A recent article published in Advances in Experimental Medicine and Biology stated that clinical hypoglycemia rarely occurs in nondiabetic individuals but is frequent in patients with type-1 or advanced insulin-treated type-2 diabetes mellitus. Advocated strict glycemic control, involving treatment with insulin, sulfonylureas, or glinides, can cause recurrent episodes of iatrogenic hypoglycemia due to impaired counter-regulation, including reduced glycemic thresholds and diminished magnitude of motor responses. Multiple components of the bodys pervasive energy balance regulatory network, including the hindbrain dorsal vagal complex, provide dynamic record of cellular energetic disequilibrium, signals that are employed by the hypothalamus programme counter-regulatory autonomic, neuroendocrine, and behavioral outflow toward restoration of glucostasis. The article revealed that ovarian steroid hormone 17β-estradiol acts on central substrates to preserve nerve cell energy stability brain-wide, thereby providing neuroprotection against bio-energetic insults such as neurodegenerative diseases and acute brain ischemia. This new understanding of the mechanistic basis of how estradiol influences metabolic sensory input from this critical brain locus to discrete downstream regulatory network substrates is expected to disclose viable new molecular targets for therapeutic simulation of hormone actions that promote positive neuronal metabolic state during acute and recurring hypoglycemia.