Hypoglycemic Counterregulation Is Impaired following Exposure to 72 Hours of Fasting in Male and Female Rats

Introduction and Objective: Hypoglycemia-associated autonomic failure (HAAF), a common complication of diabetes, is caused by recurrent exposure to treatment-induced hypoglycemia. Starvation is the only normal physiological process which induces prolonged exposure to hypoglycemia similar to the antecedent of HAAF. This study tested whether exposure to starvation in rats would lead to impairments in hypoglycemic counterregulation following short-term refeeding. Methods: Two groups of rats were used, an ad libitum fed group and a 72-h fasted group. Following an 8-h refeeding period in fasted rats, both groups were fasted for 8-10 hours and then subjected to a hyperinsulinemic-hypoglycemic clamp procedure and blood was collected for determination of plasma levels of the counterregulatory hormones glucagon (GCG) and epinephrine (EPI). The experiment was conducted in both male and female rats (n=7-8/group and n=4/group, respectively). A two-way ANOVA was used to test the effect of exposure to 72 h of fasting on hypoglycemia-induced GCG and EPI levels during the clamp procedure. Results: As expected, male and female rats exposed to the 72-h fast lost ≈20 % of their initial body weight and experienced a gradual fall in blood glucose. Clamp glucose levels following insulin administration were well matched in each of the groups. Male rats exposed to the 72-h fast had significantly reduced GCG and EPI levels during the clamp relative to controls (11.3 vs 25.9 pg/mL, p=0.003; 1321 vs 2077 pg/mL, p=0.018, respectively). Clamp GCG levels were also significantly reduced in female rats exposed to the 72-h fast relative to controls (7.8 vs 19.3 pg/mL, p=0.048). Conclusion: Our results reveal that exposure to starvation induces a HAAF-like syndrome in both male and female rats following refeeding. Our data suggests that HAAF may result from an adaptive response to starvation which is inappropriately elicited by diabetes treatments. Future studies will be needed to determine how starvation leads to impairment of hypoglycemic counterregulation. Disclosure: L. DePrimo: None. A. Narez: None. A. Bui: None. S. Junot: None. C.R. Meaux: None. D. McDougal: None. Funding: NIH (R01DK131165)