Toxic human islet amyloid polypeptide (h-IAPP) oligomers are intracellular, and vaccination to induce anti-toxic oligomer antibodies does not prevent h-IAPP-induced β-cell apoptosis in h-IAPP transgenic mice

Chia Yu Lin, Tatyana Gurlo, Rakez Kayed, Alexandra E. Butler, Leena Haataja, Charles G. Glabe, Peter C. Butler

Research output: Contribution to journalArticle

128 Citations (Scopus)

Abstract

OBJECTIVE - Islets in type 2 diabetes are characterized by a deficit in β-cells, increased β-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). The toxic form of amyloidogenic protein oligomers are distinct and smaller than amyloid fibrils and act by disrupting membranes. Using antibodies that bind to toxic IAPP oligomers (but not IAPP monomers or fibrils) and a vaccination-based approach, we sought to establish whether IAPP toxic oligomers form intra- or extracellularly and whether vaccination to induce anti-toxic oligomer antibodies prevents IAPP-induced apoptosis in human IAPP (h-IAPP) transgenic mice. RESEARCH DESIGN AND METHODS - Pancreas was sampled from two h-IAPP transgenic mouse models and examined by immunohistochemistry for toxic oligomers. The same murine models were vaccinated with toxic oligomers of Alzheimer protein (AβP1-40) and anti-oligomer titers, and blood glucose and islet pathology were monitored. RESULTS - Toxic oligomers were detected intracellularly in ∼20-40% of h-IAPP transgenic β-cells. Vaccine induced high titers of anti-h-IAPP toxic oligomers in both transgenic models, but β-cell apoptosis was, if anything, further increased in vaccinated mice, so that neither loss of β-cell mass nor diabetes onset was delayed. CONCLUSIONS - IAPP toxic oligomers form in h-IAPP transgenic mouse models, and anti-toxic oligomer antibodies do not prevent h-IAPP-induced β-cell apoptosis. These data suggest that prevention of h-IAPP oligomer formation may be more useful than a vaccination-based approach in the prevention of type 2 diabetes.

Original languageEnglish (US)
Pages (from-to)1324-1332
Number of pages9
JournalDiabetes
Volume56
Issue number5
DOIs
StatePublished - May 2007
Externally publishedYes

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Islet Amyloid Polypeptide
Poisons
Transgenic Mice
Vaccination
Apoptosis
Antibodies
Amyloid
Type 2 Diabetes Mellitus
Amyloidogenic Proteins
Islets of Langerhans

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Toxic human islet amyloid polypeptide (h-IAPP) oligomers are intracellular, and vaccination to induce anti-toxic oligomer antibodies does not prevent h-IAPP-induced β-cell apoptosis in h-IAPP transgenic mice. / Lin, Chia Yu; Gurlo, Tatyana; Kayed, Rakez; Butler, Alexandra E.; Haataja, Leena; Glabe, Charles G.; Butler, Peter C.

In: Diabetes, Vol. 56, No. 5, 05.2007, p. 1324-1332.

Research output: Contribution to journalArticle

Lin, Chia Yu ; Gurlo, Tatyana ; Kayed, Rakez ; Butler, Alexandra E. ; Haataja, Leena ; Glabe, Charles G. ; Butler, Peter C. / Toxic human islet amyloid polypeptide (h-IAPP) oligomers are intracellular, and vaccination to induce anti-toxic oligomer antibodies does not prevent h-IAPP-induced β-cell apoptosis in h-IAPP transgenic mice. In: Diabetes. 2007 ; Vol. 56, No. 5. pp. 1324-1332.
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title = "Toxic human islet amyloid polypeptide (h-IAPP) oligomers are intracellular, and vaccination to induce anti-toxic oligomer antibodies does not prevent h-IAPP-induced β-cell apoptosis in h-IAPP transgenic mice",
abstract = "OBJECTIVE - Islets in type 2 diabetes are characterized by a deficit in β-cells, increased β-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). The toxic form of amyloidogenic protein oligomers are distinct and smaller than amyloid fibrils and act by disrupting membranes. Using antibodies that bind to toxic IAPP oligomers (but not IAPP monomers or fibrils) and a vaccination-based approach, we sought to establish whether IAPP toxic oligomers form intra- or extracellularly and whether vaccination to induce anti-toxic oligomer antibodies prevents IAPP-induced apoptosis in human IAPP (h-IAPP) transgenic mice. RESEARCH DESIGN AND METHODS - Pancreas was sampled from two h-IAPP transgenic mouse models and examined by immunohistochemistry for toxic oligomers. The same murine models were vaccinated with toxic oligomers of Alzheimer protein (AβP1-40) and anti-oligomer titers, and blood glucose and islet pathology were monitored. RESULTS - Toxic oligomers were detected intracellularly in ∼20-40{\%} of h-IAPP transgenic β-cells. Vaccine induced high titers of anti-h-IAPP toxic oligomers in both transgenic models, but β-cell apoptosis was, if anything, further increased in vaccinated mice, so that neither loss of β-cell mass nor diabetes onset was delayed. CONCLUSIONS - IAPP toxic oligomers form in h-IAPP transgenic mouse models, and anti-toxic oligomer antibodies do not prevent h-IAPP-induced β-cell apoptosis. These data suggest that prevention of h-IAPP oligomer formation may be more useful than a vaccination-based approach in the prevention of type 2 diabetes.",
author = "Lin, {Chia Yu} and Tatyana Gurlo and Rakez Kayed and Butler, {Alexandra E.} and Leena Haataja and Glabe, {Charles G.} and Butler, {Peter C.}",
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T1 - Toxic human islet amyloid polypeptide (h-IAPP) oligomers are intracellular, and vaccination to induce anti-toxic oligomer antibodies does not prevent h-IAPP-induced β-cell apoptosis in h-IAPP transgenic mice

AU - Lin, Chia Yu

AU - Gurlo, Tatyana

AU - Kayed, Rakez

AU - Butler, Alexandra E.

AU - Haataja, Leena

AU - Glabe, Charles G.

AU - Butler, Peter C.

PY - 2007/5

Y1 - 2007/5

N2 - OBJECTIVE - Islets in type 2 diabetes are characterized by a deficit in β-cells, increased β-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). The toxic form of amyloidogenic protein oligomers are distinct and smaller than amyloid fibrils and act by disrupting membranes. Using antibodies that bind to toxic IAPP oligomers (but not IAPP monomers or fibrils) and a vaccination-based approach, we sought to establish whether IAPP toxic oligomers form intra- or extracellularly and whether vaccination to induce anti-toxic oligomer antibodies prevents IAPP-induced apoptosis in human IAPP (h-IAPP) transgenic mice. RESEARCH DESIGN AND METHODS - Pancreas was sampled from two h-IAPP transgenic mouse models and examined by immunohistochemistry for toxic oligomers. The same murine models were vaccinated with toxic oligomers of Alzheimer protein (AβP1-40) and anti-oligomer titers, and blood glucose and islet pathology were monitored. RESULTS - Toxic oligomers were detected intracellularly in ∼20-40% of h-IAPP transgenic β-cells. Vaccine induced high titers of anti-h-IAPP toxic oligomers in both transgenic models, but β-cell apoptosis was, if anything, further increased in vaccinated mice, so that neither loss of β-cell mass nor diabetes onset was delayed. CONCLUSIONS - IAPP toxic oligomers form in h-IAPP transgenic mouse models, and anti-toxic oligomer antibodies do not prevent h-IAPP-induced β-cell apoptosis. These data suggest that prevention of h-IAPP oligomer formation may be more useful than a vaccination-based approach in the prevention of type 2 diabetes.

AB - OBJECTIVE - Islets in type 2 diabetes are characterized by a deficit in β-cells, increased β-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). The toxic form of amyloidogenic protein oligomers are distinct and smaller than amyloid fibrils and act by disrupting membranes. Using antibodies that bind to toxic IAPP oligomers (but not IAPP monomers or fibrils) and a vaccination-based approach, we sought to establish whether IAPP toxic oligomers form intra- or extracellularly and whether vaccination to induce anti-toxic oligomer antibodies prevents IAPP-induced apoptosis in human IAPP (h-IAPP) transgenic mice. RESEARCH DESIGN AND METHODS - Pancreas was sampled from two h-IAPP transgenic mouse models and examined by immunohistochemistry for toxic oligomers. The same murine models were vaccinated with toxic oligomers of Alzheimer protein (AβP1-40) and anti-oligomer titers, and blood glucose and islet pathology were monitored. RESULTS - Toxic oligomers were detected intracellularly in ∼20-40% of h-IAPP transgenic β-cells. Vaccine induced high titers of anti-h-IAPP toxic oligomers in both transgenic models, but β-cell apoptosis was, if anything, further increased in vaccinated mice, so that neither loss of β-cell mass nor diabetes onset was delayed. CONCLUSIONS - IAPP toxic oligomers form in h-IAPP transgenic mouse models, and anti-toxic oligomer antibodies do not prevent h-IAPP-induced β-cell apoptosis. These data suggest that prevention of h-IAPP oligomer formation may be more useful than a vaccination-based approach in the prevention of type 2 diabetes.

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U2 - 10.2337/db06-1579

DO - 10.2337/db06-1579

M3 - Article

VL - 56

SP - 1324

EP - 1332

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 5

ER -