The Glucagon-Centric Theory of Diabetes Pathology

Perhaps we’ve been wrong about diabetes all along: the problem isn’t so much with insulin as with glucagon.

At least one diabetes researcher would say that’s the case. Roger Unger, M.D., is a professor at the University of Texas Southwestern Medical Center. That’s one of the best medical schools in the U.S., by the way.

Glucagon is a hormone secreted by the alpha cells of the pancreas; it raises blood sugar. (There are also glucagon-secreting alpha cells in the lining of the stomach, and I believe also in the duodenum.) In the pancreas, the insulin-producing beta cells are adjacent to the glucagon-secreting alpha cells. Released insulin directly suppresses glucagon. So if your blood sugar’s too high, as in diabetes, may be you’ve got too much glucagon action rather than too little insulin action.


Don’t ask me what delta cells do

Dr. Unger says that insulin regulates glucagon. If your sugar’s too high, your insulin isn’t adequately keeping a lid on glucagon. Without glucagon, your blood sugar wouldn’t be high. All known forms of diabetes mellitus have been found to have high glucagon levels (if not in peripheral blood, then in veins draining glucagon-secreting organs).

This is pretty well proven in mice. And maybe hamsters. I don’t know if we have all the pertinent evidence in humans, because it’s harder to do the testing.

Here’s Dr. Unger’s glucagon-centric theory of the pathway to insulin-resistant type 2 diabetes: First we over-eat too many calories, leading to insulin over-secretion, leading to increased fat production (lipogenesis) and storage in pancreatic islet cells as triglycerides, in turn leading to increased ceramide (toxic) in those islet cells, leading to pancreas beta cell death (apoptosis) and insulin resistance in the alpha cell (so glucagon is over-produced), all culminating in type 2 diabetes.

For a diagram of this, click forward minute 40 and 10 seconds in the video below.

If this is all true, so what? It could lead to some new and more effective treatments for diabetes. Dr. Unger says that in type 2 diabetes, we need to suppress glucagon. Potential ways to do that include a chemical called somatostatin, glucagon receptor antibodies, and leptin (the latter mentioned in a 2012 article, I think). The glucagon-centric theory of diabetes also explains why type 1 diabetics rarely have totally normal blood sugars no matter how hard they try: we’re ignoring the glucagon side of the equation. I don’t yet understand his argument, but he also says that giving higher doses of insulin to T2 diabetics may well be harmful. I’m guessing the insulin leads to increased accumulation of lipids (and the associated toxic ceramide) in cells.

Not making sense? Try this YouTube video:

Steve Parker, M.D.

PS: Dr. Unger Says: “Without insulin, you can’t get fat.”

Apoptosis: the second p is apparently silent.

h/t George Henderson

9 responses to “The Glucagon-Centric Theory of Diabetes Pathology

  1. Hi Dr. Parker, re your comment: ” I don’t yet understand his argument, but he also says that giving higher doses of insulin to T2 diabetics may well be harmful,” — you might want to take a look at the work of Dr. Jason Fung, a nephrologist in Canada (he’s at Scarborough General in Toronto) who has put together a lot of information about this very topic.

    His blog is:

    Like you, he advocates a high healthy-fat, low carb approach, but also adds in fasting since his practice tends to see people with very advanced Type 2 diabetes who are progressing towards complications from their disease.

    He has some good presentations about the problems with giving progressively higher doses of insulin — i.e. treating the blood sugars — compared to intensive dietary approaches, which directly address the insulin resistance and insulin levels.

    One of the presentations was geared towards medical colleagues, “Insulin Toxicity and How to Cure Type 2 Diabetes”:

    The other — which has over 300,000 views — was given to a group of patients:
    “How to Reverse Type 2 Diabetes Naturally”

  2. Let’s not make the mistake of swinging all the way to the other side from ignoring glucagon to focussing on it completely. Insulin:glucagon are merry dance partners/partners in crime – depending on the milieu.

    • Hi, Ash.
      I’ve run across some very difficult-to-manage cases of T1 diabetes over the years; blood sugars all over the map, 40 to 400 mg/dl in a day without explanation, despite best efforts of doc and patient. We call it brittle diabetes. I now wonder if glutton is the culprit.

      • T1 is actually a great study opportunity, congenital defects and not onset defects (T2) represent a decent way of testing stuff and finding real answers.

  3. Actually, type 2 diabetes is not “too little insulin action”. The patient is hyperinsulinemic, and this insulin is acting all over the place, especially to create vascular problems, only it’s not lowering blood sugar.
    Now, let’s turn off glucagon! Voila, the patient is not diabetic! But he’s still in bad shape.

  4. What I loved about the Unger video and the “explanation” of the Glucagon/Insulin relationship is that it is difficult to understand. It is not simple. There are different ratios that need to be created in different places in the body and glucagon is possibly more important than insulin, but obviously both are needed in the proper functioning of glucose regulation. Yes, a lot of people have been wrong, and they have been not been seeing the full picture.

    I am sure there is a bottom line to the research, which looks to me now to be like what the Paleo movement has been saying: Don’t eat too many processed (grain) carbs. Don’t make that (sugar level maintenance) system work constantly at a high level of exertion. If that is the take home message, how is that much different from the useful message for almost any biologic process or activity? Such as exercise?

    And yet the good news could be that the system may be able to recover with some period of rest, or reduced stress.

    • Insulin:glucagon is super difficult to understand, which is why when I “discovered” glucagon I’ve been harping on about it ever since.

      Insulin is “easy” to get, and to spray words about in 140 characters or less, which is why it gets all the attention.

  5. After watching the presentation of Dr. Fung, which I highly recommend, I realized that although it may be important to understand both sides of the Glucagon and Insulin interaction for type 1 Diabetes, it may be quite sufficient to simply follow the dietary instructions he provides, when it comes to type 2 diabetes.

    Second, I have been trying my own intermittent fasting regimen, and so far as I can see the main cause of type 2 diabetes is (wait for IT:) Breakfast. Yes, breakfast. And that includes all the (cereal company) promotion and blather about breakfast being the most important meal of the day, etc. Yes, in a perverse way that might be true, but only if you consider “breakfast” to be the meal you eat at around noon, after having not eaten since dinner at 6 or 7pm or so the night before. Wake up, have coffee (no sugar), don’t eat until at least 14 or 16 hours have passed since dinner. And don’t eat or consume carbs (ie, beer and chips or pretzels etc….) after dinner.

    You will lose weight and your waist will get smaller, as Dr. Fung’s results indicate. Yes, I eat a high fat diet, and I try to eat few carbs and only minimal grain carbs and sugars, but the real “treatment” is the fasting.

    After watching the videos I began to wonder if waist size (excess weight) is a non-invasive surrogate/marker for the high sugar excess insulin problem/issue.