Scientists have found that insulin has met an evolutionary cul-de-sac, limiting its ability to adapt to obesity, thereby rendering most people vulnerable to type 2 diabetes.

A recent study from scientists at Indiana University School of Medicine, the University of Michigan, and Case Western Reserve University has determined that the sequence of insulin has become entrenched at the edge of impaired production, an intrinsic vulnerability unmasked by rare mutations in the insulin gene causing diabetes in childhood.

Insulin is produced by a series of highly specific processes in specialized cells, called beta cells. A critical step is the folding of a biosynthetic precursor, called proinsulin, to achieve the hormone’s functional three-dimensional structure. Past studies from this and other groups have suggested that impaired biosynthesis could result from diverse mutations that hinder proinsulin’s foldability.  This group sought to determine if the evolution of insulin in vertebrates—including humans—has encountered a roadblock.

The researchers looked at a subtle mutation in human insulin and other animals’ insulins, such as cows and porcupines. The mutant human insulin functions within the range of natural variation among animal insulins, yet this mutation has been excluded by evolution. The answer to this seeming paradox is that the forbidden mutation selectively blocks the folding of proinsulin and stresses beta cells. The group discovered that even the slightest variation of the insulin-sequencing process not only impairs insulin folding (and eventual insulin secretion) but also induces cellular stress that leads to beta-cell dysfunction and, eventually, permanent damage. The study highlights the importance of folding efficiency as a critical but hidden factor in insulin evolution over the past 540 million years. Humans have evolved to be vulnerable to diverse mutations in the insulin gene. This vulnerability underlies a rare monogenic form of diabetes and provides an evolutionary backdrop to the present obesity-related diabetes pandemic. National experts agree that this discovery offers critical insight to better understanding the development of type 2 diabetes in adults and children—which both are rising at alarming rates around the world.

Proceedings of the National Academy of Sciences PNAS Nov, 2nd 2020