A new study suggests that most people are susceptible to type 2 diabetes mellitus. The researchers found that the insulin sequence was stuck on the verge of a production failure. This is an intrinsic vulnerability caused by rare mutations in the insulin generecognized as diabeteswhich is already exposed in childhood. The study uses biophysical concepts and methods to relate protein chemistry to the emerging field of evolutionary medicine.
Susceptibility to type 2 diabetes mellitus
Insulin is produced through a series of highly specific processes. These take place in specialized cells called beta cells. An important step is the folding of a biosynthetic precursor called proinsulin, which can achieve the functional three-dimensional structure of the hormone. Previous studies from this and other groups have shown that impaired biosynthesis could be the result of various mutations. These can hinder the foldability of proinsulin. So the research group sought to determine whether insulin development has encountered obstacles in vertebrates, including humans. Biological processes typically evolve robustly and, in most cases, protect against birth defects and disease. Nevertheless, type 2 diabetes mellitus seems to be an exception.
The scientists examined a subtle mutation in human insulin in relation to the insulins of other animals such as cows and porcupines. Such a mutated human insulin works within the range of natural variation between animal insulins. Nevertheless, this mutation was ruled out by evolution. The answer to this apparent paradox is that such a mutation selectively blocks the folding of proinsulin and emphasizes beta cells. So the research group discovered that even the slightest variation in the process of sequencing insulin not only affects insulin folding and eventual insulin secretion, but also induces cellular stress. The latter leads to beta cell dysfunction and ultimately permanent damage. Humans have been shown to be susceptible to various mutations, and this susceptibility underlies a rare monogenic form of diabetes and provides an evolutionary background for the current obesity-related diabetes pandemic.
Medical perspectives
Experts agree that this discovery provides important insights for a better understanding of the development of type 2 diabetes in adults and children. The present onesResults of the studythus defining an important question for the future: whether deleterious misfolding of proinsulin may occur even at lower levels in patients with INS gene variants, but more generally in the population of type 2 diabetes patients around the world. Next, the research team will work to fully define the sequence determinants that make proinsulin foldable in beta cells. They hope this work will eventually lead to a new category of medicines. This could alleviate the cellular stress caused by the precarious foldability of proinsulin. In this way, cellular stress in beta cells is combated while physicians maintain insulin production for high-risk patients.
