Genes and Diabetes

Gretchen Becker Health Guide
  • This Sharepost might be a bit muddled because, according to the latest news buzz, people with diabetes are apt to have "cognitive decline," a polite word for senility. So bear with me if I end up talking about the 1938 World's Fair instead of diabetes. It's not my fault; I have diabetes.

    Of course, what these popular press stories don't emphasize is that it's likely high blood glucose (BG) levels rather than a diabetes diagnosis that seem to accelerate aging, including "senior moments" and other signs of brain decline. Although the Time Magazine story does mention "spikes in blood-glucose levels," the assumption is that everyone with diabetes continues to eat the "standard American diet" and hence has spikes in BG levels.

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    But we know better: that working out an eating plan that controls these spikes contributes to our health and means that all the deleterious things the media is so fond of telling us about are not inevitable.

    Nevertheless, diets are not what I wanted to talk about today. Instead I wanted to talk about genes and diabetes.

    All types of diabetes have a genetic basis. Some people have the misconception that type 1 diabetes is caused by bad luck in having diabetes genes whereas type 2 is caused by sloth and gluttony. In fact, the genetic connection to type 2 diabetes is even stronger than that to type 1. An identical twin whose twin has type 1 diabetes is less likely to become diabetic than an identical twin whose twin has type 2 diabetes.

    And in both cases, a genetic susceptibility is brought on by an environmental trigger. In the case of type 1, that trigger is often a viral infection. In the case of type 2, it's often genetic or environmental factors that contribute to obesity.

    An example of a genetic factor causing obesity would be the tiny number of people in the world who lack the hormone leptin. This gives them an insatiable appetite, and small children eat constantly and may weigh more than 100 pounds. One 8-year-old weighed 190 pounds. When you give them leptin injections, their appetite becomes normal and they lose weight. They're not eating because they're unhappy; they're eating because they're ravenously hungry.

    Although leptin deficiency is rare, this is a good illustration of the fact that genes can affect appetite, and it's not surprising that people who are constantly hungry will eat more than people who aren't. Those who don't have genetic appetite problems but who have ever had a low-BG episode can imagine what it must be like by remembering that episode, when you wanted to eat everything in sight to get rid of that horrible feeling. The intellectual part of brain knows you should use restraint, but the emotional part of the brain says, "Who cares! I need food and I need it now!" A person with leptin deficiency might feel like that 24/7.

    Even if genes don't affect your appetite, they can affect how efficient you are at converting your food to fat. So Frank and Anthony might eat exactly the same things in the same amounts every day, but Frank might be thin and Anthony might be fat.

  • When it comes to "diabetes genes," the situation is complex. There is a fairly uncommon form of diabetes that is caused by a mutation in one of several single genes. Hence it's called "monogenic." This is "mature-onset diabetes of the young," or MODY, because it used to be considered a form of type 2 diabetes that occurred in children. Now it's considered a separate category, because today type 2 diabetes is defined as diabetes caused by insulin resistance (IR), and people with MODY are very insulin sensitive.

    The best place to learn about MODY is Jenny's MODY pages. If you read those pages you'll probably know a lot more about MODY than your doctor. Because the condition is fairly uncommon, many doctors don't know much -- if anything -- about it.

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    The genetic basis for type 2 diabetes is more complex. It's generally agreed that type 2 diabetes is "multigenic," meaning that you have to have mutations in several genes to get the disease. People with type 2 have genetic defects in their beta cells that limit the production of insulin. This means that as long as their IR is low, they can produce enough insulin to cover the carbohydrates that they eat and they won't be diagnosed with diabetes. But when their IR increases, the beta cells can't cope and BG levels rise.

    This is what happens in gestational diabetes. IR normally goes up during the third trimester, and women whose beta cells can't cope with extra IR have high BG levels then. After the baby is born, the diabetes usually goes away, although it returns later in a majority of these women as age causes increased IR.

    The IR, in turn, probably also has a genetic basis. Normal-weight relatives of people with type 2 diabetes tend to have more IR, and certain ethnic groups also have more IR than others. In addition, increased weight adds even more IR to whatever genetic IR you already have. The inherent IR may actually contribute to the weight gain in the first place, so you get into a vicious circle in which IR causes weight gain that causes additional IR that causes more weight gain.

    Assuming there are many genes that can contribute to type 2, you can see why the YMMV (your mileage may vary) concept applies. Let's say 10 different genes can contribute to type 2 when they're mutated. In order to actually get diabetes, let's say you need mutations in 4 of them. You might have mutations in genes 1, 4, 8, and 9, and I might have mutations in genes 2, 5, 6, and 7, with all the permutations and combinations that could occur. Some people might have mutations in more than 4 genes, and they'd have a more severe diabetes that began at a younger age. Other people might have mutations in only 3 or 2 genes, and they might have prediabetes that never progressed to full-blown diabetes.

    Some of those genes might affect beta cells, and some of them might affect IR. Some might affect appetite, and some might affect metabolic efficiency. Some might affect the metabolism of carbohydrate, and others might affect the metabolism of fats.

  • Now, to make things even more complex, let's imagine we both have mutations in gene 6. Genes consist of long chains of nucleic acids, which determine the sequence of amino acids in your proteins. Imagine the proteins are like a chain of pearls. Each amino acid is one white pearl. When you get a mutation, think of the pearl as turning red.

    Now, you could get a mutation that turned a sequence of 5 (or any other number) pearls in a row red. You could get a mutation that turned 5 (or any other number) pearls scattered throughout the chain red. Or you could get a mutation that turned only 1 pearl red (these are called "SNPs," or "single-nucleotide polymorphisms").

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    Some of these mutations wouldn't be very important because they wouldn't change the structure of the protein much -- if at all -- in areas that were crucial to its function. Others would have a small effect on the protein's function. And others would have a large effect.

    So even if you and I had mutations in the same gene, we might be affected differently. Considering all the possibilities for variation, it's no surprise that scientists haven't yet deciphered all the ins and outs of type 2 diabetes. And it's no surprise that we can react in different ways to different drugs and different diet and exercise regimens.

    I like to play around with ideas, and in doing so, I once came up with a theory about type 1 and type 2 diabetes.

    Let's imagine that in order to get diabetes, you needed a mutation in a gene or genes that made you produce antibodies against your own beta cells. I'll call these "diabetes genes." People who had this mutation alone -- if exposed to a trigger like a viral infection -- would get type 1 diabetes, which is clearly an autoimmune disease.

    Now let's imagine that there were other genes that modulated the effect of the diabetes genes, that turned the immune system attack down. Without the diabetes genes, the modulating genes would have no effect. But people who had the modulating genes in addition to the diabetes genes would have a very low level of immune attack against the beta cells, so low that it wouldn't show on the tests for immune attack, such as the GAD antibody test.

    Furthermore, because the attack on the beta cells was turned down, the disease wouldn't show in childhood, but only after many years of slow deterioration of the beta cells. If the beta cells weren't challenged by high IR, the disease might never manifest itself.

    People who had two copies of the modulating genes (one from the mother and one from the father) would get type 2 diabetes, with very slow deterioration and no detectable beta cell antibodies. But someone who had only one copy of the modulating gene would develop LADA, or latent autoimmune diabetes of adults, with faster deterioration and detectable antibodies. LADA is a form of diabetes that appears later than type 1 and proceeds more slowly. They're now saying it has characteristics of both type 1 and type 2.

    A scheme such as this would explain why a both types of diabetes tend to occur in the same family. If they were totally different diseases united only by a common symptom -- high BG levels -- then you'd expect to find some families with only type 1 and other families with only type 2. That's not what we see. There's got to be some common denominator.

  • Remember, I'm just playing around with ideas. This scheme is not something that has been tested, and for all I know, there might be experiments that prove that it couldn't work. I'm sure reality is much more complex. But it's a way of trying to understand why some type 2s do show anti-GAD antibodies, why diabetes of both types shows up in the same families, why LADA is similar to but different from type 1, and why rates of both types of diabetes are increasing in the modern world. They must share some common cause.

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    This type of intellectual exercise has no practical application, and maybe I'm wasting my time thinking about it when I could be doing more useful things like hoovering the living room rug, but I find it more interesting than doing crossword puzzles. Maybe playing with ideas like this will help delay the onset of senility that Time Magazine says is nipping at my heels.



Published On: January 07, 2009