Amyloid formation disrupts the balance between interleukin-1ß and interleukin-1 receptor antagonist in human islets.
Mol Metab
; 6(8): 833-844, 2017 08.
Article
em En
| MEDLINE
| ID: mdl-28752047
ABSTRACT
OBJECTIVES:
ß-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 ß-cell death in T2D. We recently showed the role of interleukin-1ß (IL-1ß)/Fas/caspase-8 apoptotic pathway in amyloid-induced ß-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-1ß/IL-1Ra balance can prevent amyloid-induced ß-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-1ß 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). ß-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-1ß levels, ß-cell Fas expression and apoptosis. Treatment with IL-1ß neutralizing antibody markedly reduced amyloid-induced ß-cell Fas expression and apoptosis, thereby improving islet ß-cell survival and function during culture.CONCLUSIONS:
These data suggest that amyloid formation impairs the balance between IL-1ß and IL-1Ra in islets by increasing IL-1ß production and reducing IL-1Ra levels thereby promoting ß-cell dysfunction and death. Restoring the IL-1ß/IL-1Ra ratio may provide an effective strategy to protect islet ß-cells from amyloid toxicity in T2D.Palavras-chave
Amylin; BSA, bovine serum albumin; ER, endoplasmic reticulum; FBS, fetal bovine serum; IL-1R1, IL-1 receptor type I; IL-1Ra, IL-1 receptor antagonist; IL-1ß, interleukin-1ß; Interleukin-1 receptor antagonist; Interleukin-1ß; Islet amyloid; Islet amyloid polypeptide; Islet inflammation; KRB, KrebsRinger bicarbonate; PFA, paraformaldehyde; T2D, type 2 diabetes; Type 2 diabetes; hIAPP, human islet amyloid polypeptide; nIL1ß, neutralizing IL-1ß; rIAPP, rat islet amyloid polypeptide; ß-cell apoptosis
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Apoptose
/
Células Secretoras de Insulina
/
Proteína Antagonista do Receptor de Interleucina 1
/
Interleucina-1beta
/
Amiloide
Tipo de estudo:
Prognostic_studies
Limite:
Adolescent
/
Adult
/
Animals
/
Humans
/
Middle aged
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article