16-LB: N-Hydroxylethyl-1-Deoxynojirimycin (Miglitol) Infusion Rescues the Sympathoadrenal Response to Hypoglycemia following Antecedent Hypoglycemia in Rats

Abstract

Antecedent hypoglycemia leads to a blunting of the sympathoadrenal response during subsequent hypoglycemia, which can largely be prevented by normalizing portal-mesenteric vein (PMV) glycemia during the antecedent bout. As SGLT3 has recently been implicated in PMV glucosensing, we hypothesized that PMV infusion of the imino sugar N-hydroxylethyl-1-deoxynojirimycin (miglitol), a potent SGLT3 agonist, during hypoglycemia would prevent or rescue the sympathoadrenal response to subsequent hypoglycemia. Wistar rats underwent hyperinsulinemic-hypoglycemic clamps on two consecutive days. Control animals were exposed to either euglycemia (EUG-CON: 5.73 ± 0.37 mM) or hypoglycemia (HYPO-CON: 2.39 ± 0.07 mM) on Day 1 without miglitol infusion, followed by a hypoglycemic bout on Day 2. Treatment groups were exposed to hypoglycemia (2.52 ± 0.07 mM) on both days with miglitol (1.45 μmol/kg/min) infused either upstream, perfusing the PMV glucosensors (PORups), or adjacent to the liver, bypassing the PMV glucosensors (PORadj), on Day 1 (PORups1, PORadj1) or Day2 (PORups2, PORadj2). Serial plasma samples drawn on the Day 2 experiment were assayed for glucose, insulin, epinephrine (EPI) and norepinephrine (NE). Compared to EUG-CON, peak EPI responses for HYPO-CON on Day 2 were significantly blunted (34.1 ± 4.3 vs. 15.4 ± 3.5 nmol/L; P < 0.05). EPI responses for PORups1 (11.8 ± 4.7 nmol/L) and PORadj1 (12.83 ± 3.4 nmol/L) were also suppressed on Day 2 compared with HYPO-CON (P<0.05). In contrast, EPI responses for PORups2 (31.5 ± 8.2 nmol/L) and PORadj2 (32.9 ± 13.2 nmol/L) were not significantly different from HYPO-CON (P = 0.74 and 0.90, respectively). NE demonstrated a similar trend to EPI. Conclusion: The impaired sympathoadrenal response following antecedent hypoglycemia in rats is restored by miglitol (NEOH-DNJ) treatment during a subsequent bout of hypoglycemia. Whether this is mediated via PMV glucosensors remains unclear. Disclosure A.J. Jokiaho: None. M. Winchester: None. C. Donovan: None. Funding JDRF