395-P: N-hydroxyethyl-1-deoxynojirimycin (Miglitol) Restores the Sympathoadrenal Response to Hypoglycemia following Antecedent Hypoglycemia in Diabetic Rats

Abstract

Antecedent hypoglycemia leads to a reduction in the sympathoadrenal response during subsequent hypoglycemia, i.e., HAAF. We’ve shown previously that this can be corrected in nondiabetic rats by portal vein infusion of N-hydroxyethyl-1-deoxynojirimycin (NEOH-DNJ; miglitol). In the current study we examined the efficacy of portal vein NEOH-DNJ infusion in restoring the sympathoadrenal response for diabetic animals. Diabetes was induced in rats via streptozotocin (STZ) injection (65mg/kg) 4 weeks prior to experiments. Conscious, unrestrained STZ-diabetic rats underwent hyperinsulinemic-hypoglycemic clamps on two consecutive days with a glycemic nadir of 2.6 ± 0.04 mM. On Day 2 animals received portal vein miglitol infusions (1.45 μmol/kg/min) either upstream, (PORups) or liver adjacent (PORadj), while hypoglycemic controls (HYPO) received normal saline infusion. Serial plasma samples were assayed for glucose, insulin, epinephrine (EPI) and norepinephrine (NE). On Day1 peak epinephrine (22.7 ± 2.1 nM) and norepinephrine (2.92 ± 0.3 nM) values were not significantly different between HYPO, PORups and PORadj (P>0.38). On Day 2, EPI values for untreated HYPO controls were suppressed by 85% relative to Day 1 (P < 0.0001). In contrast, EPI responses for miglitol infused groups, PORups (21.3 ± 2.2 nM) and PORadj (16.1 ± 2.01 nM) were not significantly different from Day 1 values (P = 0.75 and 0.50, respectively). NE demonstrated similar responses with HYPO suppressed by 63% on Day 2 (P<0.05), while miglitol treated groups, PORups and PORadj, demonstrated Day 2 NE values not significantly different from Day 1 (P>0.85). Conclusion: The impaired sympathoadrenal response following antecedent hypoglycemia is restored in STZ-diabetic rats by miglitol (NEOH-DNJ) treatment during subsequent hypoglycemia. As with nondiabetic rats, STZ-diabetic animals demonstrated no differences between portal miglitol infusion sites. Disclosure C. Donovan: None. A.J. Jokiaho: None. Funding JDRF (3-SRA-2017-486-S-B)