Molecular and cellular biology of PCSK9: impact on glucose homeostasis

Proprotein convertase substilisin/kexin 9 (PCSK9) inhibitors (PCSK9i) revolutionised the lipid-lowering therapy. However, a risk of type 2 diabetes mellitus (T2DM) is evoked under PCSK9i therapy. In this review, we summarise the current knowledge on the link of PCSK9 with T2DM. A significant correlation was found between PCSK9 and insulin, homeostasis model assessment (HOMA) of insulin resistance and glycated haemoglobin. PCSK9 is also involved in inflammation. PCSK9 loss-of-function variants increased T2DM risk by altering insulin secretion. Local pancreatic low PCSK9 regulates β-cell LDLR expression which in turn promotes intracellular cholesterol accumulation and hampers insulin secretion. Nevertheless, the association of PCSK9 loss-of-function variants and T2DM is inconsistent. InsLeu and R46L polymorphisms were associated with T2DM, low HOMA for β-cell function and impaired fasting glucose, while the C679X polymorphism was associated with low fasting glucose in Black South African people. Hence, we assume that the impact of these variants on glucose homeostasis may vary depending on the genetic background of the studied populations and the type of effect caused by those genetic variants on the PCSK9 protein. Accordingly, these factors should be considered when choosing a genetic variant of PCSK9 to assess the impact of long-term use of PCSK9i on glucose homeostasis.