Shining light on the hexosamine pathway

[Evermont]

Novel Link Between Excessive Nutrient Levels And Insulin Resistance Uncovered

ScienceDaily (http://www.sciencedaily.com/releases/2008/02/080221143325.htm) (Feb. 24, 2008) — For quite some time now, scientists suspected the so-called hexosamine pathway -- a small side business of the main sugar processing enterprise inside a cell -- to be involved in the development of insulin resistance. But they could never quite put their finger on the underlying mechanism.

Now, researchers at the Salk Institute for Biological Studies have uncovered the long-missing molecular link: the enzyme OGT (short for O-linked ß-N-acetylglucosamine transferase), the last in a line of enzymes that shuttle sugars through the hexosamine pathway.

Their study revealed that OGT slams the brake on insulin signaling soon after insulin fires up the machinery that pulls glucose from the blood stream and squirrels it away inside liver or stashes the surplus energy in fat pads.

"For the first time we have a real understanding of how the insulin signaling system is turned on and off," says Howard Hughes Medical Investigator Ronald M. Evans, Ph.D., a professor in the Salk Institute's Gene Expression Laboratory, who led the study that appears in the Feb. 21 issue of Nature.

He hopes that "this could lead to a new class of insulin-sensitizing drugs that loosen the brake and let insulin work a little bit longer."

When insulin binds its receptor on the cell surface it sets off a cascade of intracellular signals resulting in the production of PIP3, a specialized lipid molecule that masterminds a whole army of molecules that work together to synthesize and store carbohydrates, lipids and proteins. "But turning on a physiological process is only half the story," explains Evans. "You also need instructions that tell the cell to get off the accelerator and put on the brake."

Postdoctoral researcher and first author Xiaoyong Yang, Ph.D., discovered that PIP3 oversees both. His experiments revealed that within minutes activation of the insulin signaling network coaxes OGT out of the nucleus and into the cytoplasm. It travels to the plasma membrane and hooks up with PIP3.

"It uses a novel PIP3 binding domain to interact with the same lipid that just turned on the system," describes Xiaoyong. "After OGT is recruited to the plasma membrane it starts turning off the system."

It accomplishes this task by tagging key members of the insulin signaling network with sugar molecules, specifically O-linked ß-N-acetylglucosamine or O-GlcNAc, which are produced by the hexosamine pathway.

Since the amount of O-GlcNAc is directly tied to availability of glucose, lipids and other nutrients in the bloodstream, the researchers believe that the hexosamine pathway acts as fuel gauge, protecting the body's cells against the toxic effects of too much glucose and other high-energy molecules.

Excessive quantities of nutrients -- the result of a lifestyle where food is plentiful and exercise is optional -- drive O-GlcNAc levels up, which in turn dampen the insulin response, paving the way for a relentless progression of insulin resistance.

Though it may not be as simple as that, when Xiaoyong put OGT into overdrive in the livers of mice, the animals developed insulin resistance and abnormal blood lipid levels, emphasizing the importance of the hexosamine pathway for the development of insulin resistance, the first step towards full-blown type 2 diabetes.

Most people with insulin resistance go on to develop type 2 diabetes within 10 years, unless they lose 5 to 7 percent of their body weight--approximately 10 to 15 pounds for someone who weighs 200 pounds--by making modest changes in their diet and level of physical activity. But making permanent lifestyle changes is difficult and studies predict that one in three Americans born in the year 2000 will develop diabetes in their life time. A similar fate awaits most developed nations.

Researchers who contributed to the study include Joyce C. Havstad in the Evans laboratory, Pat P. Ongusaha at the Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, Philip D. Miles, Seth J. Field and Jerrold M. Olefsky at University of California, San Diego, Jeffrey E. Kudlow and Fengxue Zhang at University of Alabama, Birmingham, W. Venus So at Hoffmann-La Roche, Inc., Nutley, New Jersey and Robert H. Michell at the University of Birmingham, Birmingham, United Kingdom.

Adapted from materials provided by Salk Institute.

(link (http://www.sciencedaily.com/releases/2008/02/080221143325.htm))

[BlueSky]

Interesting article. But it raises a difficult question. Essentially they are saying that eating too much carbo causes insulin resistance. But they are now saying that they want to develop drugs that will interrupt the pathway through which this happens. Presumably, this will result in muscle cells accepting glucose that they can't use. So what are these cells going to do with this excess glucose, and what kind of damage might it do?

[xMenace]

Interesting article. But it raises a difficult question. Essentially they are saying that eating too much carbo causes insulin resistance. But they are now saying that they want to develop drugs that will interrupt the pathway through which this happens. Presumably, this will result in muscle cells accepting glucose that they can't use. So what are these cells going to do with this excess glucose, and what kind of damage might it do?


Mmmm. The studies, if they happen, should be interesting.

Does this explain why when we have very high blood sugars our normal correction doses don't seem to work as well?

[BlueSky]

... Does this explain why when we have very high blood sugars our normal correction doses don't seem to work as well?
That effect certainly is consistent with the process described in the article. It also explains how glucose either gets used or stored as fat. Activation of this pathway is presumably staggered across different types of cell. As blood glucose rises, the door is first shut in organ cells to protect them from the toxic effects of excess glucose. Next the muscles restrict entry of glucose they can't use, and any excess glucose that is left ends up being stored in fat cells. It is an effective and efficient system that enables us to store energy.

Attempts to undermine this process by taking away the ability of cells to resist insulin action sounds like a bad idea to me. What are our organs and muscles going to do with the excess glucose? I guess they could also store it as fat. In addition to fatty livers, there will also be fatty hearts, fatty lungs, fatty kidneys and fatty muscles :eek: .

[morrisma]

May not make an effective therapy directly but the better understanding could certainly pave the way for some interesting knowledge gathering. It may be that variations of the enzyme could selectively open or close the pathway or provide a way to shunt excess glucose away entirely by binding it up. Could be some real weight-loss-in-a-pill possibilities down the road. The holy grail of drugs!
Mike

[REDLAN]

it's an interesting article - there are some unsupportable hypotheses from the data - particularly the over-eating and not taking exercise causes insulin resistance.

This is fine if you ignore certain things - like the insulin resistance in type 2 is not insulin resistance as such rather it is a loss of flexibility - in ordinary individuals there is a natural variation in insulin resistance - it rises as you fast, and drops when you eat. People with type 2 lose this adaptability - they experience less variation of insulin resistance throughout the day.

and I still find the glucose is toxic argument rather absurd - I'd really like someone to prove this. Glucose toxicity takes a rather long time to kill cells. I'm more convinced by the idea that glucose regulation is more to do with energy balance and ensuring that the energy of food is efficiently distributed between various organs and tissues.

the results of the study actually show that raised OGT levels cause insulin resistance. What the study does NOT show is that insulin resistance typical in type 2 is caused by raised OGT. The 2 contentions are completely different.

It's fascinating for me, because back in the days when I did biochem, no one had any idea that sugars were so important to cell function. Everyone thought they were just there for energy. They knew that sugars were important in plant structures - (plants are pretty much made from sugars), just not in animals. It was believed that animal cell structure came entirely from proteins wedged into cholesterol and fat. Then they started to discover that animal cells spent a good deal of their time sticking sugars on proteins, and here with the hexosamine pathway we see how it can be used to regulate cell processes.

For those who didn't understand all the O-linked ß-N-acetylglucosamine or O-GlcNAc stuff, essentially what happens is that the enzymes in the hexosamine pathway stick sugars to the proteins involved in insulin signalling. This changes their shape, and stops them functioning, so when insulin binds to the cell, it's signal is weakened, less GLUT4 migrates to the surface, less glucose is taken up by the cell.

the point is the more glucose that is available in the cell the more glucose that can be stuck to these proteins, and the weaker the insulin signal becomes - in essence you have a classic biological negative feedback system.

there are things I don't understand - such as the hexosamine pathway also uses fructose - I thought fructose was converted to glucose and/or fat by the liver - this is interesting because animals can't synthesise fructose.

{I have also to confess that I haven't the faintest idea what O-linked ß-N-acetylglucosamine or O-GlcNAc actually is either but I don't think it matters much}

It potentially explains some phenomenon, such as how muscle cells become insulin resistant with a high fat diet.

And the best bit is, you now have an answer to anyone who says that sugar is empty calories :D

[BlueSky]

.... Excessive quantities of nutrients -- the result of a lifestyle where food is plentiful and exercise is optional -- drive O-GlcNAc levels up, which in turn dampen the insulin response, paving the way for a relentless progression of insulin resistance. ...
This makes a strong argument for reducing portion sizes. But it doesn't explain how thin people become insulin resistant, or how reducing weight increases insulin sensitivity.:confused:

[Evermont]

This makes a strong argument for reducing portion sizes. But it doesn't explain how thin people become insulin resistant, or how reducing weight increases insulin sensitivity.:confused:

Often answers beget more questions. If there's any solace for us perhaps it is that our questions improve. :questionm

It's becoming clear to me that I'm in dire need of some biochemistry and molecular biology classes myself.

It seems to me though, that with all these highly complex topics there is always this desire for simplified models and explanations leading to basic day-to-day recommendations that real people can put into practice. Then there's this reality of underlying complexity that always messes things up. Argh! :hmmmm: It would not surprise me to learn that there is more than one kind of insulin resistance - I think you're almost saying that yourself.

[morrisma]

... It would not surprise me to learn that there is more than one kind of insulin resistance ...

Indeed, this seems likely the case. They may have found one mechanism but that doesn't mean there are no others. Then there's the "1.5" issue where you get a mix of causes that make it difficult to determine the root(s) of the thing.

I wouldn't mind a little bio-chem classwork myself. It would certainly make understanding the tech work easier. Just need a spare 10 hours a week - that ought to do it!
Mike

[REDLAN]

But it doesn't explain how reducing weight increases insulin sensitivity.

suspect that it is by a different mechanism - in the same way that cells have an I'm full signal via the hexosamine pathway, they also have an I'm empty system too.

This is driven by AMP activated kinase - this enzyme is extremely sensitive to AMP concentration within the cell. Essentially the cells use an energy carrier called Adenosine Tri-phosphate - you have an amino acid Adenosine with 3 phosphate groups bonded to it. Breaking a phosphate group releases energy, and gives you ADP, Breaking another phosphate bond gives you Adenosine Mono phosphate. so....

low energy states switch this enzyme on. One of it's actions is to increase the expression of GLUT4 by the cell. More GLUT4 means that more glucose is absorbed by the cell in the presence of insulin ergo the cell becomes more insulin sensitive.

AMP activated Kinase expression by the cell is influenced by various cytokines (cell signalling proteins), such as Adiponectin secreted by fat cells increases the expression of AMP activated Kinase. And...

adiponectin levels are known to rise dramatically when you restrict calorie intake. (although this does not always happen)
with some groups of people)

This hypothesis is a long way from being verified it is only believed to be the case. The hexosamine pathway is still very much at the hypothesis stage.