Fig. 2

Summary of the effects of different types of PCSK9 loss on glucose homeostasis. Mice with loss of liver-derived circulating PCSK9 or partial loss of local expression in islets upon β-cell-specific KO remain normoglycaemic. Systemic Pcsk9 KO (not in all models) and loss of all local PCSK9 throughout pancreas resulted in moderately reduced insulin response and glucose tolerance. This underlines the importance of local PCSK9 expression in pancreatic islets for proper β-cell function. Similarly in patients, inhibition of circulating PCSK9 by alirocumab and evolocumab has no effect on glucose homeostasis, whereas loss of local tissue-derived PCSK9 in patients with LOF variants leads to worsening of glycaemia depending on the degree of functional loss. In general, the deterioration of glucose homeostasis observed under certain conditions was moderate. Possibly, the assumed lipotoxicity of increased LDLR-mediated cholesterol import was counter-regulated by increased cholesterol export via ABCA1. KO, knockout; inhibitors, alirocumab and evolocumab; LOF, loss-of-function