Tag Archives: Roger Unger

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.

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

If You Have Diabetes, You Need to Know About Glucagon

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.

Dr. Roy Taylor on the Cause of Type 2 Diabetes and What To Do About It

diabetic diet, low-carb Mediterranean Diet, low-carb, Conquer Diabetes and Prediabetes

Warning: this is a sciencey post

According to Roy Taylor, M.D., “type 2 diabetes is a potentially reversible metabolic state precipitated by the single cause of chronic excess intraorgan fat.” The organs accumulating fat are the pancreas and liver. He is certain “…that the disease process can be halted with restoration of normal carbohydrate and fat metabolism.” I read Taylor’s article published last year in Diabetes Care.

(Do you remember that report in 2011 touting cure of T2 diabetes with a very low calorie diet? Taylor was the leader. The study involved only 11 patients, eating 600 calories a day for eight weeks.)

Dr. Taylor says that severe calorie restriction is similar to the effect of bariatric surgery in curing or controlling diabetes. Within a week of either intervention, liver fat content is greatly reduced, liver insulin sensitivity returns, and fasting blood sugar levels can return to normal. During the first eight weeks after intervention, pancreatic fat content falls, with associated steadily increasing rates of insulin secretion by the pancreas beta cells.

bariatric surgery, Steve Parker MD

Band Gastric Bypass Surgery (not the only type of gastric bypass): very successful at “curing” T2 diabetes if you survive the operation

Taylor’s ideas, by the way, dovetail with Roger Unger’s 2008 lipocentric theory of diabetes. Click for more ideas on the cause of T2 diabetes.

Here are some scattered points from Taylors article. He backs up most of them with references:

  • In T2 diabetes, improvement in fasting blood sugar reflects improved liver insulin sensitivity more than muscle insulin sensitivity.
  • The more fat accumulation in the liver, the less it is sensitive to insulin. If a T2 is treated with insulin, the required insulin dose is positively linked to how much fat is in the liver.
  • In a T2 who starts insulin injections, liver fat stores tend to decrease. That’s because of suppression of the body’s own insulin delivery from the pancreas to the liver via the portal vein.
  • Whether obese or not, those with higher circulating insulin levels “…have markedly increased rates of hepatic de novo lipogenesis.” That means their livers are making fat. That fat (triglycerides or triacylglycerol) will be either burned in the liver for energy (oxidized), pushed into the blood stream for use elsewhere, or stored in the liver. Fatty acids are components of triglycerides. Excessive fatty acid intermediaries in liver cells—diglycerides and ceramide—are thought to interfere with insulin’s action, i.e., contribute to insulin resistance in the liver.
  • “Fasting plasma glucose concentration depends entirely on the fasting rate of hepatic [liver] glucose production and, hence, on its sensitivity to suppression by insulin.”
  • Physical activity, low-calorie diets, and thiazolidinediones reduce the pancreas’ insulin output and reduce liver fat levels.
  • Most T2 diabetics have above-average liver fat content. MRI scans are more accurate than ultrasound for finding it.
  • T2 diabetics have on average only half of the pancreas beta cell mass of non-diabetics. As the years pass, more beta cells are lost. Is the a way to preserve these insulin-producing cells, or to increase their numbers? “…it is conceivable that removal of adverse factors could result in restoration of normal beta cell number, even late in the disease.”
  • “Chronic exposure of [pancreatic] beta cells to triacylglycerol [triglycerides] or fatty acids…decreases beta cell capacity to respond to an acute increase in glucose levels.” In test tubes, fatty acids inhibit formation of new beta cells, an effect enhanced by increased glucose concentration.
  • There’s a fair amount of overlap in pancreas fat content comparing T2 diabetics and non-diabetics. It may be that people with T2 diabetes are somehow more susceptible to adverse effects of the fat via genetic and epigenetic factors.
  • “If a person has type 2 diabetes, there is more fat in the liver and pancreas than he or she can cope with.”
  • Here’s Dr. Taylor’s Twin Cycle Hypothesis of Etiology of Type 2 Diabetes: “The accumulation of fat in liver and secondarily in the pancreas will lead to self-reinforcing cycles that interact to bring about type 2 diabetes. Fatty liver leads to impaired fasting glucose metabolism and increases export of VLDL triacylglcerol [triglycerides], which increases fat delivery to all tissues, including the [pancreas] islets. The liver and pancreas cycles drive onward after diagnosis with steadily decreasing beta cell function. However, of note, observations of the reversal of type 2 diabetes confirm that if the primary influence of positive calorie balance is removed, the the processes are reversible.”
diabetic diet, etiology of type 2 diabetes, Roy Taylor, type 2 diabetes reversal

Figure 6 from the article: Dr. Taylor’s Twin Cycle Hypothesis of Etiology of Type 2 Diabetes

  • The caption with Figure 6 states: “During long-term intake of more calories than are expended each day, any excess carbohydrate must undergo de novo lipogenesis [creation of fat], which particularly promotes fat accumulation in the liver.”
  • “The extent of weight gloss required to reverse type 2 diabetes is much greater than conventionally advised.” We’re looking at around 15 kg (33 lb) or 20% of body weight, assuming the patient is obese to start.  “The initial major loss of body weight demands a substantial reduction in energy intake. After weight loss, steady weight is most effectively achieved by a combination of dietary restriction and physical activity.”

Dr. Taylor doesn’t specify how much calorie restriction he recommends, but reading between the lines, I think he likes his 600 cals/day for eight weeks program. That will have a have a high drop-out rate. I suspect a variety of existing ketogenic diets may be just as successful and more realistic, even if it takes more than eight weeks. I wonder how many of the 11 “cures” from the 2011 study have persisted.

Steve Parker, M.D.

Reference: Taylor, Roy. Type 2 diabetes: Etiology and reversibility. Diabetes Care, April 2013, vol. 36, no. 4, pp:1047-1055.

Update: Some wild and crazy guys tried the Taylor method at home. Click for results.