Inhibition of human IAPP fibril formation does not prevent β-cell death: Evidence for distinct actions of oligomers and fibrils of human IAPP

Juris J. Meier, Rakez Kayed, Chia Yu Lin, Tatyana Gurlo, Leena Haataja, Sajith Jayasinghe, Ralf Langen, Charles G. Glabe, Peter C. Butler

Research output: Contribution to journalArticle

135 Citations (Scopus)

Abstract

Type 2 diabetes mellitus (T2DM) is characterized by an ∼60% deficit in β-cell mass, increased β-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). Human IAPP (hIAPP) forms oligomers, leading to either amyloid fibrils or toxic oligomers in an aqueous solution in vitro. Either application of hIAPP on or overexpression of hIAPP in cells induces apoptosis. It remains controversial whether the fibrils or smaller toxic oligomers induce β-cell apoptosis. Rifampicin prevents hIAPP amyloid fibril formation and has been proposed as a potential target for prevention of T2DM. We examined the actions of rifampicin on hIAPP amyloid fibril and toxic oligomer formation as well as its ability to protect β-cells from either application of hIAPP or endogenous overexpression of hIAPP (transgenic rats and adenovirus-transduced β-cells). We report that rifampicin (Acocella G. Clin Pharmacokinet 3: 108 -127, 1978) prevents hIAPP fibril formation, but not formation of toxic hIAPP oligomers (Bates G. Lancet 361: 1642-1644, 2003), and does not protect β-cells from apoptosis induced by either overexpression or application of hIAPP. These data emphasize that toxic hIAPP oligomers, rather than hIAPP fibrils, initiate β-cell apoptosis and that screening tools to identify inhibitors of amyloid fibril formation are likely to be less useful than those that identify inhibitors of toxic oligomer formation. Finally, rifampicin and related molecules do not appear to be useful as candidates for prevention of T2DM.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume291
Issue number6
DOIs
StatePublished - 2006
Externally publishedYes

Fingerprint

Islet Amyloid Polypeptide
Cell death
Oligomers
Amyloid
Poisons
Cell Death
Rifampin
Apoptosis
Medical problems
Type 2 Diabetes Mellitus
Rats
Screening
Transgenic Rats
Molecules
Islets of Langerhans
Adenoviridae

Keywords

  • Human islet amyloid polypeptide
  • Islet amyloid polypeptide
  • Rifampicin

ASJC Scopus subject areas

  • Physiology
  • Endocrinology
  • Biochemistry

Cite this

Inhibition of human IAPP fibril formation does not prevent β-cell death : Evidence for distinct actions of oligomers and fibrils of human IAPP. / Meier, Juris J.; Kayed, Rakez; Lin, Chia Yu; Gurlo, Tatyana; Haataja, Leena; Jayasinghe, Sajith; Langen, Ralf; Glabe, Charles G.; Butler, Peter C.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 291, No. 6, 2006.

Research output: Contribution to journalArticle

Meier, Juris J. ; Kayed, Rakez ; Lin, Chia Yu ; Gurlo, Tatyana ; Haataja, Leena ; Jayasinghe, Sajith ; Langen, Ralf ; Glabe, Charles G. ; Butler, Peter C. / Inhibition of human IAPP fibril formation does not prevent β-cell death : Evidence for distinct actions of oligomers and fibrils of human IAPP. In: American Journal of Physiology - Endocrinology and Metabolism. 2006 ; Vol. 291, No. 6.
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AU - Lin, Chia Yu

AU - Gurlo, Tatyana

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AU - Jayasinghe, Sajith

AU - Langen, Ralf

AU - Glabe, Charles G.

AU - Butler, Peter C.

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AB - Type 2 diabetes mellitus (T2DM) is characterized by an ∼60% deficit in β-cell mass, increased β-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). Human IAPP (hIAPP) forms oligomers, leading to either amyloid fibrils or toxic oligomers in an aqueous solution in vitro. Either application of hIAPP on or overexpression of hIAPP in cells induces apoptosis. It remains controversial whether the fibrils or smaller toxic oligomers induce β-cell apoptosis. Rifampicin prevents hIAPP amyloid fibril formation and has been proposed as a potential target for prevention of T2DM. We examined the actions of rifampicin on hIAPP amyloid fibril and toxic oligomer formation as well as its ability to protect β-cells from either application of hIAPP or endogenous overexpression of hIAPP (transgenic rats and adenovirus-transduced β-cells). We report that rifampicin (Acocella G. Clin Pharmacokinet 3: 108 -127, 1978) prevents hIAPP fibril formation, but not formation of toxic hIAPP oligomers (Bates G. Lancet 361: 1642-1644, 2003), and does not protect β-cells from apoptosis induced by either overexpression or application of hIAPP. These data emphasize that toxic hIAPP oligomers, rather than hIAPP fibrils, initiate β-cell apoptosis and that screening tools to identify inhibitors of amyloid fibril formation are likely to be less useful than those that identify inhibitors of toxic oligomer formation. Finally, rifampicin and related molecules do not appear to be useful as candidates for prevention of T2DM.

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