Introduction and Objective: Recurrent iatrogenic hypoglycemia blunts the counterregulatory response (CRR) to hypoglycemia. This study tested the hypothesis that RH induces insulin resistance and that the insulin sensitizer, pioglitazone, prevents the development of insulin resistance and consequently prevents the development of a blunted epinephrine response to hypoglycemia.Methods: 8-10-week-old rats were randomized to 1 of 3 treatments. Following 4 weeks of chow feeding, rats underwent 3 days of recurrent saline (RS) or recurrent hypoglycemia (RH, 2U/kg). A third group of rats were treated with pioglitazone supplemented chow (167ppm) for 4 weeks and underwent RH (RHP). Following preconditioning, all rats underwent a hyperinsulinemic (50mU/kg/min) stepped euglycemic (80-120 mg/dL)-hypoglycemic (40-45 mg/dL) clamp (Fig 1A).Results: During the euglycemic phase of the clamp, RH rats exhibited reduced glucose infusion rates compared to RS. This RH-induced insulin resistance was prevented with antecedent pioglitazone treatment (Fig 1B). During hypoglycemia, the epinephrine response was blunted in RH rats compared to RS. Pioglitazone treatment prevented the RH-induced blunting of the epinephrine response to hypoglycemia (Fig 1C).Conclusion: The insulin sensitizer, pioglitazone, 1) prevented the development of RH-induced insulin resistance, and 2) prevented the development of RH-induced blunting of the epinephrine response to hypoglycemia.
Z. Beckner: None. M. Devore: None. L. Schoeder: None. R. Zohary: None. J. Zohary: None. W.H. Hall: None. S. Fisher: None.
NIDDK (R01DK118082NIH T32DK138894)
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