Is type 2 diabetes an amyloidosis and does it really matter (to patients)?

Cooper, Garth J. S.; Aitken, Jacqueline F.; Zhang, Shaoping

doi:10.1007/s00125-010-1715-y

Cited by 24 publications

(26 citation statements)

References 56 publications

(77 reference statements)

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“…In summary, there are compelling genetic, biochemical, cellular and animal data to support both natural biological functions for hIAPP and a toxic role of hIAPP leading to β-cell death [14], [34], [37], [104]–[107]. Combining these functional data with our structural models of four IAPP variants, we put forth the structure-activity relationship (SAR) that the helix-coil conformations are responsible for the normal hormone function of IAPP; and that β-rich conformations of IAPP may be linked to β-rich aggregation and contribute, along with other mechanisms, to the toxicity of IAPP.…”

Section: Discussionmentioning

confidence: 99%

“…Further support for a toxic role of IAPP aggregates include 1) the observation that human hIAPP amyloids play a deleterious role in transplanted islet tissue [27]–[30] and that aggregates of synthetic hIAPP induce apoptotic β-cell death in vitro [31]–[33]. 2) The recent experimental observation of two parallel pathways leading to β-cell apoptosis by hIAPP: one involving extrinsic death signals triggered by extracellular hIAPP aggregates [34], [35], and an intrinsic endoplasmic reticulum (ER) stress pathway linked to the presence of intracellular hIAPP aggregates [36]–[40]. 3) Experimental evidence of a membrane-damaging effect of hIAPP aggregates leading to β-cell dysfunction [41], [42].…”

Section: Introductionmentioning

confidence: 99%

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Structural Similarities and Differences between Amyloidogenic and Non-Amyloidogenic Islet Amyloid Polypeptide (IAPP) Sequences and Implications for the Dual Physiological and Pathological Activities of These Peptides

Shea

2013

PLoS Comput Biol

123

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IAPP, a 37 amino-acid peptide hormone belonging to the calcitonin family, is an intrinsically disordered protein that is coexpressed and cosecreted along with insulin by pancreatic islet β-cells in response to meals. IAPP plays a physiological role in glucose regulation; however, in certain species, IAPP can aggregate and this process is linked to β-cell death and Type II Diabetes. Using replica exchange molecular dynamics with extensive sampling (16 replicas per sequence and 600 ns per replica), we investigate the structure of the monomeric state of two species of aggregating peptides (human and cat IAPP) and two species of non-aggregating peptides (pig and rat IAPP). Our simulations reveal that the pig and rat conformations are very similar, and consist of helix-coil and helix-hairpin conformations. The aggregating sequences, on the other hand, populate the same helix-coil and helix-hairpin conformations as the non-aggregating sequence, but, in addition, populate a hairpin structure. Our exhaustive simulations, coupled with available peptide-activity data, leads us to a structure-activity relationship (SAR) in which we propose that the functional role of IAPP is carried out by the helix-coil conformation, a structure common to both aggregating and non-aggregating species. The pathological role of this peptide may have multiple origins, including the interaction of the helical elements with membranes. Nonetheless, our simulations suggest that the hairpin structure, only observed in the aggregating species, might be linked to the pathological role of this peptide, either as a direct precursor to amyloid fibrils, or as part of a cylindrin type of toxic oligomer. We further propose that the helix-hairpin fold is also a possible aggregation prone conformation that would lead normally non-aggregating variants of IAPP to form fibrils under conditions where an external perturbation is applied. The SAR relationship is used to suggest the rational design of therapeutics for treating diabetes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structural Similarities and Differences between Amyloidogenic and Non-Amyloidogenic Islet Amyloid Polypeptide (IAPP) Sequences and Implications for the Dual Physiological and Pathological Activities of These Peptides

Shea

2013

PLoS Comput Biol

123

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“…Different strains of hA‐transgenic mice have been constructed by several groups, and each strain exhibits particular phenotypic characteristics (15, 34, 35, 38, 39, 46, 47). The differences in genetic backgrounds of these different models, taken together with possible genetic background‐transgene interactions and differences in hA transgene expression, could account for the between‐model phenotypic variation that has been reported (14, 38). Our hemizygous mice reported here may be closest to the homozygous mice reported by Janson et al (15).…”

Section: Discussionmentioning

confidence: 99%

The pathogenic mechanism of diabetes varies with the degree of overexpression and oligomerization of human amylin in the pancreatic islet β cells

Zhang

Liu²,

Chuang³

et al. 2014

FASEB j.

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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.

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“…The process of amyloid formation by hIAPP is toxic to cultured β-cells and induces apoptosis and β-cell dysfunction in isolated human islets [6–8,44,51,52,53 •• ]. The literature strongly suggests that there are multiple mechanisms of hIAPP induced β-cell dysfunction and cell death.…”

Section: The Mechanism Of Hiapp Induced β-Cell Toxicity and The Initimentioning

confidence: 99%

Aggregation of islet amyloid polypeptide: from physical chemistry to cell biology

Cao

Abedini

Raleigh

2013

Current Opinion in Structural Biology

107

136

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Amyloid formation in the pancreas by islet amyloid polypeptide (IAPP) leads to β-cell death and dysfunction, contributing to islet transplant failure and to type-2 diabetes. IAPP is stored in the β-cell insulin secretory granules and cosecreted with insulin in response to β-cell secretagogues. IAPP is believed to play a role in the control of food intake, in controlling gastric emptying and in glucose homeostasis. The polypeptide is natively unfolded in its monomeric state, but is one of the most amyloidogenic sequences known. The mechanisms of IAPP amyloid formation in vivo and in vitro are not understood; the mechanisms of IAPP induced cell death are unclear; and the nature of the toxic species is not completely defined. Recent work is shedding light on these important issues.

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Is type 2 diabetes an amyloidosis and does it really matter (to patients)?

Cited by 24 publications

References 56 publications

Structural Similarities and Differences between Amyloidogenic and Non-Amyloidogenic Islet Amyloid Polypeptide (IAPP) Sequences and Implications for the Dual Physiological and Pathological Activities of These Peptides

Structural Similarities and Differences between Amyloidogenic and Non-Amyloidogenic Islet Amyloid Polypeptide (IAPP) Sequences and Implications for the Dual Physiological and Pathological Activities of These Peptides

The pathogenic mechanism of diabetes varies with the degree of overexpression and oligomerization of human amylin in the pancreatic islet β cells

Aggregation of islet amyloid polypeptide: from physical chemistry to cell biology

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