Journal
PHARMACOLOGICAL RESEARCH
Volume 167, Issue -, Pages -Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2021.105539
Keywords
Beta-cell protection; Calcium influx; CREB activation; Neuropeptide; Sortilin-released propeptide
Categories
Funding
- Centre National de la Recherche Scientifique
- Agence Nationale de la Recherche [ANR-13-SAMA-0002-VASPAC, ANR-13-RPIB-0002 MEDINCOD]
- French Government [ANR-11 LabEx 0015]
- LabEx ICST
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The study demonstrates that PE and its derivatives can protect beta-cells against death induced by inflammation by inducing a rise of intracellular calcium concentration. In addition, Mini-Spadin promotes beta-cell proliferation, suggesting a possible regenerative effect. The findings highlight the potential roles of PE and its derivatives as pharmacological tools against diabetes.
Deterioration of insulin secretion and pancreatic beta-cell mass by inflammatory attacks is one of the main pathophysiological features of type 2 diabetes (T2D). Therefore, preserving beta-cell mass and stimulating insulin secretion only in response to glucose for avoiding the hypoglycemia risks, are the most state-of-the-art option for the treatment of T2D. In this study we tested two correlated hypothesis that 1/ the endogenous peptide released from sortilin, known as PE, that stimulates insulin secretion only in response to glucose, protects beta-cells against death induced by cytokines, and 2/ Spadin and Mini-Spadin, two synthetic peptides derived from PE, that mimic the effects of PE in insulin secretion, also provide beneficial effect on beta-cells survival. We show that PE and its derivatives by inducing a rise of intracellular calcium concentration by depolarizing the membrane protect beta-cells against death induced by Interleukin-1 beta. Using biochemical, confocal imaging and cell biology techniques, we reveal that the protective effects of PE and its derivatives rely on the activation of the CaM-Kinase pathway, and on the phosphorylation and activation of the transcription factor CREB. In addition, Mini-Spadin promotes beta-cell proliferation, suggesting its possible regenerative effect. This study highlights new possible roles of PE in pancreatic beta-cell survival and its derivatives as pharmacological tools against diabetes.
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