(a) Experimental procedure and pancreatic (basal-insulin) euglycemic clamp protocol for 28 day HFD-fed rats. (b,c) The glucose infusion rate (b), rate of GP (c) during the pancreatic (basal insulin) euglycemic clamp in 28 day HFD-fed rats with intraduodenal saline or metformin infusion (***p < 0.001, versus saline as compared by unpaired t-test; n=6 for each group). (d,e) Plasma glucose levels (d) and the rate of GP (e) in NA-STZ/HFD induced hyperglycemic rats with intraduodenal saline or metformin (n=8 for each group). (f) Experimental procedure and gastric infusion protocol. (g,h) The plasma glucose levels (different letter denotes significant difference of p < 0.05 between groups as calculated by two-way ANOVA with Tukey’s post hoc test) (g) and the percent suppression of plasma glucose from basal levels (**p < 0.01, versus saline as compared by unpaired t-test within each timepoint) (h) in NA-STZ/HFD induced hyperglycemic rats injected with either intraduodenal GFP or dnAMPK for 5 days with a gastric bolus treatment of metformin (n=8 for each group). Values are shown as mean ± s.e.m. Unless noted, ***p < 0.001, versus saline, as calculated by one-way ANOVA with Tukey’s post hoc test. GP, glucose production; AMPK, AMP-activated protein kinase; NA, nicotinamide; STZ, streptozotocin. HFD, high fat diet.