*2.5. Amylin and Diabetes*

Diabetes (Type II) is a multifactorial disease characterized by dysfunction of insulin action (insulin resistance) and failure of insulin secretion by pancreatic β-cells [11,170]. One hallmark feature of this disease is the accumulation of amyloid fibrils into pancreatic islets (islets of Langerhans). These amyloid deposits are majority composed by islet amyloid polypeptides (IAPP), also called amylin. Islet amyloid polypeptides are IDPs composed of 37 amino acid residues, co-secreted with insulin by the same pancreatic cells, and its gene is located on chromosome 12 in humans [171–173].

The process of aggregation of IAPP seems to be initiated by interaction of one IAPP monomer to another, progressively leading to the formation of aggregates [174,175]. Analysis of human IAPP using circular dichroism spectroscopy demonstrated that the fibril formation was accompanied by a conformational change of random coil to β-sheet/α-helical structure [176]. These transient conformations were further confirmed by other studies [177–179].

Cytotoxicity of IAPP accumulated as amyloid deposits could be associated with loss of pancreatic β-cells functions and cells apoptosis [180,181]. Recent reviews of computational studies provided mechanistic insights of IAPP structure as monomers and oligomers and their interaction with lipid bilayers in order to understand the IAPP cytotoxicity mediated by membranes [175,182].

#### **3. Strategies for IDP Modulation**

Intrinsically disordered proteins can rapidly populate different conformations in solution, usually not assuming a well-defined three-dimensional structure in their native state, as a result of their signature low-sequence complexity and low proportion of bulky hydrophobic amino acids (instead, charged and hydrophilic residues are common) that lead to a flexible, dynamically disordered behavior and larger interaction surface areas than analogous folded regions in globular proteins [183–186]. Considering that IDPs participate in numerous key processes in cell metabolism, it is expected that their activity would be regulated by multiple mechanisms at transcriptional, post-transcriptional, and translational levels, which makes active IDPs accessible in shorter periods compared to structured proteins [187,188]. Some aspects of IDP modulation (mainly for IDPs involved in cell signaling) are covered in this section, arbitrarily grouped in mechanisms that engage in direct structural changes on IDPs in order to achieve stabilization (coupled folding and binding, post-translational modifications), and mechanisms that control IDPs abundance in the cell (mRNA decay, IDP proteasomal degradation, nanny model for stabilization).
