The Cause Of Diabetes Type 2.
Also known as non-insulin-dependent diabetes mellitus, adult-onset diabetes, maturity-onset diabetes, ketosis-resistant diabetes, and stable diabetes.
This is the type that affects 90% of diabetics. It is an ever expanding disease and is now thought to affect around 4% of the world population. In some countries the number of people aged 45 and over who have Type 2 diabetes is as high as 20%.
The modern trend to emphasise solely the role of obesity and inactivity in this type of diabetes has led to the belief by many non-diabetics that having this disease is your own fault, you needed to have eaten less and exercised more. This can make many a Type 2 want to scream with frustration, especially as they watch those same people devour huge quantities of forbidden foods while lolling around viewing the next sport fixture. If what they thought held true they would soon be joining you in your battle to cope with this disease, but they don't - so why not?
That is because the causes of Type 2 diabetes are not that simple. There is a complicated weave of factors that play a role.
Listed below are some of the most important:-
1. Genetics
2. Defective hormonal secretions.
3. Insulin abnormalities - insulin resistance and subsequent overproduction leading to beta cell 'wear out'.
4. Environment.
5. Increased glucose production by the liver.
6. Sedentary lifestyle.
7. Visceral obesity
Let us take a look at some of them:-
1. Genetics
I have heard people say that it is very easy to 'blame it on one's genes' instead of taking responsibility for one's own actions. If you are wondering if there really is a genetic link in Type 2 diabetes take a look at these statistics:-
If one of your parents has Type 2 diabetes, you have a 15% of getting it.
If both your parents have it your chances of getting it rise to a massive 75%.
If your brother or sister has it your risk is around 10% of getting it too.
If your non-identical twin has it the risk is the same as a sibling, 10%.
If your identical twin has Type 2 diabetes you are looking at a 90% chance.
With those stats there can be no argument about whether diabetes runs in families or not and therefore it very obviously is a hereditary genetic disease. But it would appear to be even more complicated than Type 1. Researchers are trying to find out which genes, if any, are responsible for Type 2 diabetes.
This is no easy task. There are genes for the secretion of insulin, for the metabolism of glucose, for how we use the energy we get from food and ones that determine insulin resistance. All play a part in glucose metabolism. Finding out which of the myriad of genes may be faulty and the results of that fault is rather like looking for the proverbial needle in a haystack.
Also it is possible that even if they do find a mutated gene it by itself may not cause diabetes. It may require more than one gene, or a gene plus another factor, eg. lifestyle, to trigger the disease.
Each Type 2 diabetic is an individual and what causes diabetes in one may not do so in another - no wonder the 'cause' is so hard to quantify!
And then there is the non-faulty gene..........
This is just a normal gene that is a hang over from former times. Our ancestors tended to live in a time of feast or famine.
Those with the so called 'thrifty gene' were better able to store food as fat during the good times. When lean times came they had all this fat that could be converted into glucose, and thus energy.
Unfortunately (or fortunately, depending on your viewpoint) we live in a time when food is constantly available and this gene is no longer an asset. The carefully hoarded fat is never needed but the body does not know that and keeps on storing more, with the result that we become obese.
That aforementioned person, eating their forbidden food in front of the TV, may well not have this gene and so will never gain weight and (sob) never know what it is like to be a diabetic.
However there are some defective genes that may play a role in Type 2 diabetes.
For instance there is a fatty-acid binding protein gene (FABP2) which, if defective, can result in high levels of triglycerides. This may be the link between insulin resistance and obesity in some type 2 diabetics.
The lipoprotein lipase (LPL) gene, which is a gene that controls the delivery of fatty acids to muscle and tissues and, if defective, may be a cause of insulin resistance in type 2 diabetics.
Researchers at the Cedar-Sinai Medical Center and the University of California have been studying this gene and state "This is the first study to definitively show that LPL is a gene for common insulin resistance."
A gene that makes a protein called Calpain-10, may be implicated in Type 2 diabetes. Calpain-10 is a protease, in other words a protein that splits other proteins. The research into this is very new and exactly why it affects the action of insulin and it's secretion is not yet understood.
For more information see:-
GeneticHealth.com
ScienceWatch.com
If genes that regulate a molecule called peroxisome proliferator-activated receptor (PPAR) gamma are defective it may contribute to type 2 diabetes.
A protein called beta3-adrenergic receptor is found in visceral fat cells. A gene, the Beta3-adrenergic receptor gene, makes this protein. The protein is involved in the determination of the amount of fuel your body burns when it is at rest. If this gene is faulty your metabolism slows down and you burn less fat, resulting in obesity.
MODY, or Mature Onset Diabetes of the Young is also a rare form of genetically caused diabetes that we deal with in depth elsewhere. You can jump to the MODY section at the end of this page or go to the main MODY page if you would like more information on MODY.
2. Defective Hormonal Secretions
Leptin is a hormone, produced by fat cells, that regulates blood sugar by controlling the messages sent to the brain re appetite and fat storage and also by telling the liver what to do with it's stored glucose. Increased levels of Leptin are thought to play a part in diabetes.
Resistin is another hormone secreted by the fat cells and if present in elevated levels appears to play a role in diabetes by making other cells resistant to insulin. Much research is going into studying this hormone.
High levels of growth hormones in overweight pubescent adolescents appear to increase the risk of insulin resistance.
Amylin and CGRP, both peptides, appear to have a role in the liver's glucose metabolism. Excess amylin may also be deposited in the beta cells and can alter their response to stimuli.
It has also been suggested that if the regulation of these two peptides is faulty the circulatory system will be affected, leading to changes in blood flow. This may increase insulin resistance.
Increased levels of interleukin 6 (IL-6) and C-reactive protein (CRP) have been shown to be associated with an increased risk of Type 2 diabetes.
3. Insulin Abnormalities
Abnormal insulin.
Though rare, this does occur. The faulty insulin may not respond as normal. For instance it may have decreased ability to bind to the receptors and reduced ability to take up glucose. This will lead to diabetes sooner or later, depending on how much of the insulin produced is faulty.
Insulin Resistance
This is a result of insulin receptors on the cells, that normally respond to the action of insulin, not working properly. These receptors, with the help of insulin, allow glucose into the cells.
When they are faulty the cells are starved of glucose, they call for more, the body assumes that the glucose is not getting through because there is too little insulin, the beta-cells of the pancreas go into overdrive trying to meet the increased demand, the amount of both insulin and glucose in the bloodstream rises, leading to diabetes and the wearing out, from overwork, of many of the beta-cells.
4. Environmental and lifestyle factors
Perhaps the most important factor here is obesity. Virtually all Type 2 diabetics are overweight.
As not all overweight people are diabetic we must assume that first there has to be a genetic susceptibility which is then triggered by the weight gain. (Or, that the weight gain is possibly triggered by the diabetes.)
Certain drugs used to treat other disease can affect the production of insulin and possible trigger diabetes. Steroids are known to do this, as are beta blockers and protease inhibitors. See the page on Steroid Diabetes.
Infection by a virus that causes damage to the pancreas may trigger diabetes.
Age appears to be a factor as half of all newly diagnosed type 2 diabetics are over 55. Maybe it is just that they have been around long enough for the other causative factors to have developed.
A diet low in fibre may increase your chances of developing diabetes. Fibre tends to slow down the rate at which glucose passes into the bloodstream and so stops you from getting large amounts at one time that your insulin production cannot cope with.
Stress lowers the body's ability to fight infections and these can trigger diabetes. The body calls for more energy (glucose) under these conditions which increases the amount of insulin needed. If the pancreas is unable to supply this, blood glucose rise and diabetes is diagnosed.
5. Increased glucose production by the liver
Your liver both stores glucose and can make glucose from other substances.
When your cells are not getting enough glucose, due to insulin resistance, the body calls for more glucose. The liver then kicks in and begins to release glucose. This causes elevated blood glucose levels.
6. Sedentary lifestyle
A lack of exercise might not trigger diabetes by and of itself but it contributes to the weight gain and therefore to the development of the disease.
7. Visceral obesity
Visceral, or abdominal, fat, that stuff that builds up around your middle, is associated with insulin resistance and therefore with diabetes.
Prevention.
If only the genetic factors were understood then researchers could put their efforts into finding what particular environmental or lifestyle factors were responsible for converting the genetic predisposition into the actual disease. However until this occurs we have to work with what we've got. And in Type 2 that is quite a lot.
One of the advantages of Type 2 diabetes is that the warning signs are usually very clear and show up well before actual diagnosis - if you trouble to keep an eye out for them!
It is possible to delay, and sometimes prevent the onset of Type 2 diabetes by sensible choices.
Being as diabetes is a genetic disease the first thing one should do is take a look at one's immediate relatives. If any are diabetic the initial step in primary prevention would be to get yourself checked on a yearly basis. Usually this is done with a fasting glucose tolerance test.
Then there are the simple lifestyle changes that can be made:-
1. Weight control
2. Exercise
3. Healthy diet
4. Quit smoking
5. Moderate alcohol consumption - yip, the occasional drink helps!
To see more on the subject of prevention go to:-
The Harvard School of Public Health.
National Center for Chronic Disease Prevention.
HelpTheAged.org
MODY
A rare type of Type 2 diabetes is MODY - Maturity-onset diabetes of the young.
There is no doubt that this is an inherited genetic disease - it runs in families and appears in every generation. A person only has to inherit the faulty gene from one of their parents to be at risk. So their chances are literally 50/50.
What makes it Type 2 and not Type 1 is the fact that MODY patients have viable beta cells, the faulty gene just interferes with the release of insulin from the pancreas.
So far scientists have found 6 different genes that cause MODY and they are looking for more because the ones they have found only account for diabetes in about one-third of the families.
Type 1 - Affected gene HNF4alpha
- Affected protein Hepatocyte nuclear factor 4 alpha
- Prevalence Uncommon
This was the first gene discovered. It causes a severe form of diabetes and affects the fatty acid synthesis in the liver. 30% of people with this gene require insulin to survive.
Type 2 - Affected gene GCK
- Affected protein Glucokinase
- Prevalence Common
This is the gene that is responsible for the largest number of MODY cases, around 50-60%. It affects pancreatic regulation. It is often symptomless, producing a mild glucose intolerance that does not require insulin treatment.
Type 3 - Affected gene TCF1
- Affected protein Hepatic nuclear factor 1 alpha (HNF1alpha)
- Prevalence Most common
This gene accounts for 25% of MODY cases. The disease is much more serious, being of a progressive type - in other words you may produce sufficient insulin as a child but as you get older the amount decreases. It is usually diagnosed sometime after puberty.
You need to control your blood glucose well with this type as you are susceptible to diabetic complications such as retinopathy (eye problems) and nephropathy (kidney damage).
The gene defect causes a decrease in the kidneys re-absorption of glucose which results in glucose being secreted in the urine (Glycosuria).
Type 4 - Affected gene IPF1
- Affected protein Insulin promotor factor 1
- Prevalence Uncommon
This type produces a relatively mild form of diabetes. It is rare, (having only been found in one family to date in the UK) so not much is known about it.
Type 5 - Affected gene TCF2
- Affected protein Hepatic nuclear factor 1 beta (HNF1 beta)
- Prevalence Uncommon
A problem one this, as defects in the HNF-1ß protein have also been known to cause renal cysts and other abnormalities in kidney development. That is why it is often only diagnosed after the diagnosis for kidney disease.
MODY 5 is also known to cause internal genital abnormalities and atrophy of the pancreas. Fortunately it is very rare.
Type 6 - Affected gene Neuro D1
- Affected protein Neurogenic differentiation factor 1
- Prevalence Very rare
Only found in 2 families in the UK to date. Little is understood about it as yet.
Prevention.
There are genetic tests that can be done to see if you have one of the genes but this is not commercially available and usually only gets done for research purposes.
If you have a family history of MODY all you can really do is what all potential Type 2's do - control weight, exercise, eat healthy, don't smoke and drink moderate amounts of alcohol.