Abstract
Previous studies have demonstrated the important role of kisspeptin in impaired glucose-stimulated insulin secretion (GSIS). In addition, it was reported that the activation of autophagy in pancreatic β-cells decreases insulin secretion by selectively degrading insulin granules. However, it is currently unknown whether kisspeptin suppresses GSIS in β-cells by activating autophagy. To investigate the involvement of autophagy in kisspeptin–regulated insulin secretion, we overexpressed Kiss1 in NIT-1 cells to mimic the long-term exposure of pancreatic β-cells to kisspeptin during type 2 diabetes (T2D). Interestingly, our data showed that although kisspeptin potently decreases the intracellular proinsulin and insulin ((pro)insulin) content and insulin secretion of NIT-1 cells, autophagy inhibition using bafilomycin A1 and Atg5 siRNAs only rescues basal insulin secretion, not kisspeptin-impaired GSIS. We also generated a novel in vivo model to investigate the long-term exposure of kisspeptin by osmotic pump. The in vivo data demonstrated that kisspeptin lowers GSIS and (pro)insulin levels and also activated pancreatic autophagy in mice. Collectively, our data demonstrated that kisspeptin suppresses both GSIS and non-glucose-stimulated insulin secretion of pancreatic β-cells, but only non-glucose-stimulated insulin secretion depends on activated autophagic degradation of (pro)insulin. Our study provides novel insights for the development of impaired insulin secretion during T2D progression.
Highlights
Many of the signaling pathways involved in the regulation of β-cell insulin secretion remain unclear, recent studies have highlighted the role of autophagy in insulin homeostasis
It was reported that both patients with type 2 diabetes (T2D) and an obese mouse model exhibit increased kisspeptin mRNA in the liver and elevated protein levels in plasma[10]
We aimed to evaluate the direct effects of kisspeptin on β-cell insulin secretion and clarify the underlying mechanisms
Summary
Many of the signaling pathways involved in the regulation of β-cell insulin secretion remain unclear, recent studies have highlighted the role of autophagy in insulin homeostasis. Previous studies have individually identified the important roles of kisspeptin and autophagy in T2D development, none of them have investigated whether kisspeptin impairs insulin secretion by activating autophagy in pancreatic β-cells. We overexpressed Kiss[1] in mouse pancreatic β-cells as in vitro model and continuously injected kisspeptin to mice as in vivo model. In both models, we analyzed autophagy activity and proinsulin and insulin ((pro)insulin) in pancreatic β-cells and measured the changes in insulin secretion
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