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Islet Amyloid Polypeptide: Structure, Function, and Pathophysiology

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Akter, Rehana, Cao, Ping, Noor, Harris, Ridgway, Zachary, Tu, Ling-Hsien, Wang, Hui, Wong, Amy G., Zhang, Xiaoxue, Abedini, Andisheh, Schmidt, Ann Marie, Raleigh, Daniel P.·2016·Journal of Diabetes Research
DOI 10.1155/2016/2798269PMC PMC4662979
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Abstract

The hormone islet amyloid polypeptide (IAPP, or amylin) plays a role in glucose homeostasis but aggregates to form islet amyloid in type-2 diabetes. Islet amyloid formation contributes to β -cell dysfunction and death in the disease and to the failure of islet transplants. Recent work suggests a role for IAPP aggregation in cardiovascular complications of type-2 diabetes and hints at a possible role in type-1 diabetes. The mechanisms of IAPP amyloid formation in vivo or in vitro are not understood and the mechanisms of IAPP induced β -cell death are not fully defined. Activation of the inflammasome, defects in autophagy, ER stress, generation of reactive oxygen species, membrane disruption, and receptor mediated mechanisms have all been proposed to play a role. Open questions in the field include the relative importance of the various mechanisms of β -cell death, the relevance of reductionist biophysical studies to the situation in vivo , the molecular mechanism of amyloid formation in vitro and in vivo , the factors which trigger amyloid formation in type-2 diabetes, the potential role of IAPP in type-1 diabetes, the development of clinically relevant inhibitors of islet amyloidosis toxicity, and the design of soluble, bioactive variants of IAPP for use as adjuncts to insulin therapy.

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Figures

Figure 1 Primary sequences of human CGRP and of IAPP from different species. Residues that differ from the human IAPP sequence are in italics and underlined. The biologically active sequences all contain a disulfide bridge between Cys-2 and Cys-7 and have an amidated C-terminus. Primates and cats have been reported to form islet amyloid while, rodents, and dogs do not. Ferret and porcine IAPP are reported to be significantly less amyloidogenic than human IAPP. The ability of cow, bear, and puffer fish IAPP to form amyloid have not been investigated. Islet amyloid is found in the degu, a rodent, but it is derived from insulin, not from IAPP. Only partial sequences are available for rabbit and hare.
Figure 1 Primary sequences of human CGRP and of IAPP from different species. Residues that differ from the human IAPP sequence are in italics and underlined. The biologically active sequences all contain a disulfide bridge between Cys-2 and Cys-7 and have an amidated C-terminus. Primates and cats have been reported to form islet amyloid while, rodents, and dogs do not. Ferret and porcine IAPP are reported to be significantly less amyloidogenic than human IAPP. The ability of cow, bear, and puffer fish IAPP to form amyloid have not been investigated. Islet amyloid is found in the degu, a rodent, but it is derived from insulin, not from IAPP. Only partial sequences are available for rabbit and hare.CC BY · PubMed Central
Figure 2 Processing of human PreProIAPP to produce mature IAPP. (a) The primary sequence of the 89-residue human PreProIAPP. The 22-residue signal sequence is shown in italics; the N- and C-terminal proIAPP flanking regions are underlined. (b) Primary sequence of the 67-residue proform of human IAPP. Pro-hIAPP is cleaved by the prohormone convertases PC(1/3) and PC2 at two conserved dibasic sites, indicated by arrows. The amidated C-terminus is produced after further processing by CPE/PAM. (c) The sequence of the mature 37-residue human IAPP. The biologically active peptide has an amidated C-terminus and a disulfide bridge between Cys-2 and Cys-7.
Figure 2 Processing of human PreProIAPP to produce mature IAPP. (a) The primary sequence of the 89-residue human PreProIAPP. The 22-residue signal sequence is shown in italics; the N- and C-terminal proIAPP flanking regions are underlined. (b) Primary sequence of the 67-residue proform of human IAPP. Pro-hIAPP is cleaved by the prohormone convertases PC(1/3) and PC2 at two conserved dibasic sites, indicated by arrows. The amidated C-terminus is produced after further processing by CPE/PAM. (c) The sequence of the mature 37-residue human IAPP. The biologically active peptide has an amidated C-terminus and a disulfide bridge between Cys-2 and Cys-7.CC BY · PubMed Central
Figure 3 A model of the hIAPP fibril based on crystal structures of small peptide fragments of hIAPP. (a) Primary sequence of human IAPP. Residues color-coded red are found in the first β-strand in the fibril; those colored blue in the second β-strand and the ones located in the partially ordered loop that connects the two stands are colored green. The first seven residues are believed to be outside of the structured core of the fibril and are color-coded black. (b) Top down view of the model with several key residues shown. The N-termini are labeled. (c) View rotated by 90° showing the arrangement of the two stacks as a ribbon diagram.
Figure 3 A model of the hIAPP fibril based on crystal structures of small peptide fragments of hIAPP. (a) Primary sequence of human IAPP. Residues color-coded red are found in the first β-strand in the fibril; those colored blue in the second β-strand and the ones located in the partially ordered loop that connects the two stands are colored green. The first seven residues are believed to be outside of the structured core of the fibril and are color-coded black. (b) Top down view of the model with several key residues shown. The N-termini are labeled. (c) View rotated by 90° showing the arrangement of the two stacks as a ribbon diagram.CC BY · PubMed Central
Figure 4 Primary sequences of human IAPP, Pramlintide, and four rationally designed sequences with improved solubility, denoted by Seq-A through Seq-D. The final sequence, denoted by hIAPP ∗, represents a family of designed bioactive analogs of human IAPP in which one of the Asn residues indicated with a ( ∗) has been glycosylated.
Figure 4 Primary sequences of human IAPP, Pramlintide, and four rationally designed sequences with improved solubility, denoted by Seq-A through Seq-D. The final sequence, denoted by hIAPP ∗, represents a family of designed bioactive analogs of human IAPP in which one of the Asn residues indicated with a ( ∗) has been glycosylated.CC BY · PubMed Central

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Show all 181 references

Research works printed but not linked: 6

  1. 2010, Angewandte Chemie International Edition, 45, 6476
  2. 10.1210/en.140.6.2924 · DOI · Paper page
  3. 10.1021/bi00044a038 · DOI
  4. 1992, Archives of Pathology and Laboratory Medicine, 116, 951
  5. 10.1210/en.143.2.339 · DOI · Paper page
  6. 2005, Current Opinion in Endocrinology and Diabetes, 12, 303

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Metadata

Authors
Akter, R., Cao, P., Noor, H., Ridgway, Z., Tu, L.-H., Wang, H., Wong, A. G., Zhang, X., Abedini, A., Schmidt, A. M., & Raleigh, D. P.
Affiliations
  • Stony Brook University (US)
  • NYU Langone Health (US)
  • University College London (GB)
Corresponding author
Raleigh, Daniel P.
ORCID
Venue
Journal of Diabetes Research
Publisher
Wiley
Published
2016
Volume
2016
Pages
1-18
ISSN
  • 2314-6745 (ISSN-L)
  • 2314-6753
DOI
10.1155/2016/2798269
PMC
PMC4662979
OpenAlex
W2209022283
Cited by
273
References
181
Citations by year
2026: 23 · 2025: 33 · 2024: 37 · 2023: 14 · 2022: 26 · 2021: 32 · 2020: 36 · 2019: 21 · 2018: 28 · 2017: 13 · 2016: 10
FWCI
3.26
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Diabetes Research (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
National Institutes of Health (GM078114, 5T32GM09271405)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Keywords
amylin, islet amyloid, type 2 diabetes, beta-cell dysfunction, beta-cell death, islet transplantation, cardiovascular complications, type 1 diabetes, inflammasome, autophagy, endoplasmic reticulum stress, reactive oxygen species, glucose homeostasis
MeSH terms
Diabetes Mellitus, Type 2, Humans, Islets of Langerhans, Structure-Activity Relationship, Insulin-Secreting Cells, Islet Amyloid Polypeptide

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