Impact of hepatic or pancreatic tissue selective PCSK9-deficiency on pancreas morphology, insulin release and glucose metabolism.

Background and aims: The proprotein convertase subtilisin/kexin type 9 (PCSK9) is crucially involved in regulating plasma cholesterol levels by controlling LDL-R expression. Loss of function genetic variants are associated with lower LDL cholesterol, but higher plasma glucose levels and increased risk of T2D. Although the liver is the main contributor to circulating PCSK9, also the endocrine pancreas produces PCSK9, pointing to a possible direct role of this protein in this tissue. Pcsk9-KO mice show impaired glucose tolerance, which appears to be the consequence of decreased insulin secretion rather that insulin resistance. Aim of this work was to understand the contribution of selective liver and pancreatic PCSK9 production on beta cell physiology and glucose homeostasis. fl/fl) Pcsk9-KO mice were generated and 20 weeks after, they were characterized for islet morphology, insulin release and glucose tolerance. Clonal beta cells (INS1E, βTC1 and RIN-5F) and human islets of Langerhans were used to verify the PCSK9 localization and impact on insulin content and release. Results: Liver-specific Pcsk9-KO mice, as expected, lack detectable circulating PCSK9 protein, but express PCSK9 in the islets. They showed GTT curves and plasma glucose levels following fast and refeeding experiments similar to control littermates, paralleled by pancreatic islets comparable in size, organization and insulin content to those of littermates. Pancreas specific Pcsk9-KO mice present normal PCSK9 circulating levels but lack PCSK9 expression in pancreatic delta cells. The analysis of pancreas morphology revealed islets comparable in size to littermates but with a decreased insulin content. In line with these findings, insulin levels following fast and refeeding experiments were significantly lower than in littermates. While little or non-detectable amount of PCSK9 is found in beta cells of human isolated islets, a variable amount of PCSK9 expression is observed in rat and mouse beta cell lines. Immunostaining of human pancreas tissue sections confirmed the results and revealed a prevalent PCSK9 localization in delta cells. Studies are in progress to understand the role of pancreatic PCSK9 on insulin synthesis and secretion. Conclusion: These data, suggest that pancreatic and not circulating (liver produced) PCSK9 plays a prevalent role in beta cell physiology. Ongoing studies are directed to shed light on the mechanisms connecting PCSK9 with beta cell dysfunction in diabetes but also to address the safety of anti-PCSK9 therapies which have been proposed to patients with severe hypercholesterolemia and/or very high cardiovascular risk.