Background and Aim: PCSK9 genetic polymorphisms are associated with lower LDL-Cholesterol levels but also with higher plasma glucose levels and increased risk of developing T2D. We investigated the molecular mechanisms beyond this association. Methods: Pcsk9 KO, WT, albumin (Alb)Cre+/Pcsk9LoxP/LoxP (liver selective Pcsk9-KO mice) and Pdx1 (Pdx1)Cre+/Pcsk9LoxP/LoxP (pancreas selective Pcsk9-KO mice) were used and fed for 20 week with chow diet and Standard Fed Diet. GTT, ITT, insulin and C-peptide plasma levels, pancreas morphology and cholesterol accumulation in pancreatic islets were studied in the different animal models. Results: Glucose clearance was impaired in PCSK9 KO mice compare to WT while no difference were observed in insulin tolerance. Glucose tolerance was not impaired in (Alb)Cre+ mice fed with standard fat diet compared to WT animals; insulin sensitivity was not affected; both animal models showed a similar decrease in plasma glucose levels during ITT. A detailed analysis on (Alb)Cre+ pancreas morphology revealed no difference in islets. (Pdx1)Cre+ presented a similar phenotype observed in full PCSK9 KO mice. Conclusion: The PCSK9/LDLr axis affects beta cell function and insulin secretion. Our current findings confirm our previous observation that this effect is related to local PCSK9 and support the observations available that anti-PCSK9 antibodies or liver specific therapies, such as siRNAs, have a limited impact on glucose metabolism as opposed to statins.
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