IAPP in type II diabetes: Basic research on structure, molecular interactions, and disease mechanisms suggests potential intervention strategies

Abstract

Islet amyloid polypeptide (a.k.a. IAPP, amylin) is a 37 amino acid hormone that has long been associated with the progression of type II diabetes mellitus (TIIDM) disease. The endocrine peptide hormone aggregatively misfolds to form amyloid deposits in and around the pancreatic islet β-cells that synthesize both insulin and IAPP, leading to a decrease in β-cell mass in patients with the disease. Extracellular IAPP amyloids induce β-cell death through the formation of reactive oxygen species, mitochondrial dysfunction, chromatin condensation, and apoptotic mechanisms, although the precise roles of IAPP in TIIDM are yet to be established. Here we review aspects of the normal physiological function of IAPP in glucose regulation together with insulin, and its misfolding which contributes to TIIDM, and may also play roles in other pathologies such as Alzheimer's and heart disease. We summarize information on expression of the IAPP gene, the regulation of the hormone by post-translational modifications, the structural properties of the peptide in various states, the kinetics of misfolding to amyloid fibrils, and the interactions of the peptide with insulin, membranes, glycosaminoglycans, and nanoparticles. Finally, we describe how basic research is starting to have a positive impact on the development of approaches to circumvent IAPP amyloidogenesis. These include therapeutic strategies aimed at stabilizing non-amyloidogenic states, inhibition of amyloid growth or disruption of amyloid fibrils, antibodies directed towards amyloid structures, and inhibition of interactions with cofactors that facilitate aggregation or stabilize amyloids.

Link between Diabetes and Alzheimer’s Disease Due to the Shared Amyloid Aggregation and Deposition Involving Both Neurodegenerative Changes and Neurovascular Damages

“…The first IAPP-positive cell appears after only 13 weeks of gestation. The gene encoding IAPP is located on chromosome number 12 [ 29 ]. IAPP is synthesized as a pre-pro form of IAPP that contains 89 amino acids.…”

“…IAPP is a gluco-modulatory hormone that inhibits insulin secretion, delays gastric emptying inhibits appetite, and plays a role in regulating food intake and controlling body weight [ 31 ]. The IAPP belongs to the calcitonin family of hormones, presents the functions of “bone remodelling”, inhibits osteoclast activity, and enhances osteoblast proliferation [ 29 ]. Several studies have explored the mechanisms responsible for the formation of amyloid deposits, which explain the cytotoxic effects of IAPP.…”

Tyrosine carbon dots inhibit fibrillation and toxicity of the human islet amyloid polypeptide

“…4,5 hIAPP oligomers, however, are believed to be the main toxic species, likely through disruption of cell membranes. [6][7][8] In light of the presumed closed relationship between hIAPP aggregation and its pathogenicity, inhibition of hIAPP selfassembly and bril formation have been a major strategy aimed at identifying therapeutic treatments to T2D. 9 Synthetic aggregation inhibitors such as short peptides 9,10 metal nanoparticles [11][12][13] have been reported.…”

Aggregation of biologically important peptides and proteins: inhibition or acceleration depending on protein and metal ion concentrations

“…35,36 Human IAPP (hIAPP) plays an active role in glycemic regulation by slowing gastric emptying and promoting satiety, thereby preventing postprandial spikes in blood glucose levels. However, it cannot be used as a drug for the treatment of diabetes because of its tendency to mis-fold and subsequently aggregate, resulting in the formation of cytotoxic brils, 13,37 which are strongly associated with b-cell degeneration in Type 2 Diabetes Mellitus (T2DM). 38 The rate of hIAPP aggregation depends on many factors that we discuss below.…”