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
Chapter
First Online:
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1043)

Abstract

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.

Abbreviations

4CIN

Alpha-cyano-4-hydroxycinnamate

6-OHDA

6-Hydroxydopamine

AICAR

5-Aminoimidazole-4-carboxamide-riboside

AMPK

Adenosine 5′-monophosphate-activated protein kinase

ANLSH

Astrocyte-neuron lactate shuttle hypothesis

ARH

Arcuate hypothalamic nucleus

CA

Catecholamine

CaMMKβ

Ca++/calmodulin-dependent protein kinase-beta

CRH

Corticotropin-releasing hormone

CV4

Caudal fourth ventricle

DAB

1,4-Dideoxy-1,4-imino-d-arabinitol

DBH

Dopamine-beta-hydroxylase

DMH

Dorsomedial hypothalamic nucleus

DVC

Dorsal vagal complex

ERα

Estrogen receptor-alpha

ERβ

Estrogen receptor-beta

FD

Food deprivation

GABA

γ-Aminobutyric acid

GAD65/67

Glutamate decarboxylase65/67

GCK

Glucokinase

GE

Glucose-excited

GI

Glucose-inhibited

GnRH

Gonadotropin-releasing hormone

GP

Glycogen phosphorylase

GS

Glycogen synthase

HAAF

Hypoglycemia-associated autonomic failure

icv

Intracerebroventricular

ir

Immunoreactivity

KATP

ATP-dependent potassium channel

LH

Luteinizing hormone

LHA

Lateral hypothalamic area

NE

Norepinephrine

nNOS

Neuronal nitric oxide synthase

NPY

Neuropeptide Y

OGDH

Alpha ketoglutarate dehydrogenase

ORDX

Orchidectomy

OVX

Ovariectomy

pAMPK

PhosphoAMPK

PFKL

Phosphofructokinase

PHTPP

4-[2-Phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol

PVH

Paraventricular hypothalamic nucleus

RIIH

Recurring insulin-induced hypoglycemia

rPO

Rostral preoptic area

NTS

Nucleus of the solitary tract

T1DM

Type 1 diabetes mellitus

T2DM

Type 2 diabetes mellitus

TCA

Tricarboxylic acid cycle

VMH

Ventromedial hypothalamic nucleus

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Copyright information

© Springer International Publishing AG 2017

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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