The role of amylin, a gut-brain axis hormone, in metabolic and neurological disorders

Abstract

Amylin, also known as islet amyloid polypeptide (IAPP), is a pancreatic β-cell peptide hormone involved in satiation and control food intake. It is also produced in smaller quantities by neurons, the gastrointestinal tract, and spinal ganglia. Numerous studies have revealed that patients with type 2 diabetes mellitus (T2DM) and cognitive deficits exhibit IAPP deposits in the pancreas, brain, and blood vessels. IAPP has also been shown to exert neuroprotective effects against Alzheimer's disease (AD) and cognitive impairments. The objective of this review paper is to provide recent information about the pathophysiological roles of IAPP in metabolic and in neurological disorders, and its potential as a druggable target. We have reviewed preclinical and clinical human and animal research studies of IAPP. We discuss the IAPP structure, its receptors, and its physiological functions in metabolism, satiation, adiposity, obesity, and in the brain. Then we discuss its role in metabolic and neurological disorders like diabetes, obesity, bone disorder, neurodegeneration, cerebrovascular disorders, depression, alcohol use disorder, epilepsy, and in ovarian cysts. Overall, this review provides information on the progress of research into the roles of IAPP and its receptor in food intake, energy homeostasis, glucose regulation, satiation, and its role in metabolic and neurological disorders making it a potential target for therapeutic approaches. This review also suggests that the utilization of rodents overexpressing human IAPP in neurodegeneration models may unearth some significant therapeutic potentials for neurological disorders.

Keywords: amylin (IAPP); amyloid aggregates; calcitonin; neurodegeneration; satiation; type 2 diabetes.

FIGURE 1

Amino acid sequences and processing of the human Amylin (hIAPP), its domains and 3D crystal structure: (A) The 89 amino acid pre‐pro‐hIAPP having the signal peptide from residue 1 to residue 22 is cleaved. (B) The 67 residue pro‐hIAPP peptide cleaved by PC2, PC1/2 and CPE to a mature 37 residue hIAPP. (C) Mature hIAPP with a disulfide bond (green) between cysteine 2 and cysteine 7, amphipathic α‐helix and C‐terminal helix amidation (based on Westermark et al., 2011 ¹⁵ ). (D) 3D crystal structure of hIAPP (PDB: 5MGQ) showing the disulfide bond (yellow) and its spatial orientation as a U‐shaped protein. Residues 1–7 form a loop outside the U‐shape, residues 8–18 form the n‐terminal helix, residues 18–22 form a loop and residues 23–35 form the C‐terminal helix.

FIGURE 2

Illustration of the CT and IAPP receptor and reported and predicted protein interactions of hIAPP. (A) Receptor activity‐modifying protein 1–3 (RAMP1‐3) for complex with a CT receptor, a seven‐pass transmembrane receptor, making it IAPP receptor1‐3 (based on Hay et al., 2015 ⁹ ). (B) Representative illustration of the protein–protein interaction network of hIAPP. The 10 most common protein interactions of hIAPP were generated using the STRING database (https://string‐db.org/). The number of lines represents the relative interaction.

FIGURE 3

3D illustration of the hIAPP aggregate formation and multiple sequence alignment for orthologues of the IAPP protein: (A) Mature hIAPP as a monomer (PDB: 5MGQ). (B) Amyloid fibrils formation showing hIAPP aggregates without any solvent interactions in between (PDB: 7 M61). (C) β‐sheets showing hIAPP stacked with each other and having water interactions (Red balls) apart from their hydrogen bonds (PDB: 5KNZ). (D) Sequence alignment of the IAPP protein showing conservation of the cysteine 2 and 7 across vertebrates and invertebrates (based on Jeong et al., 2015 ⁴¹ ). Sequences shown are for human (Uniprot: P10997), mouse(Uniprot: P12968), chicken (Uniprot: A0A8V0YAM5), opossum (Uniprot: A0A5F8H6U1), coelacanth (Uniprot: H3AWW1), platypus (Uniprot: A0A6I8PDA3), frog (Uniprot: A0A1L8GQE1), and zebrafish (Uniprot: A0A286YA88). F15L and S20G are highly amyloidogenic while the G24P and I16P mutations have less amyloidogenicity as compared to wild type hIAPP.