A big fat introduction to fat

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It is common knowledge that if you become overweight your chances of getting diabetes increases. Why? What is the relationship between fat and diabetes? As it happens, the relationship is deep and complex and well worth discussing. Fat affects both those who might develop diabetes sometime in that fuzzy future as well as those dealing with diabetes in the hard present.

Before we start we need to introduce a bit of biochemistry and cell biology. Sorry. The problem is that the word “fat” can mean so many different things. Tissue which we refer to as fat is made up of cells called adipocytes. Of course, one of the things they do is store fat. Fat (the stored molecule) is actually a good thing if you do not have a steady food source. It is the most concentrated form of energy storage available to our bodies and so it is a great way to store food derived energy inside the body for the bad times that are sure to come. Another name for that wonderful molecule that stores so much energy is a “triglyceride”. If we break that triglyceride apart, we get 3 smaller molecules of fat called fatty acids (FA). These are long chains of carbons. The 3 are bound together by a tiny 3 carbon molecule called glycerol; hence the name triglyceride. Don’t fall asleep, we are almost done. Butters, oils, etc are made up of these long chain FAs. when they get stored in cells they are stored as triglycerides. Hopefully this will keep things straight.

We are addicted to fat. This makes sense when we think about where we came from. Hunter gatherers did not have a steady food source and when they had the chance to take in a nice big fatty meal, those primitive cravings made them partake of the meal even if they were not all that hungry right then. They would be hungry again soon enough given the vagaries of hunting. Now, with a surplus of food and fatty meals available for incredibly cheap prices, this craving has become a curse.

Once it became clear that being overweight was a risk factor for developing type 2 diabetes, it made sense for researchers to begin looking for differences in how overweight people responded to insulin. Almost immediately, they hit the jackpot. Being overweight was highly correlated with increased insulin resistance; another major risk factor for developing type 2 diabetes. Conversely, losing weight resulted in a restoration of insulin sensitivity (decreased insulin resistance).

What do we mean by insulin resistance? As I have written before in this blog, insulin is the hormone that gets the body ready to deal with the influx of nutrients during a meal. It promotes glucose storage. Additionally, as a separate matter, it blocks the synthesis of new glucose in the liver (a process called gluconeogenesis). This is pretty important as liver derived glucose is a major source of blood glucose for the diabetic person trying to control blood sugar levels. Storing glucose involves getting it out of the blood quickly and into tissues. If we think about the ebb and flow of glucose currents in the body it turns out that the vast majority (approximately 80%) passes into muscle. Thus muscle tissue is the great glucose sponge of the body and, as it absorbs glucose in response to insulin, this is the tissue most sensitive to changes in insulin resistance. Generally, insulin resistance is measured as the lack of ability of a known quantity of insulin to get a known quantity of glucose out of the blood in some specific period of time. It can easily be measured by giving the patient a sugar pill and then taking blood samples over the course of a couple of hours. Insulin levels and glucose levels are measured and from this the level of insulin resistance is determined.

What isit about being overweight that screws up the ability of insulin to do its job? This is a big question and while we now know quite a lot we still do not have the whole story. One obvious thing to look at was the presence of fat in the blood stream. When normal healthy non-obese volunteers were administered an exact amount of FA intravenously, they became insulin resistant. (I should mention that when FAs are floating freely around in the blood, they are called “free fatty acids”, FFA). Also, since what was being measured was the ability of insulin to clear glucose from the blood and since skeletal muscle is the main tissue that functions as the “glucose sponge” it was pretty certain that muscle tissue would be a good place to look for the mechanism. It was observed in the experiments I just described that it took about 3 hours for insulin resistance to develop after the injection of FFA into the blood stream. Since it took about 3 hours for FFA to get absorbed by muscle (and stored as triglycerides), researchers decided to test the hypothesis that FFA worked inside of the muscle cell. Indeed, all sorts of subsequent experiments generated data consistent with this idea. For example, if one genetically engineers a mouse to store more FFA as triglycerides within the muscle cells, that mouse is insulin resistant. Furthermore, when volunteers’ muscle biopsies were examined for triglyceride content, it was found that their degree of insulin resistance correlated strikingly well with the amount of triglyceride within the muscle cells.

Showing that muscle triglycerides correlated with insulin resistance does not prove that the triglycerides themselves are directly responsible for insulin resistance but it certainly is one possibility. Another possibility is that increasing the amount of triglycerides inside a muscle cell might alter some other aspect of the muscle cell rendering it less able to respond to the insulin signal. We do not know whether one or both of these possibilities are correct. However, it is possible to begin to forge a path; a biochemical chain of events, from triglycerides to insulin resistance.

Starting at the insulin receptor; it sits in the cell membrane with half sticking out of the cell to bind to insulin and half sticking into the cytoplasm of the cell to transmit the signal. The insulin receptor is actually an enzyme. When insulin binds on the outside, the shape of the receptor changes in a subtle fashion such that the enzymatic activity within the cell is now turned on. Enzymes require substrates and the insulin receptor has special proteins that bind just inside the cell. These insulin receptor substrates (IRS) get modified by the insulin receptor and, in turn, change their shape. Certain other proteins then find that these IRS proteins have become excellent binding sites and begin the process of creating a molecular machine that will do all sorts of things. That is the normal course of events that occur when the insulin signal appears.

However, IRS proteins are not just substrates for the insulin receptor enzyme activity. They are actually substrates for a number of other enzymes. These other enzymes modify IRS proteins in a different way such that the shape is no longer conducive for the formation of the molecular machine. As it turns out, increased triglycerides can activate some of these other enzymes. Thus are we beginning to forge that chain of events which will take us from triglycerides to insulin signaling.

What we have learned is that IRS proteins are points of regulation of insulin signaling strength. They may, perhaps, be the key to understanding how to help patients regain their sensitivity to insulin. This will help those that make their own insulin as well as those that must inject their insulin. The details of these events are quite beautiful and I will try to describe them in subsequent posts.

In the meantime, I will leave you with the following observation. When you exercise, insulin sensitivity improves. As little as 15 minutes of exercise can increase insulin sensitivity and the more you exercise the better it gets. Muscles burn those triglycerides as fuel during exercise and also begin to take up glucose in the absence of insulin. Exercise is one key behavior that will change everything. As someone who has been diagnosed as prediabetic, I did not really change my eating habits all that much. I increased my exercise. As of my last doctor appointment, I am no longer prediabetic. Now my father was thin as a rail and got type 2. So did all of his brothers. My BMI is good so it is not that I am dealing with a weight issue (although I would like to lose 10 pounds). Rather, I am fighting genetics. Nevertheless, exercise will probably stave off my diabetes for one or more decades. Mobilizing muscle triglycerides is an essential process for all of us if we are to fight the diabetes pandemic. So, stop reading this article and go out and play!

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CkoeiRobert ScheinmanLarry Matthewsrebecca Recent comment authors
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Ckoei
Ckoei

So the release of FFAs when hyper- and hypoglycaemic is  like fat and water on fire?
(Does the “free” in “free fatty acid” only refer to escape from glycerolic bondage? Because FFAs are technically speaking still the prisoners of an apoprotein. And what happens when these prison ships get to the blood-brain-barrier: they’re a bit too big&clunky to pass;  does it mean the brain produces all of its fats de novo from glucose? )

Larry Matthews
Larry Matthews

I’m not sure I had ever seen an explanation of triglycerides and how they are formed and the percentage in the body that is stored in muscles. When you are tested for a physical, my assumption is that the number they give you is in your blood. Is the level in the blood also indicative of the level in your muscles? Could the reading in a Dr’s office change substantially if a patient exercised vigorously for 1-1.5 hours about 4-6 hours before a visit for testing. This might give us a view as to whether the issue is with diet… Read more »

rebecca
rebecca

great motivation for my new year’s resolution to get fit!  thank you.

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