Abstract 10006: Expression and Function of Pcsk9 in Human Pancreatic Beta Cells

• Published in: Circulation (New York, N.Y.) N.Y.), 2019-11, Vol.140 (Suppl_1 Suppl 1), p.A10006-A10006
• Main Authors: Ramin-Mangata, Stephane, Lambert, Gilles
• Format: Article
• Language: English
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.140.suppl_1.10006

IntroductionLike statins, PCSK9 inhibitors (e.g. alirocumab) are hypocholesterolemic agents that increase the abundance of the LDL-receptor (LDLR). While mendelian randomization studies suggest that PCSK9 deficiency may promote new onset diabetes (NOD), the underlying molecular mechanisms for a link between PCSK9 and diabetes remain largely unknown.HypothesisPCSK9 inhibition could alter pancreatic beta cells function and increase the risk of NOD.MethodsTo investigate PCSK9 expression and the modulation of LDLR function in human beta cells, PCSK9 mRNA expression was assessed by RT-PCR in isolated human pancreatic islets. PCSK9 and insulin were visualized by immunofluorescence on human pancreatic sections. LDLR expression and function were investigated in human clonal beta cells by flow cytometry after treatment with statins ± recombinant PCSK9 ± alirocumab. Endogenous PCSK9 secretion and glucose-stimulated insulin secretion (GSIS) were assessed by ELISA. Signalling pathways were investigated by targeting transcription factors such as HNF1 and SREBP2 with siRNAs.ResultsPCSK9 is expressed, synthesized and secreted from human clonal beta cells and isolated human pancreatic islets, an effect primarily mediated by HNF1. PCSK9 expression was restricted to beta cells in human pancreas sections. PCSK9 secretion is enhanced following incubation with statins by 88% (n=20, p=10). Similar results were observed in isolated islets (+49%, n=6, p=0.03). In contrast rPCSK9 reduced LDLR cell surface expression by 67% (n=20, p=0.0001), an effect reversed by alirocumab. Regarding beta cells functionality, GSIS was not significantly altered by statins or rPCSK9 in the absence or presence of LDL. Noteworthy, the addition of high LDL concentrations promoted significant increases in intracellular cholesterol content as well as in non-stimulated insulin secretion and in glucose-stimulated insulin secretion.ConclusionWe conclude that human beta cells synthesize and secrete PCSK9. They express a functional LDLR duly regulated by statins and PCSK9. However, exogenous PCSK9 does not significantly impact GSIS, indicating that PCSK9 inhibition in the plasma with alirocumab is safe.