Investigators 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.
Investigators 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).
Insulin is produced by a series of processes occurring in specialized cells, called β cells, according to the study’s authors at Indiana University School of Medicine, the University of Michigan, and Case Western Reserve University in Ohio.
The folding of a biosynthetic precursor called proinsulin is a key step in achieving the hormone’s functional 3-dimensional structure. Findings from prior studies had suggested that impaired biosynthesis could be the result of diverse mutations hindering the folding of proinsulin.
The mutant human insulin functions within the range of natural variation, though this mutation has been excluded by evolution, according to the findings of this study.
The answer to this seeming paradox is that the forbidden mutation selectively blocks the folding of proinsulin and stresses β cells, the study authors say.
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 β-cell dysfunction and, eventually, permanent damage.
National experts agree that this discovery provides key insights into the development of T2D in adults and children; both groups have rising rates of diabetes, according to a statement from the investigators.
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. Accessed December 7, 2020. https://medicine.iu.edu/news/2020/11/study-suggests-most-humans-are-vulnerable-to-type-2-diabetes