Evidence That Extrapancreatic GLUT2-Dependent Glucose Sensors Control Glucagon Secretion
Article Figures & Tables
Figures
- FIG. 1.
Impaired glucagon response to hypoglycemia and hyperglycemia. Mice were infused with insulin at a constant rate (18 mU · kg–1 · min–1) for 60 min and co-infused with glucose to reach the desired glycemic levels. A: Glycemic profiles obtained over the time course of the experiments for control and mutant mice. B: Plasma glucagon levels measured at the end of the 60-min infusion. C: Relative plasma glucagon levels at the end of the experiments. Hypoglycemia induces a strong increase in plasma glucagon in control mice and only a small increase in mutant mice. Hyperglycemia has no effect in these conditions on glucagon plasma levels. Data are means ± SE; n = 6–7 for each data point. *P < 0.05 vs. 5.5 mmol/l glucose; #P < 0.05 vs. corresponding values of control mice. ▪, Control; □, RIPGLUT1 × GLUT2–/–.
- FIG. 2.
Impaired glucagon response to hypoglycemic and hyperglycemic-hyperinsulinemic clamps. Mice were infused with insulin at a constant rate (18 mU · kg–1 · min–1) for 180 min and co-infused with glucose to maintain the desired glycemic levels. A: Glycemic profiles obtained over the time course of the experiments for control and mutant mice. B: Plasma glucagon levels measured at the end of the 180-min clamps. C: Relative plasma glucagon levels at the end of the clamp experiments. Hypoglycemia induces a 1.7-fold increase in plasma glucagon in control mice and no increase in mutant mice. Hyperglycemia decreased plasma glucagon levels by half in control mice but had no significant effect in mutant mice. Data are means ± SE; n = 5–8 for each data point. *P < 0.05 vs. 5.5 mmol/l glucose; #P < 0.05 vs. corresponding values of control mice. ▪, Control; □, RIPGLUT1 × GLUT2–/–.
- FIG. 3.
Impaired glucagon response, but normal insulin secretion, during hyperglycemic clamps. Mice were infused with saline or with a glucose solution to maintain glycemia at 20 mmol/l for 3 h. At the end of the experiments, plasma glucagon and insulin were determined. A: Glycemic profiles maintained over the time of the experiment. B: Plasma glucagon at the end of the 3-h clamp experiments. C: Insulin levels at the end of the 3-h clamp experiments. Hyperglycemia induced an identical secretion of insulin in control and mutant mice. However, glucagon levels were not suppressed in mutant mice, indicating a lack of suppressive effect of intra-islet insulin in these experimental conditions. Data are means ± SE; n = 5–8 for each data point. *P < 0.05 vs. 5.5 mmol/l glucose; #P < 0.05 vs. corresponding values of control mice. ▪, Control; □, RIPGLUT1 × GLUT2–/–.
- FIG. 4.
Induction of severe hypoglycemia induces a strong glucagon response in both control and mutant mice. Mice were injected intraperitoneally with insulin (0.7 U/kg), and plasma glucagon was measured 30 and 60 min after the injection. A: Glycemic profiles obtained over the time course of the experiments for control and mutant mice. B: Plasma glucagon levels measured 30 and 60 min after insulin injection. C: Relative plasma glucagon levels 30 and 60 min after insulin injection. Hypoglycemia induced plasma glucagon both in control (∼8-fold and ∼2.5-fold over basal at 30 and 60 min, respectively) and mutant mice (∼5-fold and ∼2-fold over basal at 30 and 60 min, respectively). Data are means ± SE; n = 6 for each data point. *P < 0.05 vs. time 0; #P < 0.05 vs. corresponding values of control mice. ▪, Control; □, RIPGLUT1 × GLUT2–/–.
- FIG. 5.
Ganglionic blockade reduces plasma glucagon levels of mutant mice to the value of control mice. Fed mice were injected intraperitoneally with a saline solution (Sal) or a solution containing the ganglionic blockers hexamethonium (Hexa) or chlorisondamine (Chlo). Blood was collected for glucagon, insulin, and glucose measurements 30 min later. A: Ganglionic blockade decreased plasma glucagon levels in mutant mice but did not affect that of control mice. B: Insulin levels were decreased similarly in control and mutant mice. C: Plasma glucose was similarly affected in control and mutant mice. Data are means ± SE; n = 5–6 for each data point. *P < 0.05 vs. saline-injected mice; #P < 0.05 vs. corresponding values of control mice. ▪, Control; □, RIPGLUT1 × GLUT2–/–.
Tables
- TABLE 1
Plasma insulin, glucagon, and glucose levels in control and RIPGLUT1 × GLUT2–/– mice in the fed state and after a 6-h fast
Glucose (mmol/l) Glucagon (ng/ml) Insulin (μU/ml) Control Fed 7.9 ± 0.3 61.2 ± 4.8 76.2 ± 11.4 Fasted 4.8 ± 0.1 50.6 ± 3.3 10.0 ± 2.9 RIPGLUT1 × GLUT2−/− Fed 8.6 ± 0.2 108.1 ± 9.2* 17.7 ± 3.3* Fasted 4.2 ± 0.1* 42.0 ± 3.3 2.0 ± 0.1* Data are means ± SE.
* Significantly different from control mice: P < 0.05.
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