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Sex differences in ventromedial hypothalamic nucleus glucoregulatory transmitter biomarker protein during recurring insulin-induced hypoglycemia

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Abstract

Recurring insulin-induced hypoglycemia (RIIH) in males correlates with maladaptive glucose counter-regulatory collapse and acclimated expression of ventromedial hypothalamic nucleus (VMN) nitric oxide (NO) and γ-aminobutyric acid (GABA) metabolic transmitter biomarkers, e.g., neuronal nitric oxide synthase (nNOS) and glutamate decarboxylase65/67 (GAD). Hindbrain noradrenergic neurons innervate the VMN, where norepinephrine regulates nNOS and GAD expression. Current research investigated the hypothesis that antecedent hypoglycemia (AH) exposure causes sex-dimorphic habituation of VMN glucoregulatory biomarker proteins between and/or during serial hypoglycemic bouts, and that hindbrain catecholaminergic (CA) signaling may control sex-specific adaptation of one or more of these proteins. Data show that upon recovery from AH, females exhibit CA-mediated reductions in baseline VMN nNOS, GAD, steroidogenic factor-1 (SF-1), and brain-derived neurotrophic factor (BNDF) expression compared to euglycemic profiles. In males, however, AH caused 6-OHDA-insensitive suppression of only basal SF-1 levels in the VMN. VMN transmitter protein acclimation to RIIH was sex-contingent, as differential nNOS, GAD, SF-1, and BDNF responses to a single vs final bout of hypoglycemia occur in males, whereas females show acclimated reactivity of GAD and SF-1 only to renewed hypoglycemia. CA-mediated and -independent habituation of distinctive VMN protein profiles occurred in each sex. Further research is necessary to evaluate, in each sex, effects of altered baseline VMN metabolic neurotransmitter signals on glucose homeostasis as well as non-metabolic functions under the control of those neurochemicals. It would also be insightful to learn if and how sex-contingent habituation of VMN transmitter responses to hypoglycemia contribute to sex-dimorphic patterns of glucose counter-regulation during RIIH.

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Abbreviations

6-OHDA:

6-Hydroxydopamine

AH:

Antecedent hypoglycemia

BDNF:

Brain-derived neurotrophic factor

GABA:

γ-Aminobutyric acid

GAD65/67 :

Glutamate decarboxylase65/67

IIH:

Insulin-induced hypoglycemia

MBH:

Mediobasal hypothalamus

NE:

Norepinephrine

NO:

Nitric oxide

nNOS:

Neuronal nitric oxide synthase

RIIH:

Recurrent insulin-induced hypoglycemia

SF-1:

Steroidogenic factor-1

VMN:

Ventromedial hypothalamic nucleus

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Funding

This research was funded by National Institutes of Health Grant DK-109382.

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Authors and Affiliations

  1. School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, 356 Bienville Building, 1800 Bienville Drive, Monroe, LA, 71201, USA

    K. P. Briski, Md. Haider Ali, Prabhat R. Napit, A. S. M. H. Mahmood, A. R. Alhamyani, A. A. Alshamrani & Mostafa M. H. Ibrahim

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  1. K. P. Briski
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  2. Md. Haider Ali
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  3. Prabhat R. Napit
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  4. A. S. M. H. Mahmood
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  5. A. R. Alhamyani
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  6. A. A. Alshamrani
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  7. Mostafa M. H. Ibrahim
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Correspondence to K. P. Briski.

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Briski, K.P., Ali, M.H., Napit, P.R. et al. Sex differences in ventromedial hypothalamic nucleus glucoregulatory transmitter biomarker protein during recurring insulin-induced hypoglycemia. Brain Struct Funct 226, 1053–1065 (2021). https://doi.org/10.1007/s00429-021-02225-8

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  • DOI: https://doi.org/10.1007/s00429-021-02225-8

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