Most humans vulnerable to Type 2 diabetes as insulin hits evolutionary dead-end

INDIANAPOLIS, Ind. — Could Type 2 diabetes become the next pandemic to impact future generations? Scientists at Indiana University School of Medicine say insulin has reached an evolutionary dead-end, making it unable to adapt to the body changes caused by obesity. Their study warns this could put nearly every person at risk of becoming diabetic.

Patients with type 2 diabetes have chronic issues with processing blood sugar, or glucose. This means their bodies don’t produce enough insulin or becomes resistant to the hormone. Researchers have discovered the gene sequence of insulin has become naturally impaired over time. This vulnerability was uncovered in a series of mutations in the insulin gene which causes diabetes in young children.

Normally, insulin is created by a number of bodily processes taking place in the beta cells. One of the key steps in the process is the folding of proinsulin. This biosynthetic precursor to the hormone helps insulin achieve its three-dimensional structure inside the body. Researchers say other studies have revealed that mutations can hinder the folding of proinsulin.

The new study examined if the evolution of insulin inside vertebrates (species with backbones) has reached a developmental impasse. If so, if insulin can no longer adapt in humans, then conditions like obesity may make the onset of diabetes more likely every year.

“Biological processes ordinarily evolve to be robust, and this protects us in the majority of cases from birth defects and diseases,” says lead investigator Dr. Michael Weiss in a university release. “Yet diabetes seems to be an exception.”

Small mutations of insulin gene cause big problems

Researchers looked at a slight mutation in the human insulin gene and compared it to insulin in other vertebrates. The results reveal this human mutation still functions within the normal range of genetic variations in animals, but has somehow been excluded by human evolution. Researchers believe this mutation is selectively blocking the folding process of proinsulin and puts stress on beta cells. The team adds that even a slight variation in this gene sequence can cause cellular dysfunction to occur.

Weiss says this problem highlights the vital importance of the insulin folding process over 540 million years of evolution.

“This study is a tour de force unraveling key elements of the structural biology of insulin that affect its synthesis and function,” says Barbara Kahn of Harvard Medical School. “The authors highlight the fact that the insulin gene has been susceptible throughout evolution to mutations that impair insulin’s function or stress beta cells. As we approach the 100th anniversary of the discovery of insulin, these elegant observations might lead to a better understanding of the pathogenesis of Type 2 diabetes.”

“The present findings define a major question for the future: whether harmful misfolding of proinsulin seen in patients bearing INS gene variants may also occur, at lower levels perhaps, but more broadly in the population of human Type 2 diabetes patients around the world,” Director of the University of Chicago Kolver Diabetes Center Louis Philipson adds.

The study appears in the Proceedings of the National Academy of Sciences.

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