Gc inhibition preserves insulin sensitivity and reduces body weight without loss of muscle mass

Obesity and type 2 diabetes (T2D) are metabolic diseases that have been increasing in prevalence worldwide. Obesity often leads to T2D, which is caused by an imbalanced supply and demand of insulin. Insulin resistance and impaired beta-cell function contribute to the onset of hyperglycemia. Previously, we reported that ablation of Gc, encoding a secreted protein with a primary role in vitamin D transport, improves pancreatic beta-cell function in models of diet-induced insulin resistance. Here, we show that Gc ablation has systemic insulin-sensitizing effects to prevent weight gain, hyperglycemia, glucose intolerance, and lower NEFA and triglyceride in mice fed a high-fat diet. Interestingly, weight loss in Gc-ablated mice resulted from selective fat mass loss with preserved lean mass. Hyperinsulinemic-euglycemic clamps show that Gc ablation protects insulin's ability to reduce hepatic glucose production and increases glucose uptake in skeletal muscle and adipose tissue. Moreover, acute Gc inhibition, by way of adeno-associated virus encoding a short hairpin RNA to promote Gc mRNA degradation, prevents glucose intolerance caused by high fat feeding. The data suggest that Gc inhibition can provide an approach to increase insulin production in beta-cells and insulin action in peripheral tissues, while shedding fat mass. Overall design: We performed RNAseq in liver extracts from male mice. Mice were fasted overnight and refed a high-fat diet. There were a total of 4 conditions: fasted WT, fasted GcKO, refed WT, refed GcKO.