medical community shifts its focus from a insulinocentric approach. I remember reading an article entitled MSH antagonists spefically targetting glucagon based therapies. A few days ago I chanced on a patent posted on the Net about an application for some GLP-1drug based on tarragon extracts. I guess it won't be long before other similar drugs will come our way too. Cjuan

  3. Cjuan, I'm sure there *are* creative people working on these problems, but sometimes we don't hear about it for years, when they're able to get positive results and publish.

    I read about incretins more than 10 years ago and wondered why no one was researching them. Turned out they were, but it took a long time to get the GLP-1 mimics.

  4. Michael Eades has a useful post on the reverse side of the system

    It's obvious when it's pointed out to you, except that no-one usually bothers to point it out: there's a whole bunch of work going on continuously in the background shuttling glucose in and out of store in response to demand and dietary input, and this only has to go 5g out of balance for your BG to double

  5. Hi Gretchen it's Linda Comedycook of eat less move more fame ha ha. I am glad to see you are still in good health and on your wonderful farm. I am now on insulin, 70/30, but lately things have gotten out of control. I'm hungry all the time! Anyway, I tried Byetta and it was wonderful, I lost the nagging raging hunger. But I got so sick I had to stop. Now I read about Victoza (liraglutide) and have hope again that it would help me lower my insulin so I can lose weight. Have you heard when it might be available, and any thoughts on it Gretchen? Thanks for reading this and I hope you are enjoying the nice weather up there!

  6. Hi Linda,

    So nice to hear from you again. I'm afraid I don't know when Victoza will be available.

    Were you on the 10 mg Byetta dose? Would it work for you at a lower dose?