Gene Mutation Reduces Risk of Type 2

Gretchen Becker Health Guide
  • The news services have been busy describing the recent finding that people with a rare mutation are protected from getting type 2 diabetes, even when they’re obese.


    The mutation affects a gene involved with zinc uptake into beta cells, and when the gene is knocked out, both insulin secretion and insulin clearance are affected. The level of insulin in the blood depends on both these factors. You can secrete a lot of insulin, but if the liver removes most of the insulin in the “first pass,” your levels will be lower than you’d expect.


    The first pass refers to the fact that blood from the beta cells in the pancreas go directly to the liver via the portal vein. Because the liver removes a lot of insulin, in people who don’t inject insulin, the insulin levels in the liver are usually high enough to turn down gluconeogenesis in the liver, but the levels at the periphery aren’t so high that the muscles take up all the glucose in the blood and make you go low.

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    One problem with injected insulin is that it doesn’t mimic this physiological state. Instead, when you inject insulin, the insulin levels in the muscles are higher than the insulin levels in the liver, and in many people with diabetes, the liver continues to make and secrete too much glucose.


    The researchers who discovered the rare gene’s effect on diabetes risk are hoping that someone will develop a drug that will inhibit the gene that is involved. They say that they tested the people with the “faulty” gene and found that the risk of 750 diseases they looked at were not increased. Their other physiological parameters were also not affected, just the diabetes risk. And the mutation had no effect on weight.


    Around the same time, another rare gene that reduces the risk of type 2 diabetes was discovered. Interestingly, while reducing diabetes risk, the gene also increased the height and BMI of the affected people. So in both cases of mutated genes reducing type 2 diabetes risk, weight was not a factor. However, this gene encodes a molecule that is active in many tissues, and hence it is not a good target for drug development.


    What I find especially interesting about the first gene mentioned is the fact that the same mutation in mice increased the risk for diabetes. According to a story in the New York Times, Dr David Altshuler, the lead author of the paper, submitted a paper on the study to a medical journal. But it was rejected “after one of the reviewers said it must be wrong because it contradicted what was known from studies with mice.”


    As a commenter on a great blogpost (interview with Sydney Brenner) about the current state of scientific research said, “So not only are we great at curing mice, now we refuse to publish anything that doesn't cure mice!”


    After the rejection, the scientists went back and got even more data and submitted a revised paper to Nature Genetics, which published it.


    The scientists say they don’t yet know for sure how the zinc is affecting insulin secretion and insulin clearance, and I won’t bore you with complex theories that may turn out to be wrong. If you want details, you could look at this paper.


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    But this story is a reminder that findings in mice are often not directly translated to humans. Mouse studies give scientists good ideas for what to study in humans, but by themselves they don’t prove anything about human diabetes.


    This story, and especially the interview with Sydney Brenner cited above, is also an illustration of the politics involved in who gets funded to study something and whose results get published. I recommend that you read the blogpost, which was written by a research chemist.


    Drug development is slow, and it will take years before this gene discovery has any practical application. Nevertheless, it may eventually lead to a new type of drug with fewer side effects than current diabetes drugs, and every step in that direction is a good one. Or it may turn out to be a dead end. Only time will tell.

Published On: March 07, 2014