Researchers have found that the evolutionary sequence of insulin has become stuck at the edge of impaired production, limiting its ability to adapt to obesity and rendering most people vulnerable to type 2 diabetes (T2D).

According to the study authors from the Indiana University School of Medicine, insulin is produced by a series of processes occurring in specialized cells, called beta cells. The folding of a biosynthetic precursor called proinsulin is a key step in achieving the hormone’s functional 3-dimentional structure. Earlier research has suggested that impaired biosynthesis could be the result of diverse mutations hindering the folding of proinsulin.

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

The investigators analyzed a subtle mutation in human insulin and compared it with insulins of other animals, such as cows and porcupines. According to their findings, the mutant human insulin functions within the range of natural variation, although this mutation has been excluded by evolution. According to the study authors, the answer to this seeming paradox is that the forbidden mutation selectively blocks the folding of proinsulin and stresses beta cells.

Furthermore, the investigators found that even the slightest variation in the insulin-sequencing process not only impairs insulin folding and secretion, but also induces cellular stress that leads to beta cell dysfunction and, eventually, permanent damage. According to the press release, national experts agree that this discovery provides key insights into the development of T2D in adults and children, both groups which have rising rates of diabetes.

“This study is a tour de force unraveling key elements of the structural biology of insulin that affect its synthesis and function,” said Barbara Kahn, MD, George R. Minot Professor of Medicine at 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.”

The group will soon begin working to fully define the sequence determinants that make proinsulin foldable in beta cells, with hopes that this work could lead to a new category of drugs.

“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,” said Louis Philipson, MD, director of the University of Kolver Diabetes Center, in the press release.

REFERENCE
An evolutionary cul-de-sac: Study suggests most humans are vulnerable to Type 2 diabetes [news release]. Indiana University School of Medicine; November 2, 2020. https://medicine.iu.edu/news/2020/11/study-suggests-most-humans-are-vulnerable-to-type-2-diabetes. Accessed November 9, 2020.