Metabolic Syndrome & Diabetes: what you can do to avoid it? Start with Sugar.

Metabolic Syndrome starts when you are young. Too Much Sugar Man!

In your 30s, 40s or 50s and overweight? If so, you could be on your way to developing diabetes, heart disease, and atherosclerosis. You are also increasing your overall risk for developing various cancers, but the diabetes and circulatory problems are the big risks you need to worry about.

This picture shows something we call glycated-hemoglobin from normal and diabetic blood samples. You can actually it see bound to these lab test columns (the red color in the middle and right test columns). These are test columns in a rack on the bench in my own laboratory at Oakland University. The middle and right columns are blood tests  from diabetic rats that have very high blood glucose (sugar), and this test uses a special binding material filled that binds glycated-hemoglobin. Notice that the column on the left has far less red color, as it is from a normal rat without diabetes. Like diabetic rats, diabetic humans can have much more glycated-hemoglobin than normal.

These test columns are actually designed for measuring the glycated-hemoglobin from human patients, and in the Eye Research Institute here at Oakland Univeristy we use them to test diabetic rats. I first learned how to use this test as a PhD student in John Trevithick's lab (University of Western Ontario), where we studied diabetic cataract. The amount of glycated-hemoglobin (called HbA1c or your "A1C") in our red blood cells increases with higher blood glucose concentration, over many days. Many proteins "soaked" in higher glucose concentrations will become cross-linked to the sugar "glucose", on specific amino-acids that are the building blocks of all proteins. If you are diabetic, you already know that your Doctor measures your "A1C" as part of your blood tests. While you may use your glucose meter to measure your blood glucose concentration at home,  the HbA1c test will tell your doctor if you can really control your glucose over several weeks. Because it takes a few weeks for the glycated hemoglobin to become replaced by new hemoglobin in your blood, your doctor will know from this test if you are being careful with your blood sugar all the time. Makes it hard to fib to them.

The point of this glycated hemoglobin story is to make an important point to anyone who is diabetic, or close to being diabetic:

high blood glucose ("blood sugar") causes your normal biochemistry to change. Proteins, like hemoglobin, get linked to glucose.

The higher the sugar concentration over time, the more glycated hemoglobin is produced. But this is just one protein that we can test easily because its in your blood. But, what about the other proteins of your body? Do they get more linked to glucose too?

The answer to the last question is yes. Hemoglobin is a protein and, like all the proteins at work in our cells, hemoglobin is made up of amino acids. There are 20 different amino acids used to make up thousands of different proteins in our cells. Its like using the same box of Lego blocks to make many different Lego models. One of these "Lego blocks", named Lysine, tends to become cross-linked to glucose. Most proteins contain one more more Lysines and, like hemoglobin, higher sugar concentrations will cross-link them to more glucose. When glucose concentration is higher than normal, it also enters our cells at higher concentration. Thus, proteins outside and inside our cells can start to experience more glycation.

Over time, glycation (and other processes I won't cover in this posting) causes subtle but harmful alterations of your cell and tissue chemistry. Some of these changes happen in days, others happen in months. If you do not listen to your doctor and are not careful with your blood sugar control, diet and exercise, then bad things can happen to your metabolism over time.While any single protein may seem to have a relatively small increase in amount of glycation, this particular chemical modification is happening to thousands of different proteins all at the same time. All together, the consequences for your health bad.

Systems that regulate the normal interconversion of sugars, lipids (fats), and proteins in your metabolism start to become uncoordinated. In part, this is due to the fact that Enzymes, which regulate and control these biochemical reactions, are themselves proteins. Enzymes suffering extra protein glycation may not function optimally for good health. If you are over weight and storing a lot more body fat, then both your blood sugar and the systems that regulate glucose uptake by your tissues start to change. While our pancreas normally shoots insulin into our blood stream to cause our liver and muscles to suck up most of the sugar from a meal, we can instead begin to develop insulin tolerance. That is, insulin stops working for the body. When your liver and muscles stop responding to insulin, their cells stop making glucose transporters to facilitate the transport of glucose from the blood into the cell, where it can be used for normal metabolism. In this situation we have developed age-onset diabetes. Our blood sugar stays high, and it will continue to make the imbalances of our metabolism worst. Then we are in danger of suffering the same medical difficulties that insulin dependent, or juvenile diabetic, patients can suffer: loss of peripheral nerves in the feet, ankles and hands, poor circulation in the feet and lower legs, amputation of feet or legs,  loss of normal kidney function, and diabetic retinopathy that robs you of your sight.

Metabolic Memory - when metabolic syndrome becomes permanent

Well, you might ask me " Dr. Mitton, can we put off getting healthy today and make the healthy changes later: finally listening to my doctor, loosing the excess weight and body fat? Can't we reverse all the bad changes happening to our body later?" Unfortunately, the answer is often NO. 

It turns out that your healthier life style in the future may not stop the peripheral nerve loss, kidney failure, break down of ankle joints, and ongoing damage to the retinal vasculature and your vision. It may slow it down, but often will not stop it completely. It is as if your metabolism has changed..... permanently. Some parts of your metabolic regulation have become shifted so far that they have "dropped off a cliff", and the progress of the disease will not stop. This phenomena is very  real and we call it "metabolic memory".

Metabolic memory was not understood a decade ago, but today we know much more. It turns out that some of these changes are Epigenetic and have to do with the expression or activity of some important genes. We have been talking about proteins so far, but where are proteins encoded? Where are their blue-prints? Where are the instructions on how to assemble 20 amino acids in a specific order to make a chain that is Hemoglobin, Insulin,or any one of over 20,000 different proteins required by our different cells? They are encoded in our genes of course.

Our "gene closet" and how over eating messes up our genetic"wardrobe".

Our genes: some are fully off, some are fully on, or they may be somewhere in between, in different tissues and at different times. Turning our genes on and off is done by  specialized proteins we call Transcription Factors. There are genes that also encode how to make Transcription Factors, and Transcription factors then regulate genes. Do you get the idea? There is a circular regulation here. If you push this system a bit out of balance for a short time, it can get itself back into a safe and healthy range of control. But, if you push it out of balance for a long period of time, you can end up with a vicious cycle of changes that continue to reinforce each other. Sort of a downward spiral dive.

In the case of metabolic syndrome, some regulation of gene expression becomes permanently changed, and these changes do not reverse when you finally loose weight and exercise. Some of the chemical changes are Epigenetic changes. Epigenetic regulation refers to the control of how our genes are packaged away in our cells. Our genes are organized in structure that we all know as chromosomes. When a gene is OFF, it is literally coiled up tight and compactly stored away in as small a space as possible. Just like putting your winter clothes away in plastic bins during the summer. Your summer shirts are on the hangers, all ready to wear. Your winter clothes can be accessed, but you have to unpack them when you want to wear them. Genes work the same way. To use the gene, you need to unpack it first. It turns out that many genes can become packed away or turned off permanently in metabolic syndrome. A gene can become abnormally locked away in the closet. Over time, metabolic changes from being over weight, being inactive (weak muscles), high body fat, eating and drinking lots of sugar, can leave some genes packed away that should normally be ready for use.

How can we avoiding metabolic syndrome, age onset diabetes, and heart disease?

Simple. If you want to greatly increase your chances for a longer and healthy life, then you need to be active and eating healthy food from childhood. If this does not describe you, no matter what your age now, make the changes now. Like Mr Jagger says "Time, is on my side", but only if you start today. 

The longer you wait to get healthy, in terms of physical fitness and food selections, the less chances you will have to reverse metabolic syndrome related diseases when you are older. What you do now, WILL impact your health in near and long term.

No comments: