The highly expressed calcium‐insensitive synaptotagmin‐11 and synaptotagmin‐13 modulate insulin secretion

AIM: SYT11 and SYT13, two calcium‐insensitive synaptotagmins, are downregulated in islets from type 2 diabetic donors, but their function in insulin secretion is unknown. To address this, we investigated the physiological role of these two synaptotagmins in insulin‐secreting cells. METHODS: Correlations between gene expression levels were performed using previously described RNA‐seq data on islets from 188 human donors. SiRNA knockdown was performed in EndoC‐βH1 and INS‐1 832/13 cells. Insulin secretion was measured with ELISA. Patch‐clamp was used for single‐cell electrophysiology. Confocal microscopy was used to determine intracellular localization. RESULTS: Human islet expression of the transcription factor PDX1 was positively correlated with SYT11 (p = 2.4e(−10)) and SYT13 (p < 2.2e(−16)). Syt11 and Syt13 both co‐localized with insulin, indicating their localization in insulin granules. Downregulation of Syt11 in INS‐1 832/13 cells (siSYT11) resulted in increased basal and glucose‐induced insulin secretion. Downregulation of Syt13 (siSYT13) decreased insulin secretion induced by glucose and K(+). Interestingly, the cAMP‐raising agent forskolin was unable to enhance insulin secretion in siSYT13 cells. There was no difference in insulin content, exocytosis, or voltage‐gated Ca(2+) currents in the two models. Double knockdown of Syt11 and Syt13 (DKD) resembled the results in siSYT13 cells. CONCLUSION: SYT11 and SYT13 have similar localization and transcriptional regulation, but they regulate insulin secretion differentially. While downregulation of SYT11 might be a compensatory mechanism in type‐2 diabetes, downregulation of SYT13 reduces the insulin secretory response and overrules the compensatory regulation of SYT11 in a way that could aggravate the disease.