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Cytotoxic Mechanisms of Islet Amyloid Polypeptide in the Pathogenesis of Type-2 Diabetes Mellitus (T2DM)

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Book cover Non-fibrillar Amyloidogenic Protein Assemblies - Common Cytotoxins Underlying Degenerative Diseases

Abstract

Diabetes mellitus (DM) is a chronic syndrome that occurs due to loss of the insulin-producing β-cells in the islets of Langerhans of the pancreas by a β-cell-specific autoimmune process, leading to insulin deficiency (type-1 DM, T1DM) or when insufficient amounts of insulin are produced by β-cells, or when resistance to the action of insulin occurs in different tissues (type-2 DM, T2DM). Several mechanisms may contribute to the progressive β-cell failure in T2DM, including loss of β-cell mass, β-cell exhaustion, and the cytotoxic effects of elevated glucose and lipid levels. Another hallmark of T2DM is the accumulation of β-cell-produced amylin, also called islet amyloid polypeptide (IAPP), which forms amyloid that is present in approximately 95% of T2DM patients.

IAPP is a 37-amino-acid peptide, which is co-synthesized, co-packaged within the Golgi apparatus, and co-expressed with insulin upon exposure to glucose stimulation (nutrient stimuli). IAPP aggregation induces β-cell death and decreases β-cell proliferation. Several mechanisms have been hypothesized to explain IAPP cytotoxicity. First, IAPP may induce apoptosis through an extrinsic pathway involving overexpression of Fas ligand and IL-1 in β-cells due to glucose toxicity; and an intrinsic pathway, causing endoplasmic reticulum stress due to accumulation of aggregated proteins. Second, IAPP interaction with the cell membrane may lead to membrane permeabilization by IAPP oligomers and cause formation of membrane pores, or the process of IAPP aggregation itself can cause membrane disruption.

Development of new methods to decrease islet amyloid formation is important for prevention of β-cell mass loss and functional decline due to aggregated IAPP cytotoxicity. Reduction of amyloid formation may lead to effective treatment for T2DM and to a better understanding of the exact mechanism of IAPP cytotoxicity, which currently is debatable.

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Abbreviations

AP:

Area Postrema

A1c:

Glycated hemoglobin

C/EBP:

CCAAT-Enhancer-Binding Protein

CHOP:

C/EBP Homologous Protein

DISC:

Death-Inducing Signaling Complex

DM:

Diabetes Mellitus

T1DM:

Type-1 Diabetes Mellitus

T2DM:

Type-2 Diabetes Mellitus

ER:

Endoplasmatic Reticulum

FDA:

US Food and Drug Administration

GAGs:

Glycosaminoglycans

IAPP:

Islet Amyloid Polypeptide

hIAPP:

Human IAPP

rIAPP:

Rat IAPP

IDE:

Insulin Degrading Enzyme

IPBN:

Parabrachial Nucleus

JNK1:

Jun N-terminal Kinase 1

MAPK:

p38 Mitogen-Activated Protein Kinase

NTS:

Nucleus of the Solitary Tract

TUNEL:

Terminal deoxynucleotidyl transferase-mediated dUTP Nick-End Labeling

TXNIP:

Thioredoxin-Interacting Protein

UPR:

Unfolded-protein Response

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  1. Chemistry Institute, Pos doc of NUCEL (Cell and Molecular Therapy Center), University of São Paulo, Av. Prof. Lineu Prestes, 748 Bld 9 room 964, 05508-000, São Paulo, SP, Brazil

    Theri Leica Degaki Ph.D. & Mari Cleide Sogayar Ph.D.

  2. Department of Neurology, David Geffen School of Medicine at UCLA, Neuroscience Research Building 1, Room 455, 635 Charles E. Young Drive South, Los Angeles, CA, 90095-7334, USA

    Dahabada H. J. Lopes Ph.D.

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  1. Theri Leica Degaki Ph.D.
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Correspondence to Theri Leica Degaki Ph.D. .

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  1. , Research School of Biology, Australian National University, Linnaeus Way, Canberra, 0200, Aust Capital Terr, Australia

    Farid Rahimi

  2. , Neurology, University of California at Los Angeles, Charles E. Young Drive South 635, Los Angeles, 90095-7334, California, USA

    Gal Bitan

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Degaki, T.L., Lopes, D.H.J., Sogayar, M.C. (2012). Cytotoxic Mechanisms of Islet Amyloid Polypeptide in the Pathogenesis of Type-2 Diabetes Mellitus (T2DM). In: Rahimi, F., Bitan, G. (eds) Non-fibrillar Amyloidogenic Protein Assemblies - Common Cytotoxins Underlying Degenerative Diseases. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-2774-8_7

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