Hypothalamic KATP channels play an important role in regulating metabolism: activation of these channels with diazoxide (DZX) reduces endogenous glucose production (EGP) in rodents. When insulin is maintained at basal levels, oral DZX similarly suppresses EGP in humans (JCI 121:4916, 2011). Given the need to directly examine central regulation of EGP in humans, we developed a novel non-invasive measure of hypothalamic KATP channel activation.

Since cerebral blood flow (CBF) and neuronal activity are coupled, we mapped hypothalamic neuronal activity using pseudo-continuous arterial spin labeling (pCASL) to measure CBF using 3 Tesla MRI with high resolution 3-dimensional (3D) acquisition and published analyses approaches (MRM 73: 102, 2015). The hypothalamus was extracted from each 3D map (3x3x3mm) using a hypothalamus region-of-interest (ROI) mask delineated upon the Johns Hopkins Template. To directly assess hypothalamic KATP channel activity using pCASL, we examined the time dependent effects of DZX (6mg/kg) vs. placebo in a randomized, double blinded fashion. Eight healthy nondiabetic individuals (42±4 yr, BMI 24±1 kg/m2, 7M) underwent a baseline scan, with repeat scans at 2.5 and 5 hours following DZX or placebo. This time course was determined based on previous observations that DZX appearance in rat CSF precedes EGP suppression, which is maximal at ∼6 hours in rats and humans.

DZX induced an ∼11% drop in hypothalamic CBF, from 59.5±2.5 to 53.0±3.1 ml/100g/min at 2.5 hours (p=0.06), returning to baseline at 5 hours (57.7±2.7 ml/100g/min, p=0.3). Following placebo there was no change in CBF (p=0.8 by repeated measures ANOVA). No change in CBF was observed in other brain regions (e.g., cerebral cortex, thalamus, or hippocampus).

In conclusion, pCASL provides a novel image-based measure of hypothalamic response to KATP channel activation in vivo, and can thus be used to examine the metabolic significance of hypothalamic KATP channel activation in humans.

Disclosure

S. Sharma: None. S. Aleksic: None. R. Maginley: None. E. Lontchi Yimagou: None. L. Upadhyay: None. S. Bhansali: None. O. Sandu: None. C.A. Branch: None. M. Hawkins: Other Relationship; Self; Novo Nordisk Inc.

Funding

National Institutes of Health (R01DK069861); Albert Einstein College of Medicine

© 2019 by the American Diabetes Association.
2019
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