Sex-specific recurrent insulin-induced hypoglycemia (RIIH) effects on ventromedial hypothalamic nucleus astrocyte metabolic sensor expression and glycogen metabolism.

Brain astrocytes support neuron energy stability by maintaining an energy reserve and by catabolizing glucose to the transferrable oxidizable fuel L-lactate. Astrocyte-neuron metabolic coupling shapes ventromedial hypothalamic nucleus (VMN) counterregulatory neurotransmission. VMN astrocyte involvement in recurring insulin-induced hypoglycemia (RIIH)-associated sex-specific acclimation of these neurochemical signals is unclear. Current research implemented combinatory in situ immunocytochemistry/laser-catapult-microdissection/Western blotting and micropunch-dissection/HPLC-electrospray ionization-mass spectrometry methods to investigate whether RIIH alters VMN astrocyte glucose sensing and glycogen metabolism according to sex. Data disclose distinctive effects of single and repetitive hypoglycemia exposure on glucose transporter-2, glucokinase, and total/phosphorylated 5'-AMP-activated protein kinase protein profiles in dorsomedial (dm) versus ventrolateral (vl) VMN astrocytes. Acute hypoglycemia down-regulated VMNdm and VMNvl astrocyte glycogen synthase protein; in each sex, this inhibitory response was abolished (VMNdm) or persisted (VMNvl) during RIIH. Singular hypoglycemia respectively up- or down-regulated glycogen phosphorylase-brain (GPbb) and -muscle type (GPmm) proteins in female VMN astrocytes, responses that were correspondingly amplified by or refractory to RIIH. Male astrocytes exhibited RIIH-associated habituation of VMNdm GPbb (inhibitory) and GPmm (stimulatory) responses to hypoglycemia. Acute hypoglycemia amplified (male) or decreased (female) glycogen levels in each VMN division. RIIH exacerbated (VMNdm) or normalized (VMNvl) glycogen augmentation in males, yet reversed glycogen diminution in the female VMNdm, not VMNvl. Results show that RIIH elicits VMN division-specific adjustments in male and female astrocyte glucose and energy sensing functions and tissue glycogen content. Further research is needed to examine whether precedent hypoglycemia-associated acclimation of VMNdm and/or VMNvl astrocyte glucose handling controls sex-specific counterregulatory neurotransmission and hormone secretion during RIIH.