Wednesday, December 21, 2011

The Glucagon Connection

Most of us understand the importance of insulin in controlling our blood glucose (BG) levels. When our BG levels get too high, we can bring them down by injecting insulin. Insulin is made in and secreted by the beta cells in the pancreas.

Many of us are also aware that another hormone, glucagon, helps bring BG levels up when they get too low. Glucagon is made in and secreted by the alpha cells in the pancreas.

In nondiabetics and people with type 2 diabetes or early type 1 diabetes, glucagon automatically gets secreted when BG levels get too low. But people with longstanding type 1 diabetes often stop producing much glucagon and need glucagon shots to bring up a serious low.

Insulin and glucagon are like the accelerator and brake on your car. And it's the ratio of the two, rather than the absolute amount, that is important. If you have almost no insulin, you might be able to have normal BG levels if you also had almost no glucagon.

In fact, a study done in 1981 in a man who had no pancreas, showed that BG levels could be maintained at about 100 without insulin as long as they didn't give the man glucagon.

The problem is that when the beta cells give out, the alpha cells don't give out as well. In fact, they often secrete even more glucagon than they would in a nondiabetic. Glucagon tells the liver to produce and secrete glucose, so the BG levels stay high even when you don't eat.

Most diabetes researchers focus on beta cells and insulin production, but some are studying the alpha cells and glucagon production as well. A recent study found that hyperglucagonemia (too much glucagon in the blood) actually precedes the decline in insulin secretion seen in diabetes.

These researchers infused rats with a lot of glucose for 10 days. After initial high BG levels, the rats adapted and maintained normal BG levels for 4 days. But then their BG levels started to go up, and by 10 days 89% of the rats had high BG levels.

This isn't surprising. The traditional view is that coping with a lot of glucose and producing a lot of insulin can "exhaust" the beta cells; this is called glucotoxicity.

But the researchers found that the rats weren't producing any more insulin than normal. Instead, their glucagon levels increased fivefold. Thus endogenous glucose production, production of glucose by the liver, was what was making the BG levels go up. And infusing them with anti-glucagon antibodies made their BG levels return to normal.

That is surprising.

The authors conclude that glucotoxicity may first manifest as alpha cell malfunction, before any deficit in beta cells and insulin secretion is seen. This is a new way of looking at how diabetes procedes.

A few months earlier, another paper showed that glutamate (or glutamic acid), an important neurotransmitter in brain and pancreas, is secreted from alpha cells along with glucagon. The glutamate contributes to beta cell destruction; it doesn't affect the alpha cells.

Hence, if you're secreting more glucagon, you'd also be secreting more glutamate, thus accelerating beta cell loss and insulin production when you needed more to oppose the extra glucagon.

The authors also found that the protein GLT1 (glial glutamate transporter 1) could protect the beta cells, and they are working on finding other beta-cell-protective compounds.

Neither of these discoveries will result in an instant cure for type 2 diabetes. The first was done in rodents, and the second was done in isolated human cells. Before they can be translated into actual diabetes treatments, they'd have to be replicated in humans, not isolated cells or rats, and treatments that turned down the alpha cells would have to be developed.

However, for decades, researchers have been studying how type 2 diabetes evolves, and they're still not sure. Of course it's all terribly complex. But is it possible people are looking in the wrong places? Maybe it's time for some new ways of looking at an old problem.

Focusing on the alpha cells is one such approach. Let's hope this work continues.


  1. Gretchen:

    I just finished your book on diabetes and will be purchasing your book on prediabetes (my situation) soon. You are truly a gifted writer--you make a difficult subject comprehensible. Appreciate your blog and the comments you post at other blogs.

  2. If anyone wants to read more about this here are a few recent reviews.

    Endocrine Reviews 2007;28(3):253–283
    doi: 10.1210/er.2006-0026

    J Clin Invest. 2012;122(1):4–12

    Endocrine Reviews 2007;28(1):84–116
    doi: 10.1210/er.2006-0007

  3. I comment on blogs about glucagon getting no respect, and I'm either ignored or laughed at.

    Keep blogging!

  4. Another article about glucagon.

  5. so if there was a way of safely decreasing your glucagon stores regularly, there should be a corresponding decrease in blood glucose. how can we safely decrease glucagon levels?

  6. v/vmary: There's no method currently available, but researchers are working on the problem.

  7. is glycogen similar to glucagon? there are safe ways to decrease glycogen levels.

  8. "In agreement with this, our results in cultured human hepatocytes have shown that insulin, rather than glucose, is able to suppress the action of physiological concentrations of glucagon."

    According to 23andme, my high bg levels are caused by insufficient insulin secretion. some nights i wake up and can't get to sleep easily. i have usually eaten relatively (for my standard) low carb the preceding day. i tested my blood sugar two nights (2:30am) when this happened and had bg at 82 and 87. but when i woke up, my bg was 98 or 101. my theory is that my body senses low insulin output and so uses adrenaline to activate glucagon to initiate the liver's dumping of glucose into my blood stream. even if i eat something at 2:30am to bring up my bg level, it will do no good as the problem is a low insulin level. i could take metformin to prevent the liver from dumping glucose into my blood- and i will be seeing (begging) a doctor to prescribe it for me. he will see my a1c is 5.3 and say no, and which point i will ask (beg) for a OGTT. in the meantime, i want to experiment with trying to lower the action of glucagon by lowering my glycogen stores. my husband has really improved his morning numbers by having his last meal at 4pm. maybe that is also an avenue for me as my body might be able to store up enough insulin for the night.
    i will be testing these hypotheses, but is there anything glaring that you are aware of that is wrong in my thinking?

    1. v/vmary:

      1. What is the quote from?
      2. How does 23 and Me show that your problem is low insulin?
      3. Liver can produce glucose even with low glycogen; gluconeogenesis.
      4. You could try what your husband is doing, or try a very low carb diet.
      5. As these questions pertain to your individual situation and not to glucagon in general, why don't you write to me at my e-mail address, which is available via my Profile. It's easier that way.

  9. HI Gretchen,

    Here is the study:

  10. Gretchen, my 23 and me results show various genes that predispose me to diabetes like the TCF7L2 gene.

    "This SNP is located in the TCF7L2 gene, which encodes a protein involved in cell signalling. How TCF7L2 affects the development of type 2 diabetes is not completely understood. TCF7L2 has been shown to be involved in the development of pancreatic islets, which contain insulin-producing beta cells. Studies suggest that the T version of this SNP is associated with impaired baseline insulin secretion."

    Also both my parents have diabetes. I am not overweight, although my weight is mostly on my lower abdomen. With a glucose meter I have seen that food that will raise my husband's BG to 118 will raise mine to 150. Today my fasting BG was 110 although i had eaten low carb for much of the day. i was trying to really stop eating early, but i just got too hungry and had a piece of cheese at night. usually i won't be 110 if i control my intake better. i will be 96-101.

    1. v/vmary, You're probably not still reading, but my latest post has to do with TCF7L2 gene.

  11. Risk/predisposition is not the same as proof. You might look into MODY.

    As these questions pertain to your individual situation and not to glucagon in general, why don't you write to me at my e-mail address, which is available via my Profile. It's easier for me that way.

  12. OK, sorry i didn't use your email. i was just being lazy- but i will do that with personal questions from now on. thanks for replying :)

  13. hi Gretchen, hope you are still reading your comments. I can not find the answer to this question anywhere. how can a woman of perimenopausal age distinguish false hypos and the night heat-ups/chills that come with them from similar temp changes that come from perimenopause? thx

    1. Remember I'm not a doctor. But why are you having false hypos? And would you do anything differently if your hot flashes stemmed from perimenopause or false hypo?

  14. The liver and the glucose production by the liver by using glucagon is like the big elephant in the room no one seem to notice. All attention is on the pancreas and insulin, nothing else exists. This is the second time I hear this very interesting topic. I also notice you have not been writing lately. Enjoy reading your posts

    thank you

    1. Marcos, at least some researchers are working on this problem. Thanks for noticing my absense. I keep planning to get back to this blog, but science is moving so fast, it takes a lot of time to attempt to keep up.

  15. Gretchen,
    I am just starting to write about diabetes and my blog is not quite ready. My main idea is to search for relevant scientific journals books and articles and digest them to quick internet reading trying to provide information to diabetics which I believe is key for people with this condition and also point out to the research, mostly DM type II. I'll let you know when my site is more developed


  16. Best wishes for your blog. BTW, I'm still blogging at Health Central:

  17. Great advice! Thanks for sharing!

    -Living chemical free