High Expression Rates of Human Islet Amyloid Polypeptide Induce Endoplasmic Reticulum Stress–Mediated β-Cell Apoptosis, a Characteristic of Humans With Type 2 but Not Type 1 Diabetes

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 toβ-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 formationin vivoorin vitroare not understood and the mechanisms of IAPP inducedβ-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 ofβ-cell death, the relevance of reductionist biophysical studies to the situationin vivo, the molecular mechanism of amyloid formationin vitroandin 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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Recombinant human islet amyloid polypeptide forms shorter fibrils and mediates β-cell apoptosis via generation of oxidative stress

Biochemical Journal ◽

10.1042/bcj20170323 ◽

2017 ◽

Vol 474 (23) ◽

pp. 3915-3934 ◽

Cited By ~ 10

Author(s):

Richa Dubey ◽

Pooja Minj ◽

Nikita Malik ◽

Devika M. Sardesai ◽

Shruti H. Kulkarni ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Apoptosis ◽

Protein Misfolding ◽

Comprehensive Evaluation ◽

Islet Amyloid Polypeptide ◽

Human Islet ◽

Β Cell ◽

Islet Amyloid ◽

Isolated Pancreatic Islets ◽

Human Islet Amyloid Polypeptide

Protein misfolding and aggregation play an important role in many human diseases including Alzheimer's, Parkinson's and type 2 diabetes mellitus (T2DM). The human islet amyloid polypeptide (hIAPP) forms amyloid plaques in the pancreas of T2DM subjects (>95%) that are involved in deteriorating islet function and in mediating β-cell apoptosis. However, the detailed mechanism of action, structure and nature of toxic hIAPP species responsible for this effect remains elusive to date mainly due to the high cost associated with the chemical synthesis of pure peptide required for these studies. In the present work, we attempted to obtain structural and mechanistic insights into the hIAPP aggregation process using recombinant hIAPP (rhIAPP) isolated from Escherichia coli. Results from biophysical and structural studies indicate that the rhIAPP self-assembled into highly pure, β-sheet-rich amyloid fibrils with uniform morphology. rhIAPP-mediated apoptosis in INS-1E cells was associated with increased oxidative stress and changes in mitochondrial membrane potential. The transcript levels of apoptotic genes - Caspase-3 and Bax were found to be up-regulated, while the levels of the anti-apoptotic gene - Bcl2 were down-regulated in rhIAPP-treated cells. Additionally, the expression levels of genes involved in combating oxidative stress namely Catalase, SOD1 and GPx were down-regulated. rhIAPP exposure also affected glucose-stimulated insulin secretion from isolated pancreatic islets. The aggregation of rhIAPP also occurred significantly faster when compared with that of the chemically synthesized peptide. We also show that the rhIAPP fibrils were shorter and more cytotoxic. In summary, our study is one among the few to provide comprehensive evaluation of structural, biophysical and cytotoxic properties of rhIAPP.

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Induction of endoplasmic reticulum stress-induced β-cell apoptosis and accumulation of polyubiquitinated proteins by human islet amyloid polypeptide

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00318.2007 ◽

2007 ◽

Vol 293 (6) ◽

pp. E1656-E1662 ◽

Cited By ~ 93

Author(s):

Chang-jiang Huang ◽

Leena Haataja ◽

Tatyana Gurlo ◽

Alexandra E. Butler ◽

Xiuju Wu ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Mouse Model ◽

Transgenic Mice ◽

Er Stress ◽

Cell Apoptosis ◽

Cell Mass ◽

Islet Amyloid Polypeptide ◽

Protein Overexpression ◽

Β Cell ◽

Islet Amyloid

The islet in type 2 diabetes is characterized by an ∼60% β-cell deficit, increased β-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). Human IAPP (hIAPP) but not rodent IAPP (rIAPP) forms toxic oligomers and amyloid fibrils in an aqueous environment. We previously reported that overexpression of hIAPP in transgenic rats triggered endoplasmic reticulum (ER) stress-induced apoptosis in β-cells. In the present study, we sought to establish whether the cytotoxic effects of hIAPP depend on its propensity to oligomerize, rather than as a consequence of protein overexpression. To accomplish this, we established a novel homozygous mouse model overexpressing rIAPP at a comparable expression rate and, on the same background, as a homozygous transgenic hIAPP mouse model previously reported to develop diabetes associated with β-cell loss. We report that by 10 wk of age hIAPP mice develop diabetes with a deficit in β-cell mass due to increased β-cell apoptosis. The rIAPP transgenic mice counterparts do not develop diabetes or have decreased β-cell mass. Both rIAPP and hIAPP transgenic mice have increased expression of BiP, but only hIAPP transgenic mice have elevated ER stress markers (X-box-binding protein-1, nuclear localized CCAAT/enhancer binding-protein homologous protein, active caspase-12, and accumulation of ubiquitinated proteins). These findings indicate that the β-cell toxic effects of hIAPP depend on the propensity of IAPP to aggregate, but not on the consequence of protein overexpression.

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Environmental Factors Contribute to β Cell Endoplasmic Reticulum Stress and Neo-Antigen Formation in Type 1 Diabetes

Frontiers in Endocrinology ◽

10.3389/fendo.2017.00262 ◽

2017 ◽

Vol 8 ◽

Cited By ~ 10

Author(s):

Meghan L. Marré ◽

Jon D. Piganelli

Keyword(s):

Endoplasmic Reticulum ◽

Type 1 Diabetes ◽

Environmental Factors ◽

Endoplasmic Reticulum Stress ◽

Β Cell

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Ruthenium complexes as inhibitors of human islet amyloid polypeptide aggregation, an effect that prevents beta cell apoptosis

RSC Advances ◽

10.1039/c4ra15152f ◽

2015 ◽

Vol 5 (23) ◽

pp. 17405-17412 ◽

Cited By ~ 14

Author(s):

Lijuan Ma ◽

Yuanting Fu ◽

Lianling Yu ◽

Xiaoling Li ◽

Wenjie Zheng ◽

...

Keyword(s):

Beta Cell ◽

Cell Apoptosis ◽

Cell Damage ◽

Islet Amyloid Polypeptide ◽

Ruthenium Complexes ◽

Human Islet ◽

Ros Generation ◽

Beta Cell Apoptosis ◽

Islet Amyloid ◽

Application Potential

Herein we show that ruthenium complexes could inhibit fibrosis of hIAPP and protect the hIAPP-induced cell damage by suppressing ROS generation, indicating the application potential of the complexes in treatment of T2DM by targeting hIAPP.

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