Adenosine A₁ receptor is dispensable for hepatocyte glucose metabolism and insulin sensitivity

Hepatic insulin resistance (IR) and enhanced hepatic glucose production (HGP) are key features of type 2 diabetes (T2D), contributing to fasting hyperglycemia. Adenosine receptors (ARs) are G protein-coupled and expressed in hepatocytes. Here, we explored the role of hepatic G_i/o-coupled A₁AR on insulin resistance and glucose fluxes associated with obesity. We generated a mouse model with hepatocyte-specific deletion of A₁AR (A1L^Δ/Δ), which was compared with whole body knockout of A₁AR or A₁AR/A₃AR (both G_i-coupled). Selective deletion of hepatic A₁AR resulted in a modest improvement in insulin sensitivity. In addition, HFD A1L^Δ/Δ mice showed decreased fasting glucose levels. Hyperinsulinemic-euglycemic clamp studies demonstrated enhanced insulin sensitivity with no change in HGP in HFD A1L^Δ/Δ mice. Similar to A1L^Δ/Δ, fasting blood glucose levels were significantly reduced in whole body A1^Δ/Δ and A1^Δ/ΔA3^Δ/Δ compared to wild-type mice. Taken together, our data support the concept that blocking hepatic A₁AR may decrease fasting blood glucose levels without directly affecting hepatocyte glucose metabolism and insulin sensitivity.