WITHDRAWN: Diabetes mellitus due to toxic misfolding of proinsulin variants

Dominant mutations in the human insulin gene (INS) lead to pancreatic β-cell dysfunction and diabetes mellitus (DM) due to toxic misfolding of a mutant proinsulin. Analogous to a classical mouse model of monogenic DM ("Akita"), this syndrome highlights the susceptibility of β-cells to endoreticulum (ER) stress due to protein misfolding and aberrant aggregation.

Diverse clinical mutations directly or indirectly perturb native disulfide pairing. Whereas most introduce or remove a cysteine (Cys; leading in either case to an unpaired thiol group), non-Cys-related mutations identify key determinants of folding efficiency. Studies of such mutations suggest that the hormone's evolution has been constrained not only by structure-function relationships but also by the susceptibility of its single-chain precursor to impaired foldability. An intriguing hypothesis posits that INS overexpression in response to peripheral insulin resistance likewise leads to chronic ER stress and β-cell dysfunction in the natural history of nonsyndromic Type 2 DM.

Cryptic contributions of conserved residues to folding efficiency, as uncovered by rare genetic variants, define molecular links between biophysical principles and the emerging paradigm of Darwinian medicine: Biosynthesis of proinsulin at the edge of nonfoldability provides a key determinant of "diabesity" as a pandemic disease of civilization.