The association between circulatory, local pancreatic PCSK9 and type 2 diabetes mellitus: The effects of antidiabetic drugs on PCSK9

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a potent modulator of cholesterol metabolism and plays a crucial role in the normal functioning of pancreatic islets and the progression of diabetes. Islet autocrine PCSK9 deficiency can lead to the enrichment of low-density lipoprotein (LDL) receptor (LDLR) and excessive LDL cholesterol (LDL-C) uptake, subsequently impairing the insulin secretion in β-cells. Circulatory PCSK9 levels are primarily attributed to hepatocyte secretion. Notably, anti-PCSK9 strategies proposed for individuals with hypercholesterolemia chiefly target liver-derived PCSK9; however, these anti-PCSK9 strategies have been associated with the risk of new-onset diabetes mellitus (NODM). In the current review, we highlight a new direction in PCSK9 inhibition therapy strategies: screening candidates for anti-PCSK9 from the drugs used in type 2 diabetes mellitus (T2DM) treatment. We explored the association between circulating, local pancreatic PCSK9 and T2DM, as well as the relationship between PCSK9 monoclonal antibodies and NODM. We discussed the emergence of artificial and natural drugs in recent years, exhibiting dual benefits of antidiabetic activity and PCSK9 reduction, confirming that the diverse effects of these drugs may potentially impact the progression of diabetes and associated disorders, thereby introducing novel avenues and methodologies to enhance disease prognosis.

Keywords: Antidiabetic drugs; PCSK9; PCSK9 inhibitors; Type 2 diabetes mellitus.

Fig. 1

Suppressed PCSK9 secretion by β-cells leads to compensatory lipid accumulation in β-cells. PCSK9 secreted by islet β-cells can bind to LDLR on the cell membrane and achieve clearance of LDLR via the endosomal-lysosome pathway, thereby maintaining the appropriate LDLR density on the cell membrane. This process prevents excessive lipid uptake by β-cells owing to high LDLR density (Physiological condition). Failure of β-cells to secrete PCSK9 can increase LDLR expression on the membrane, subsequently inducing LDL-C accumulation in the cholesterol pool. Excessive lipid accumulation may lead to “lipid toxicity” and impair islet β-cell function (Local PCSK9 deficiency). Nevertheless, reduced de novo cholesterol synthesis and increased protein expression of excreted lipids can compensate for lipid toxicity and thus ensure normal pancreatic islet function. The effects of δ-cell-secreted PCSK9 on LDLR of β-cells remain controversial. Hepatogenic PCSK9 does not impact β-cell LDLR abundance. LDL-C, low-density lipoprotein cholesterol; LDLR, low-density lipoprotein receptor; PCSK9, Proprotein convertase subtilisin/kexin type 9.

Fig. 2

Synthetic or natural drugs with dual antidiabetic and PCSK9 lowering benefits. A. Chemical structures of natural antidiabetic compounds and synthetic antidiabetic drugs acting on PCSK9; B. (1) Synthetic inhibitors: a, GLP-1 (glucagon-like peptide-1) receptor agonist; b, biguanide; c, anthraquinones; d, isoquinoline alkaloids; (2) Natural inhibitors: I, isoquinoline alkaloids; II, polyphenols; III, sterol/stanols; IV, nutrients; V, anthraquinones; VI, others. PCSK9, Proprotein convertase subtilisin/kexin type 9; (−), negative regulation.

Fig. 2

Synthetic or natural drugs with dual antidiabetic and PCSK9 lowering benefits. A. Chemical structures of natural antidiabetic compounds and synthetic antidiabetic drugs acting on PCSK9; B. (1) Synthetic inhibitors: a, GLP-1 (glucagon-like peptide-1) receptor agonist; b, biguanide; c, anthraquinones; d, isoquinoline alkaloids; (2) Natural inhibitors: I, isoquinoline alkaloids; II, polyphenols; III, sterol/stanols; IV, nutrients; V, anthraquinones; VI, others. PCSK9, Proprotein convertase subtilisin/kexin type 9; (−), negative regulation.