Role of dopamine in the development of impaired counterregulation and impaired awareness of hypoglycemia

Figures

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  Figure 1. Development of IAH rodent model (A and B) Insulin-induced hypoglycemia increased food intake. (A) BG levels following s.c. injection of SAL (n = 8) or INS (n = 8). (B) Cumulative food intake for 4 h post-SAL (1 mL/kg BW; n = 8) or INS injection (NPH 15 U/kg BW; n = 8). Each bar represents the mean + SEM (∗∗∗∗p < 0.0001 as compared with SAL group). Groups were compared via unpaired t test. (C–E) RH model fails to blunt food intake. (C) schematic diagram of experimental design showing 3-day treatment with RS or recurrent insulin-induced hypoglycemia (RH) followed by indicated treatment on day 4. (D) BG levels on day 4 (following preconditioning period) in response to one single injection of saline or INS (RS + SAL, n = 6; RS + INS, n = 4; RH + INS, n = 7) (NPH 15 U/kg) (∗p < 0.005 SAL vs. RH + INS and INS). Groups were compared via one-way ANOVA. (E) Cumulative food intake over 6-h period following saline or insulin injection (∗p < 0.05 SAL vs. INS; #p < 0.005 SAL vs. RH + INS). Groups were compared via one-way ANOVA. Each bar represents the mean + SEM. (F–H) R2DG induces a blunted food intake response to hypoglycemia. (F) Schematic diagram of experimental design showing 3 days of…

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  Figure 2. MET prevents the development of hypoglycemia unawareness and restores awareness of hypoglycemia (A–D) MET effects on hypoglycemia induced food intake. (A) BG levels following an acute injection of saline (SAL, n = 6) or insulin (INS, n = 6; INS + MET, n = 8) (15 U/kg BW), (∗p < 0.0001 SAL vs. INS, ∗p < 0.0001 INS+MET vs. SAL). Groups were compared via two-way ANOVA. (B) Cumulative food intake after an acute injection of saline, insulin (15 U/kg BW), or insulin + MET (∗∗p < 0.01 INS vs. SAL; ∗∗∗∗p < 0.0001 INS + MET vs. SAL; ∗p < 0.05 INS + MET vs. INS). Groups were compared via one-way ANOVA. (C) BG levels following a singular injection of saline (SAL, n = 3) or MET (n = 4). Groups were compared via two-way ANOVA. (D) Cumulative food intake under euglycemic conditions for MET and SAL. Groups were compared via unpaired t test. Each bar represents the mean + SEM. (E–G) MET prevented the development of IAH. (E) Schematic diagram of experimental design using the prevention protocol of IAH with R2DG (RS + SAL, n = 6; RS + INS, n = 6; R2DG + INS, n = 6, R2DG + MET + INS, n = 8). (F) BG levels following 3 days of RS, R2DG, or R2DG + MET (3 mg/kg/d) followed by one single injection of…

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  Figure 3. MET restores counterregulation and prevents a blunted counterregulatory response (A–D) MET prevents blunted CRR in the R2DG model. (A) Schematic diagram of experimental design of prevention of a blunted CRR response using R2DG protocol and treatment with MET. (B) BG concentrations during hyperinsulinemic-euglycemic-hypoglycemic clamp where an infusion of INS (50 mU·kg−1·min−1) and the variable dextrose (40% [BW/vol]) was started (i.e., at −150 min) to induce euglycemia (90–110 mg/dL) and after 120 min of euglycemia, glucose infusion was decreased to induce hypoglycemia (40–50 mg/dL for 90 min). RS + INS, n = 13; R2DG + INS, n = 7; R2DG + MET + INS, n = 9. Groups were measured via two-way ANOVA. (C) Peak epinephrine concentrations at basal and hypoglycemia for all experimental groups (∗p = 0.005 RS + INS (n = 8) vs. R2DG + INS [n = 7]; #p = 0.04 R2DG + INS vs. RS + INS and R2DG + MET + INS [n = 6]). Groups were compared via two-way ANOVA. (D) Peak glucagon concentrations at basal and hypoglycemia for all experimental groups (p > 0.09). RS + INS, n = 9; R2DG + INS, n = 5; R2DG + MET + INS, n = 7. Groups were compared via two-way ANOVA. Each bar represents the mean + SEM. (E–J) MET…

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  Figure 4. Sympathoadrenal response and dopaminergic action with agonist bromocriptine (A–C) Recurrent BROMO administration in i.c.v. reduced food intake and BG response. (A) Schematic diagram of recurrent aCSF (n = 7) or recurrent BROMO (n = 7, 2 μg) for 3 days into i.c.v. (B) BG on day 4 following singular injection of INS (15 U/kg NPH) Groups were compared via two-way ANOVA. (C) Cumulative food intake after INS injection (∗p < 0.005 RBROMO i.c.v. vs. RCSF i.c.v. + INS). Groups were compared via unpaired t test. Each bar represents the mean + SEM. (D–H) Recurrent BROMO administration in i.c.v. and effects on CRR. (D) Schematic diagram of recurrent aCSF (n = 7) or recurrent BROMO (n = 7, 2 μg) into i.c.v.. (E) BG during hyperinsulinemic-hypoglycemic clamp where BG is held at 40–45 mg/dL for 90 min. Groups were compared via two-way ANOVA. (F) Ginf. Rate during clamp (∗∗∗∗p < 0.0001 vs. RBROMO). Groups were compared via unpaired t test. (G) Peak epinephrine concentrations at basal and hypoglycemia (∗p < 0.005 RCSF vs. RBROMO). Groups were compared via two-way ANOVA. (H) Peak glucagon concentrations at basal and hypoglycemia (∗p < 0.005 RCSF vs. RBROMO). Groups were compared via two-way…