Could Glucagon Be Just as Important as Insulin in Diabetes?

I couldn't find a pertinent picture

I couldn’t find a pertinent picture

Everybody knows that insulin is the key hormone gone haywire in diabetes, right? Did you know it’s not the only one out of whack? Roger Unger and Alan Cherrington in The Journal of Clinical Investigation point out that another hormone—glucagon—is also very important in regulation of blood sugar in both types of diabetes.

Insulin has a variety of actions the ultimately keep blood sugar levels from rising dangerously high. Glucagon, on the other hand, keeps blood sugar from dropping too low. For instance, when you stop eating food, as in an overnight or longer fast, glucagon stimulates glucose (sugar) production by your liver so you don’t go into a hypoglycemic coma and die. It does the same when you exercise, as your muscles soak up glucose from your blood stream.

Glucagon works so well to raise blood sugar that we inject it into diabetics who are hypoglycemic but comatose or otherwise unable to swallow carbohydrates.

Glucagon also has effects on fatty acid metabolism, ketone production, and liver protein metabolism, but this post is already complicated enough.

So where does glucagon come from? The islets of Langherhans, for one. You already know the healthy pancreas has beta cells that produce insulin. The pancreas has other cells—alpha or α cells—that produce glucagon. Furthermore, the stomach and duodenum (the first part of the small intestine) also have glucagon-producing alpha cells. The insulin and glucagon work together to keep blood sugar in an fairly narrow range. Insulin lowers blood sugar, glucagon raises it. It’s sort of like aiming for a hot bath by running a mix of cold and very hot water.

Update: I just licensed this from

Update: I just licensed this from

Ungar and Cherrington say that one reason it’s so hard to tightly control blood sugars in type 1 diabetes is because we don’t address the high levels of glucagon. The bath water’s not right because we’re fiddling with just one of the faucets. Maybe we’ll call this the Goldilocks Theory of Diabetes.

When you eat carbohydrates, your blood sugar starts to rise. Beta cells in the healthy pancreas start secreting insulin to keep a lid on the blood sugar rise. This is not the time you want uncontrolled release of glucagon from the alpha cells, which would work to raise blood sugars further. Within the pancreas, beta and alpha cells are in close proximity. Insulin from the beta cells directly affects the nearby alpha cells to suppress glucagon release. This localized hormone effect is referred to as “paracrine guidance” in the quote below, and it takes very little insulin to suppress glucagon.

From the Ungar and Cherrington article:

Here, we review evidence that the insulinocentric view of metabolic homeostasis is incomplete and that glucagon is indeed a key regulator of normal fuel metabolism, albeit under insulin’s paracrine guidance and control. Most importantly, we emphasize that, whenever paracrine control by insulin is lacking, as in T1DM, the resulting unbridled hyperglucagonemia is the proximal cause of the deadly consequences of uncontrolled diabetes and the glycemic volatility of even “well-controlled” patients.

*  *  *

All in all, it would seem that conventional monotherapy with insulin is incomplete because it can provide paracrine suppression of glucagon secretion only by seriously overdosing the extrapancreatic tissues.

So What?

Elucidation of diabetes’ disease mechanisms (pathophysiology) can lead to new drugs or other therapies that improve the lives of diabetics. A potential drug candidate is leptin, known to suppress glucagon hyper secretion in rodents with type 1 diabetes.


Steve Parker, M.D.

PS: Amylin is yet another hormone involved in blood sugar regulation, but I’ll save that for another day. If you can’t wait, read about it here in my review of pramlintide, a drug for type 1 diabetes.


Filed under Causes of Diabetes

10 responses to “Could Glucagon Be Just as Important as Insulin in Diabetes?

  1. larry r

    any impact on type 2?

  2. Virginia

    How can I keep my BS down in the mornings after waking after sleeping?

    • Good question for your personal physician, who knows your case intimately. In general, options include exercise in the morning, metformin at bedtime, eat less in the evening, adjust other diabetes drugs, etc.

    • I frequently recommend that my clients eat a solid fat at bedtime such as 1oz macadamia nuts or 1/2-1 avocado. These fats don’t stimulate a great insulin spike and subsequent drop, but tend to hold blood sugars more steady through the night.

  3. “deadly consequences of uncontrolled diabetes and the glycemic volatility of even “well-controlled” patients.”

    So I’m Type I on Dr. Bernstein’s diet for 17 years and my HbA1c is 5% – I have no complications. What am I missing? Where’s my glycemic volatility?

    It seems to me that a more fitting interpretation is that “conventional monotherapy with insulin is incomplete because” the accompanying high carb diet constantly replenishes liver glycogen which encourages glycogenolysis and high blood sugar. The low carb diet depletes glycogen and allows diabetics to enjoy normal blood sugars (Allick 2004) in spite of elevated glucagon.

    I think mainstream diabetes clings to the high carb diet to preserve it’s support from the drug industry – how long will the slaughter continue?

  4. Mrs Vimes

    For years I had my blood sugars under control. Then, my sugars of a morning began to increase no matter what I did. I had absolutely no clue. I was in work with blood sugars in the high teens and once at 25mmol/L. Eventually after hours with Dr Google I found out about Dawn Phenomenon. Took my blood sugar readings as evidence to the hospital- long story short- got on a pump. Now I’m in the 5% club whereas before I was high 6s. The hospital where telling me at the start that I was sleeping through hypos and it was a rebound effect. Not once was DP mentioned. I find information is kept to the lowest common denominator of intelligence. If we knew more then treatment costs may increase. I don’t believe it is done maliciously though. Staff are overworked.

  5. From WebMD:

    “Dawn phenomenon
    The dawn phenomenon is a normal rise in blood sugar as a person’s body prepares to wake up.
    In the early morning hours, hormones (growth hormone, cortisol, and catecholamines) cause the liver to release large amounts of sugar into the bloodstream.”

    Go lowcarb, and the liver is depleted of glucagon so it won’t release so much sugar (Allick 2004 –

    You get what you pay for at WebMD, useless dogma.