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Completely Novel Action Of Insulin Unveiled

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Newsmaker
Can I control my appetite and my hunger?
In general appetite is a learned response. It can be adaptive to stimuli and environmental factors and variable. Stress, emotional and psychological variables will result in behavioral changes, thus changes in appetite.
In contrast, hunger is an physiological response. It is an inborn behavior, common to all animals. It is a need based derive.
We can control our appetite, but not our hunger.
Ara Keshishian, MD, FACS

Completely Novel Action Of Insulin Unveiled
A Ph.D. student at Sydney's Garvan Institute of Medical Research has uncovered an important piece in the puzzle of how insulin works, a problem that has plagued researchers for more than 50 years. The research brings scientists one step closer to explaining exactly how insulin prompts fat and muscle cells to absorb glucose.

"Since the 1920s, when Banting and Best discovered insulin, scientists have been battling to discover how it actually works," said Professor David James, head of Garvan's Diabetes Program. "Then along comes Freddy Yip, doing his PhD, who unveils a completely novel action of insulin, one which we believe plays a fundamental role in glucose uptake, a process that is defective in Type 2 diabetes." There are two processes involved in Type 2 diabetes: insufficient production of insulin in the pancreas after a meal and faulty uptake and storage of glucose in fat and muscle cells, or 'insulin resistance'.

Freddy's finding focuses on the intersection between these two processes. "In the cell we have seriesof motor proteins that have the ability to move other molecules from one place to another along intracellular rail road tracks," he explained. "I have discovered that insulin activates a specific kind of motor protein known as Myo1c, which in turn performs a critical role in glucose uptake." Insulin controls glucose uptake into our fat cells by moving glucose transporter proteins from inside the cell to the surface membrane so that they can pump glucose into the cell. Myo1c aids in this process by helping the
transporters slide into the surface membrane.

In healthy people, around 80% of the glucose transporters migrate to the cell membrane after a meal, allowing plenty of glucose into the cell. In people with Type 2 diabetes, however, that figure drops to around 10%. Freddy Yip believes his study will create a strong foundation for future diabetes research. "We knew before that Myo1c was somehow involved in the regulation of glucose transport. My research indicates that Myo1c is a major target of insulin action and helps to accelerate the delivery of transporters to the membrane," he said. "We think there may be blockages in the signal between insulin and myo1c in people who develop insulin resistance. If we're correct, it should be possible to target that pathway for development of new therapies."

Professor James sees the finding as a welcome milestone on a very long road of discovery. "While we're certainly not saying we've found a way to cure diabetes, we are saying we've found a pretty significant clue."

Treatment of diabetes and weight gain: A vicious cycle

There is a common concern that some oral agents or insulin can cause weight gain.

What insulin does to the body:

1. Regulates the liver from releasing too much glucose (I like to say that insulin leans up against the door of the liver and only lets a little glucose out at a time).
2. Acts as a "doorman, or key" to open the doors of the cells and allow glucose to enter the cells.
3. Acts as a storage promoter, to store extra glucose back into the liver, along with the muscles, while the excess is stored as fat.

The person without diabetes:
So as a person without diabetes, whenever I overeat, my pancreas automatically releases extra insulin to take care of my extra food intake; if I don't exercise it off, that excess food gets stored as fat and I gain weight. Remember Rhoda on the Mary Tyler Moore Show? To paraphrase her comment, she said "don't bother giving me that candy bar-just apply it directly to my hips, since that's where it will eventually end up!"

The person with diabetes:
In contrast, with diabetes, if you don't have enough insulin, then when you overeat, not all the food can enter the cells (to store in the liver and muscles, with the excess stored as fat); some of the glucose from your food just piles up in the blood, and gets urinated out-what I call a "false" weight loss/weight control.

What insulin does to the body:
If your diabetes were out of control for awhile, you were losing weight without trying; then as your blood glucose improved from taking diabetes medication, this would mean that instead of urinating out your food/calories, you were now able to retain your food and use it as energy (as well as store the excess in muscle and fat). The long-term studies proving that good diabetes control matters (i.e. the DCCT and UKPDS) also showed that people gained weight as their control improved. Despite the fact that losing weight and exercising are the keys to decreasing the risk of developing type 2 diabetes or to controlling diabetes and decreasing the risk of heart disease, experts have also agreed
that:

1. controlling glucose is important, even if it means gaining some desirable weight (the average weight gain in the DCCT was 10 pounds);
2. certain diabetes medications may not cause as much weight gain as others;
3. careful meal planning and exercise can help to limit the weight gain.

Overeating:
True, if you are overeating and/or not exercising enough, and are thus requiring more oral agents or insulin, then you will gain weight because the diabetes medication is supporting your excess food intake. In the April, 2002 issue of Diabetes Forecast, Sheldon Gottlieb, MD addressed the issue of diabetes medication and weight gain, and commented that some people use insulin as a "carbohydrate credit card." I hope you get my point that in this instance, the diabetes medication itself did not cause weight gain, but rather the excess calories did.

Insulin sensitizers (Thiazolidinediones) and weight gain:
These drugs (trade names Actos® and Avandia®), which are used in treating insulin resistance, also are associated with weight gain. They interact with a receptor in tissue that may convert it into fat cells, although how this occurs is not yet well understood. Despite the weight gain, this class of drugs is associated with improved cardiovascular function. To limit the weight gain, the drug Metformin (trade name Glucophage®) is often added.

Insulin and weight gain:
Generally, we tend to say that people might be prone to gain more weight on insulin, rather than on oral agents. But in addition to the issues discussed above, another common reason for weight gain is often related to the actual insulin regimen one is oni. e. if you take pre-mixed, intermediate, or long-acting insulin twice daily, you are forced to eat on time, to avoid skipping meals, and to anticipate exercise by taking an extra snack or decreasing your insulin, etc.-and this restricted regimen makes it harder to control weight. Often, using a rapid-acting insulin with each meal, with a bedtime dose of Lantus or NPH, or using an insulin pump, combined with careful diet and exercise, will allow you more flexibility in your lifestyle and an easier time controlling weight.

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