Endogenous PCSK9 for Patients with Type 2 Diabetes Mellitus (T2DM)

Dear Colleagues, 

PCSK9 is a serine protease produced primarily (but not exclusively) by the liver and the intestine that acts as a regulator pathway for hepatic low-density lipoprotein receptor (LDLR) degradation through an endosomal/lysosomal pathway. PCSK9 plays additional roles in atherosclerosis development and progression via a variety of nonclassical mechanisms that involve inflammatory, apoptotic, and immune pathways.

The interplay between lipid and glucose homeostasis and the role of the PCSK9 in glucose metabolism are complex and still unclear. Evidence from epidemiological and genetic studies and clinical trials with PCSK9 inhibitors has led to controversial findings.

Low LDL-C values and/or statin therapy have been associated with the risk of developing T2DM. Mendelian randomization studies have consistently showed that PCSK9 loss-of-function mutations leading to lower LDL-C values were characterized by higher fasting glucose values and higher risk of developing T2DM. In an experimental murine model, PCSK9 deficiency increased LDLR expression and cholesterol ester accumulation in pancreatic islets, which impaired beta cell function and insulin secretion. Conversely, two large randomized double-blind placebo-controlled cardiovascular outcome trials showed that treatment with PCSK9 inhibitors was not associated with increased risk of new onset of diabetes.

In addition, endogenous PCSK9 also plays a role in the cardiovascular complications of patients with diabetes, as highlighted by genetic studies correlating gain‐of‐function and loss-of-function mutations in the PCSK9 gene with coronary artery disease, as well as by the cardiovascular benefit observed with PCSK9-inhibitors.

In this Special Issue of Cells, I invite you to contribute original research articles, reviews, or shorter perspective articles on all aspects related to the title Endogenous PCSK9 for Patients with Type 2 Diabetes Mellitus.

Expert articles describing mechanistic, functional, cellular, biochemical, or general aspects related to the role of endogenous PCSK9 in type 2 diabetes are welcome.

Dr. Francesca Santilli
Dr. Rossella Liani
Guest Editors

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