Tag Archives: glucagon

Is Diabetes Caused by Poor Regulation of Glucagon?

From Shutterstock.com

Glucagon is produced in the alpha cells and works to increase blood sugar levels. Insulin is from the beta cells.

Most folks assume that the hormone called insulin is at the heart of diabetes: either there’s not enough of it or it’s not working right.

But thats’s not the only possible mechanism for diabetes. I’ve written several times here about the glucagon-centric theory of diabetes, which is most closely associated with Roger Unger, M.D. If you’re interested in a scientific review article on glucagon and type 2 diabetes, here’s one:

Reference: Xiao C. Li and Jia L. Zhuo. Current Insights and New Perspectives on the Roles of Hyperglucagonemia in Non Insulin-dependent Type 2 DiabetesCurrent Hypertension Reports. Oct 2013; 15(5): 10.1007/s11906-013-0383-y.  doi: 10.1007/s11906-013-0383-y

Steve Parker, M.D.

low-carb mediterranean diet

Front cover of book


Filed under Causes of Diabetes

Dr. Roger Unger and his Glucagon-Centric Diabetes Model

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.

From Shutterstock.com

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


Filed under Causes of Diabetes

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 Shutterstock.com

Update: I just licensed this from Shutterstock.com

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

You Know About Insulin. And Now, the REST of the Story . . .

When we digest carbohydrates, blood sugar rises.  If it goes too high it causes problems.  Everybody knows that insulin lowers blood sugar levels, right?  Less well-known is that regulation of blood sugar is the result of complex interactions of multiple hormones, not just insulin.

[As is my habit, I will use “sugar” and “glucose” interchangeably in this post.] 

Allow me to review the main hormones involved in blood glucose regulation:

1. Insulin is made and stored in pancreas beta cells.  As a meal is digested, blood sugar rises; the pancreas releases insulin to bring blood sugar back down by driving it into cells.

2. Amylin is also made and stored in pancreas beta cells and works to reduce blood sugar levels.  Blood levels of amylin rise and fall in concert with insulin levels.  Amylin slows emptying of the stomach, reduces food consumption, and regulates another hormone—glucagon—after meals.

3. Glucagon is from pancreas alpha cells.  It works to raise blood sugar by promoting the liver’s breakdown of glycogen into glucose, and by promoting the liver’s manufacture of new glucose molecules.

4. Glucagon-like peptide -1 (GLP-1) is produced in small intestine cells and it’s main action is to promote insulin secretion by the pancreas beta cells after absorption of food, which lowers blood sugar levels.  GLP-1 (like amylin) also inhibits emptying of the stomach, inhibits glucagon release, and inhibits appetite, all of which would tend to keep a lid on blood sugar levels. 

5. Gastric inhibitory polypeptide (GIP) promotes secretion of insulin following absorption of food.  GIP is also known as glucose-dependent insulinotropic polypeptide.

You can see that some hormonal mechanisms raise glucose levels; others lower glucose levels.  Homeostasis is all about reaching a happy medium between the two, without wild swings one way or the other.  In healthy people, eating food leads to release of gastrointestinal peptides (GLP-1 and GIP), insulin, and amylin.  The interaction among them keeps blood sugar levels in a fairly level low range.  In diabetes, one or more malfunctions in the system leads to abnormally high blood sugars.

The good news is that scientists have used this knowledge to devise new, effective treatments for diabetes.  Examples are GLP-1 analogues and DPP-4 inhibitors.

Steve Parker, M.D.

PS:   In lab animals, GLP-1 stimulates formation of new pancreas beta cells, so it hold promise in halting the progressive beta cell failure characteristic of type 2 diabetes.


Filed under Carbohydrate, Causes of Diabetes