Abnormal glucagonemia in the fed state but normal glucagon secretion in response to hypoglycemia or 2-DG in ripglut1;glut2^–/– mice in the C57BL/6 background. (A) Fed glucagon levels were approximately 2-fold higher in male ripglut1;glut2^–/–(B6) than in C57BL/6 mice; (B) Fed glucagon levels were approximately 2-fold higher in female ripglut1;glut2^–/–(B6) than in C57BL/6 mice. The fed hyperglucagonemia of mutant mice was reduced to the level found in control mice after ganglionic blockade with chlorisondamine (chlori). Chlorisondamine did not change the glucagonemia of control mice. (C) Plasma glucagon levels measured at the end of 3 hours of hypoglycemic (∼2.5 mM) or euglycemic (∼5.5 mM) clamps. Hypoglycemia induced an approximately 4-fold increase in glucagon plasma levels in control mice and an approximately 2-fold increase in mutant mice. (D) Plasma glucagon levels measured 60 minutes after i.p. injections of NaCl or 2-DG in C57Bl and ripglut1;glut2^–/–(B6) mice. 2-DG induced a 5- and 3-fold increase in plasma glucagon in control and mutant mice, respectively. (E) Plasma glucagon levels measured 30 minutes after i.c.v. injection of NaCl or 2-DG. 2-DG induced a 5-fold increase in plasma glucagon in C57BL/6 mice and an approximately 3-fold increase in mutant mice. Data are indicated as mean ± SD; n = 6–8 for each data point. (C) Data are indicated as mean ± SEM of 3 experiments, each performed with 5–6 mice. **P < 0.01 and ***P < 0.005 for comparison between NaCl- and 2-DG–injected groups. ^#P < 0.05 and ^##P < 0.01 for comparison between NaCl-injected control and ripglut1;glut2^–/–(B6) groups (Student’s t test).