N-Hydroxyethyl-1-Deoxynojirimycin (Miglitol) Restores the Counterregulatory Response to Hypoglycemia Following Antecedent Hypoglycemia

Abstract

Antecedent hypoglycemia suppresses the counterregula-tory responses to subsequent hypoglycemic episodes, which can be prevented by normalizing portal-mesenteric vein (PMV) glycemia alone during the antecedent bout. Since the sodium–glucose transporter 3 receptor has been implicated in PMV glucosensing, we hypothesized that PMV infusion of the sodium–glucose cotransporter 3 receptor agonist N-hydroxyethyl-1-deoxynojirimycin (migli-tol) would rescue the sympathoadrenal response to subsequent hypoglycemia. Rats underwent hyperinsulinemic-hypoglycemic clamps on 2 consecutive days without migli-tol infusion (antecedent hypoglycemia without miglitol [HYPO]) or with miglitol infused upstream in the PMV, per-fusing the glucosensors, or adjacent to the liver, bypassing PMV glucosensors, on day 1 or day 2. Control animals underwent day 1 euglycemic clamps, followed by hypoglycemic clamps on day 2. Peak epinephrine (EPI) responses for HYPO on day 2 were significantly blunted when compared with controls. Miglitol infusion on day 1 proved inef-fective in restoring the EPI response following antecedent hypoglycemia, but day 2 miglitol infusion restored EPI responses to control levels. As norepinephrine and gluca-gon demonstrated similar responses, day 2 administration of miglitol effectively restored the counterregulatory response following antecedent hypoglycemia. In subsequent experiments, we demonstrate similar results with reduced miglitol infusion doses, approaching those cur-rently prescribed for type 2 diabetes (correcting for rodent size), as well as the efficacy of oral miglitol administration in restoring the counterregulatory responses following antecedent hypoglycemia.