(A) Measured endogenous glucose production is identical in rats and mice whether tracer is infused into the carotid artery and blood drawn from the jugular vein (A-V), or tracer is infused into the jugular vein and blood drawn from the carotid artery (V-A) (n=5 per group). (B)-(C) Blood glucose and plasma insulin concentrations in 6 hr fasted mice infused with glycerol, a gluconeogenic substrate (n=6 per group). (D)-(E) Hepatic and renal glucose production (n=6 per group). (F)-(G) Blood glucose and plasma insulin in 6 hr fasted mice treated with a glycogen phosphorylase antagonist to inhibit glycogenolysis (n=6 per group). (H)-(I) Hepatic and renal glucose production (n=6 per group). (J)-(K) Blood glucose and plasma insulin in recently fed (8 hr fasted) and starved (48 hr fasted) mice (n=5 per group). (L) Hepatic and renal glucose production (n=5 per group). (M)-(P) Blood glucose, plasma insulin, β-OHB, and bicarbonate in a mouse model of diabetic ketoacidosis (n=6 per group). (Q) Hepatic and renal glucose production (n=6 per group). (R)-(S) Body weight and liver hematoxylin & eosin staining in a mouse model of NASH (n=8 per group). Scale bar, 100 μm. (T)-(U) Liver transaminase concentrations (n=8 per group). (V)-(W) Blood glucose and plasma insulin (n=8 per group). (X) Hepatic and renal glucose production (n=7 per group). (Y)-(AA) Plasma FGF-21 concentrations in fed/fasted (n=5 per group), DKA (n=6 per group), and NASH models (n=8 per group). (BB)-(DD) Plasma FGF-21 (n=5 per group), blood glucose (n=6 per group), and plasma insulin concentrations (n=6 per group) in recently fed, fasted, and FGF-21 infused rats. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 by ANOVA with Tukey’s multiple comparisons test. (EE)-(FF) Plasma FGF-21 and insulin concentrations in FGF-21f/f;Alb-CreERT2 mice and their WT littermates fasted for 48 hr (n=3 per group). In all panels, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 by the 2-tailed unpaired Student’s t-test.