1540-P: Diazoxide (DZ) May Lower Endogenous Glucose Production (EGP) via Mitochondrial ATP-Sensitive K+ (mt KATP) Channels

Abstract

Rodent and human studies suggest that ventromedial hypothalamus (VMH) KATP channels suppress EGP. The VMH possesses glucose-sensing neurons that are either excited (GE) or inhibited (GI) by glucose. Since administration of the KATP channel activator DZ reduces EGP in rodents and humans, we examined the impact of DZ on VMH glucose sensing neurons. DZ opens both plasma membrane and mt KATP channels; the former inhibits neurons while the latter maintains mitochondrial metabolic function. We hypothesize that the concentration of brain DZ that lowers EGP affects the mt and not the plasma membrane KATP channel of VMH glucose sensing neurons. VMH glucose-excited (GE) neurons were exposed to 0.1 µM DZ in 2.5 mM glucose for 20 minutes prior to lowering glucose to 0.1 mM in the presence of DZ. DZ did not alter membrane potential (MP; 2.5 glucose: −63 ± 4 mV; DZ: −64 ± 5 mV, P = 0.3807, N = 7) or cell resistance (R; 2.5 glucose: 658 ± 136 MΩ; DZ 656 ± 146 MΩ, P = 0.9526, N = 7) in 2.5 mM glucose. There was also no difference in the MP or R response to lowering glucose from 2.5 to 0.1 mM in the presence or absence of DZ (% change MP control: −20.8 ± 3, diazoxide: −19.9 ± 3, P = 0.9044, N = 5; R control: −59.0 ± 5, diazoxide: −55.3 ± 6, P = 0.7134, N = 5). Similar results were seen with VMH glucose-inhibited neurons (N=4; Fig. 1). Our results are consistent with an action of DZ on mt but not plasma membrane KATP channels of VMH glucose sensing neurons. Disclosure G.Vail: None. V.Patel: None. P.Sarkar: None. K.Zhang: None. M.Hawkins: None. V.H.Routh: None. Funding National Institutes of Health (2R01DK069681-11)