Genes-R-Us — No simple genetic story: Insulin resistance and type-2 diabetes

Posted: Wednesday, September 26, 2012 5:00 pm

Daily Health News released an article sporting the headline, “Scientists ID the Gene for Insulin Resistance.” So what about that Daily Health News story? Have the scientists really unraveled the insulin resistance gene? Recently I was asked by a friend if I thought that she might be insulin resistant. So this column is for you, my friend. You decide.
The hormone insulin is secreted by beta cells of the pancreas. Insulin enables glucose, our bodies preferred form sugar, to be used by the cells in our body. But insulin, itself, is also important for brain functions, like memory, as well as our vascular health.
Insulin is used by our bodies to store broken down glucose, that is not immediately required for energy, in the liver, muscles, and in fat cells. These glucose stores are the “between meals” source of cellular energy.
The body must keep a very even level of glucose in the blood in order to avoid damage to our internal organs. Insulin secretion by the pancreas is balanced with the “pushing and pulling” of glucose from our liver, muscle, and fat storage “tanks”.
When cells become blunted in their ability to respond to insulin it takes increasing levels of insulin to keep glucose levels balanced in the blood. When this happens we then say a person has become insulin resistant.
Type-2 diabetes (T2D) is characterized by insulin resistance. On the other hand, an individual that is insulin sensitive requires relatively normal or low levels of insulin to process glucose. It is the opposite of insulin resistance.
Daily Health News was summarizing a research article that appeared in New England Journal Medicine (NEJM) this month that focused on the role of PTEN gene in insulin sensitivity (http://bit.ly/PRmQ7g).
This study verified in humans what scientist already knew to be true in mice. That is, if only one working copy of the gene PTEN was inherited (instead of the two usual copies, one from each parent) then an individual will be insulin sensitive even though he or she is obese.
The study was performed on 15 people with only one working copy of PTEN and 15 matched controls (people similar in body traits but with two working copies of PTEN.) All thirty people were obese by medical standards.
The fasting insulin level for those with one “broken” copy of PTEN (the experimental group) was only 39 percent of the control group, while fasting glucose levels were identical. For “data-holics”, there are tables of fascinating numbers that clearly demonstrate that the experimental group had no issues with insulin resistance as did the control group.
There are at least 130 ways that one of the eight protein-coding regions in the PTEN gene can be messed up and render the gene flat out “broken.” “Broken” means that the gene PTEN can’t make its protein and do its work.
By now, you might wish that you were one of the 1 in 200,000 people with a single broken copy of PTEN. But you really don’t want that. For one thing-you are still not protected from obesity and even more significant, PTEN gene is tumor-suppressor gene. Yes, you want two working copies. Many, many cancerous tumors have managed to turn off the PTEN gene.
So have scientists really identified “the” gene for insulin sensitivity? Well, yes, if you happen to be one of those rare persons with a single working copy of PTEN. In which case, you have an increased risk of obesity and cancer but a decreased risk of type 2 diabetes owing to enhanced insulin sensitivity.
The vast majority of people with insulin resistance have two fully functioning PTEN genes. That is why the title selected by Daily Health News was misleading. And developing a new drug that turns off one of a functioning pair of PTEN genes is just not going to happen.
The risk of developing T2D is thought to be about one-fourth due to genetics and three-quarters due to environment. Although many, many genetic risk factors are still unknown, the majority of our risk for T2D is governed by our dietary choices, our activity level, other uncontrolled health conditions (like high blood pressure), and so on.
23andme.com, my favorite direct-to-consumer genetic testing company, tests eleven SNPs that have been associated with small but significant risks for a T2D genetic predisposition. (SNPs are single point variations in our DNA that can only take on one of two base values.) My birth parents and I are assessed as having an average risk for developing T2D based on these SNPs-although I am higher than either parent.
Being overweight contributes to insulin resistance, and thus T2D, through increased circulating levels of inflammatory proteins and decreased production of adiponectin. Adiponectin helps keep our cells sensitive to insulin.
One can appear slim but still be at increased risk for insulin resistance or T2D by having extra fat around the middle. For males a waist-to-hip (w2h) ratio above 0.95, while a ratio above 0.80 for females, is defined as abdominal obesity. Abdominal obesity, not just obesity, put one at incredibly high risk for insulin resistance.
As we age many of us tend to develop an apple-shaped torso. Since high school, for each inch increase on my hip measurement, I have gained two inches on my waist.
Along with her narrow hips, I have inherited my mother’s tendency toward “appleness” around the middle. But the research is clear: apples are best eaten, not worn.
Nancy@NancyMiller Latimer.com has worked in scientific research and development for 27 years. She blogs at NeuronalBeauty.BlogSpot.com Published in The Messenger 9.26.12