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

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Sex and Gender Factors Affecting Metabolic Homeostasis, Diabetes and Obesity

Part of the book series: Advances in Experimental Medicine and Biology ((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.

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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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Authors and Affiliations

  1. Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA, USA

    Karen P. Briski, Hussain N. Alhamami, Ayed Alshamrani, Santosh K. Mandal, Manita Shakya & Mostafa H. H. Ibrahim

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  1. Karen P. Briski
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  2. Hussain N. Alhamami
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  3. Ayed Alshamrani
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  4. Santosh K. Mandal
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  5. Manita Shakya
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  6. Mostafa H. H. Ibrahim
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Correspondence to Karen P. Briski .

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  1. Department of Medicine, Section of Endocrinology and Metabolism, Tulane University Health Sciences Center, School of Medicine, New Orleans, Louisiana, USA

    Franck Mauvais-Jarvis

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Briski, K.P., Alhamami, H.N., Alshamrani, A., Mandal, S.K., Shakya, M., Ibrahim, M.H.H. (2017). Sex Differences and Role of Estradiol in Hypoglycemia-Associated Counter-Regulation. In: Mauvais-Jarvis, F. (eds) Sex and Gender Factors Affecting Metabolic Homeostasis, Diabetes and Obesity. Advances in Experimental Medicine and Biology, vol 1043. Springer, Cham. https://doi.org/10.1007/978-3-319-70178-3_17

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