On the potential of group-specific component (GC) inhibition for treating metabolic disease

Abstract

Recent advances in obesity and type 2 diabetes treatment using glucagon-like peptide-1 receptor agonist (GLP1RA)-based therapeutics have enabled major improvements in the management of these metabolic disorders. However, many patients cannot tolerate side effects associated with appetite suppression, and around 10% of those adhering to treatment do not lose weight. Thus, there is a need for alternative and/or additional treatment. Here, we examine the therapeutic potential of targeting a gene called Group-specific component (GC) to treat metabolic diseases. First, we review GC’s established roles in vitamin D transport, metabolism, and inflammation, including its structure-activity relationships as well as the phenotypes associated with genetic variation in GC. Next, we summarize studies of GC-null humans and mice, which were both generally healthy and viable, demonstrating the safety of inhibiting GC. Finally, we discuss novel evidence that among mice fed a high fat diet, Gc ablation confers protection against the development of obesity and type 2 diabetes. Notably, these benefits came without reductions in food intake or lean mass, the primary drivers of GLP1RA-associated adverse effects. GC therefore represents a promising novel therapeutic target for metabolic diseases.

Keywords

Metabolism / obesity / diabetes / group-specific component / vitamin D binding protein / insulin secretion / insulin sensitivity / therapeutics

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