Sex Differences and Role of Estradiol in Hypoglycemia-Associated Counter-Regulation

  • Karen P. Briski
  • Hussain N. Alhamami
  • Ayed Alshamrani
  • Santosh K. Mandal
  • Manita Shakya
  • Mostafa H. H. Ibrahim
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1043)


Vital nerve cell functions, including maintenance of transmembrane voltage and information transfer, occur at high energy expense. Inadequate provision of the obligate metabolic fuel glucose exposes neurons to risk of dysfunction or injury. Clinical hypoglycemia rarely occurs in nondiabetic individuals but is an unfortunate regular occurrence in patients with type 1 or advanced insulin-treated type 2 diabetes mellitus. Requisite strict glycemic control, involving treatment with insulin, sulfonylureas, or glinides, can cause frequent episodes of iatrogenic hypoglycemia due to defective counter-regulation, including reduced glycemic thresholds and diminished magnitude of motor responses. Multiple components of the body’s far-reaching energy balance regulatory network, including the hindbrain dorsal vagal complex, provide dynamic readout of cellular energetic disequilibrium, signals that are utilized by the hypothalamus to shape counterregulatory autonomic, neuroendocrine, and behavioral outflow toward restoration of glucostasis. The 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. The current review highlights recent evidence implicating estrogen in gluco-regulation in females by control of hindbrain metabolic sensor screening and signaling of hypoglycemia-associated neuro-energetic instability. It is anticipated that new understanding of the mechanistic basis of how estradiol influences metabolic sensory input from this critical brain locus to discrete downstream regulatory network substrates will likely reveal viable new molecular targets for therapeutic simulation of hormone actions that promote positive neuronal metabolic state during acute and recurring hypoglycemia.









Adenosine 5′-monophosphate-activated protein kinase


Astrocyte-neuron lactate shuttle hypothesis


Arcuate hypothalamic nucleus




Ca++/calmodulin-dependent protein kinase-beta


Corticotropin-releasing hormone


Caudal fourth ventricle






Dorsomedial hypothalamic nucleus


Dorsal vagal complex


Estrogen receptor-alpha


Estrogen receptor-beta


Food deprivation


γ-Aminobutyric acid


Glutamate decarboxylase65/67








Gonadotropin-releasing hormone


Glycogen phosphorylase


Glycogen synthase


Hypoglycemia-associated autonomic failure






ATP-dependent potassium channel


Luteinizing hormone


Lateral hypothalamic area




Neuronal nitric oxide synthase


Neuropeptide Y


Alpha ketoglutarate dehydrogenase












Paraventricular hypothalamic nucleus


Recurring insulin-induced hypoglycemia


Rostral preoptic area


Nucleus of the solitary tract


Type 1 diabetes mellitus


Type 2 diabetes mellitus


Tricarboxylic acid cycle


Ventromedial hypothalamic nucleus


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Authors and Affiliations

  • Karen P. Briski
    • 1
  • Hussain N. Alhamami
    • 1
  • Ayed Alshamrani
    • 1
  • Santosh K. Mandal
    • 1
  • Manita Shakya
    • 1
  • Mostafa H. H. Ibrahim
    • 1
  1. 1.Department of Basic Pharmaceutical SciencesSchool of Pharmacy, University of Louisiana at MonroeMonroeUSA

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