Dataset Information

Amyloid formation disrupts the balance between interleukin-1? and interleukin-1 receptor antagonist in human islets.

ABSTRACT:

Objectives

?-cell dysfunction and apoptosis associated with islet inflammation play a key role in the pathogenesis of type 2 diabetes (T2D). Growing evidence suggests that islet amyloid, formed by aggregation of human islet amyloid polypeptide (hIAPP), contributes to islet inflammation and ?-cell death in T2D. We recently showed the role of interleukin-1? (IL-1?)/Fas/caspase-8 apoptotic pathway in amyloid-induced ?-cell death. In this study, we used human islets in culture as an ex vivo model of amyloid formation to: (1) investigate the effects of amyloid on islet levels of the natural IL-1 receptor antagonist (IL-1Ra); (2) examine if modulating the IL-1?/IL-1Ra balance can prevent amyloid-induced ?-cell Fas upregulation and apoptosis.

Methods

Isolated human islets (n = 10 donors) were cultured in elevated glucose (to form amyloid) with or without a neutralizing human IL-1? antibody for up to 7 days. Parallel studies were performed with human islets in which amyloid formation was prevented by adeno-siRNA-mediated suppression of hIAPP expression (as control). ?-cell levels of IL-1Ra, Fas, apoptosis as well as islet function, insulin- and amyloid-positive areas, and IL-1Ra release were assessed.

Results

Progressive amyloid formation in human islets during culture was associated with alterations in IL-1Ra. Islet IL-1Ra levels were higher at early stages but were markedly reduced at later stages of amyloid formation. Furthermore, IL-1Ra release from human islets was reduced during 7-day culture in a time-dependent manner. These changes in IL-1Ra production and release from human islets during amyloid formation adversely correlated with islet IL-1? levels, ?-cell Fas expression and apoptosis. Treatment with IL-1? neutralizing antibody markedly reduced amyloid-induced ?-cell Fas expression and apoptosis, thereby improving islet ?-cell survival and function during culture.

Conclusions

These data suggest that amyloid formation impairs the balance between IL-1? and IL-1Ra in islets by increasing IL-1? production and reducing IL-1Ra levels thereby promoting ?-cell dysfunction and death. Restoring the IL-1?/IL-1Ra ratio may provide an effective strategy to protect islet ?-cells from amyloid toxicity in T2D.

SUBMITTER: Hui Q

PROVIDER: S-EPMC5518725 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Publications

Amyloid formation disrupts the balance between interleukin-1β and interleukin-1 receptor antagonist in human islets.

Hui Queenie Q Asadi Ali A Park Yoo Jin YJ Kieffer Timothy J TJ Ao Ziliang Z Warnock Garth L GL Marzban Lucy L

Molecular metabolism 20170531 8

<h4>Objectives</h4>β-cell dysfunction and apoptosis associated with islet inflammation play a key role in the pathogenesis of type 2 diabetes (T2D). Growing evidence suggests that islet amyloid, formed by aggregation of human islet amyloid polypeptide (hIAPP), contributes to islet inflammation and β-cell death in T2D. We recently showed the role of interleukin-1β (IL-1β)/Fas/caspase-8 apoptotic pathway in amyloid-induced β-cell death. In this study, we used human islets in culture as an <i>ex vi ...[more]

PMID: 28752047

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