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Biochimie ; 170: 26-35, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31838129

RESUMO

Type 2 diabetes mellitus is a disease characterized by the formation of amyloid fibrillar deposits consisting mainly in human islet amyloid polypeptide (hIAPP), a peptide co-produced and co-secreted with insulin. hIAPP and insulin are synthesized by pancreatic ß cells initially as prehormones resulting after sequential cleavages in the mature peptides as well as the two flanking peptides (N- and C-terminal) and the C-peptide, respectively. It has been suggested that in the secretory granules, the kinetics of hIAPP fibril formation could be modulated by some internal factors. Indeed, insulin is known to be a potent inhibitor of hIAPP fibril formation and hIAPP-induced cell toxicity. Here we investigate whether the flanking peptides could regulate hIAPP fibril formation and toxicity by combining biophysical and biological approaches. Our data reveal that both flanking peptides are not amyloidogenic. In solution and in the presence of phospholipid membranes, they are not able to totally inhibit hIAPP-fibril formation neither hIAPP-membrane damage. In the presence of INS-1 cells, a rat pancreatic ß-cell line, the flanking peptides do not modulate hIAPP fibrillation neither hIAPP-induced cell death while in the presence of human islets, they have a slightly tendency to reduce hIAPP fibril formation but not its toxicity. These data demonstrate that the flanking peptides do not strongly contribute to reduce mature hIAPP amyloidogenesis in solution and in living cells, suggesting that other biochemical factors present in the cells must act on mature hIAPP fibril formation and hIAPP-induced cell death.


Assuntos
Amiloide/química , Morte Celular , Células Secretoras de Insulina/metabolismo , Insulinoma/metabolismo , Polipeptídeo Amiloide das Ilhotas Pancreáticas/farmacologia , Neoplasias Pancreáticas/metabolismo , Vesículas Secretórias/metabolismo , Sequência de Aminoácidos , Agonistas dos Receptores da Amilina/farmacologia , Amiloide/efeitos dos fármacos , Animais , Células Cultivadas , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Insulinoma/tratamento farmacológico , Insulinoma/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Ratos , Vesículas Secretórias/efeitos dos fármacos , Vesículas Secretórias/patologia
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