title: The pathogenic mechanism of diabetes varies with the degree of overexpression and oligomerization of human amylin in the pancreatic islet β cells.
abstract: The aggregation of human amylin (hA) to form cytotoxic structures has been closely associated with the causation of type 2 diabetes. We sought to advance understanding of how altered expression and aggregation of hA might link β-cell degeneration with diabetes onset and progression, by comparing phenotypes between homozygous and hemizygous hA-transgenic mice. The homozygous mice displayed elevated islet hA that correlated positively with measures of oligomer formation (r=0.91; P<0.0001). They also developed hyperinsulinemia with transient insulin resistance during the prediabetes stage and then underwent rapid β-cell loss, culminating in severe juvenile-onset diabetes. The prediabetes stage was prolonged in the hemizygous mice, wherein β-cell dysfunction and extensive oligomer formation occurred in adulthood at a much later stage, when hA levels were lower (r=-0.60; P<0.0001). This is the first report to show that hA-evoked diabetes is associated with age, insulin resistance, progressive islet dysfunction, and β-cell apoptosis, which interact variably to cause the different diabetes syndromes. The various levels of hA elevation cause different extents of oligomer formation in the disease stages, thus eliciting early- or adult-onset diabetes syndromes, reminiscent of type 1 and 2 diabetes, respectively. Thus, the hA-evoked diabetes phenotypes differ substantively according to degree of amylin overproduction. These findings are relevant to the understanding of the pathogenesis and the development of experimental therapeutics for diabetes.
authors.affiliation: The School of Biological Sciences and The Maurice Wilkins Centre for Molecular BioDiscovery, Faculty of Science, University of Auckland, Auckland, New Zealand.
authors.forename: Shaoping
authors.initials: S
authors.lastname: Zhang
authors.affiliation: The School of Biological Sciences and.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: The School of Biological Sciences and.
authors.forename: Chia Lin
authors.initials: CL
authors.lastname: Chuang
authors.affiliation: The School of Biological Sciences and.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Li
authors.affiliation: The School of Biological Sciences and.
authors.forename: Maggie
authors.initials: M
authors.lastname: Au
authors.affiliation: The School of Biological Sciences and.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: The School of Biological Sciences and The Maurice Wilkins Centre for Molecular BioDiscovery, Faculty of Science, University of Auckland, Auckland, New Zealand.
authors.forename: Anthony R J
authors.initials: AR
authors.lastname: Phillips
authors.affiliation: The School of Biological Sciences and.
authors.forename: David W
authors.initials: DW
authors.lastname: Scott
authors.affiliation: The School of Biological Sciences and The Maurice Wilkins Centre for Molecular BioDiscovery, Faculty of Science, University of Auckland, Auckland, New Zealand Centre for Advanced Discovery and Experimental Therapeutics, Central Manchester University Hospitals National Health Service (NHS) Foundation Trust, Manchester, UK; and Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, UK g.cooper@auckland.ac.nz.
authors.forename: Garth J S
authors.initials: GJ
authors.lastname: Cooper
mesh_terms: D000818:Animals; D001483:Base Sequence; D001704:Biopolymers / Q000737:chemistry / Q000378:metabolism*; D016923:Cell Death; D017931:DNA Primers; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood; D058228:Islet Amyloid Polypeptide / Q000737:chemistry / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001704:Biopolymers; D017931:DNA Primers; D007328:Insulin; D058228:Islet Amyloid Polypeptide
keywords: apoptosis; gene–dosage effect; insulin resistance; peptide aggregation; transgenic mice