Glycogen phosphorylase isoenzyme GPbb versus GPmm regulation of ventromedial hypothalamic nucleus glucoregulatory neurotransmitter and counter-regulatory hormone profiles during hypoglycemia: Role of L-lactate and octadecaneuropeptide.

Glucose accesses the brain primarily via the astrocyte cell compartment, where it passes through the glycogen shunt before catabolism to the oxidizable fuel L-lactate. Glycogen phosphorylase (GP) isoenzymes GPbb and GPmm impose distinctive control of ventromedial hypothalamic nucleus (VMN) glucose-regulatory neurotransmission during hypoglycemia, but lactate and/or gliotransmitter involvement in those actions is unknown. Lactate or the octadecaneuropeptide receptor antagonist cyclo(1-8)[DLeu5] OP (LV-1075) did not affect gene product down-regulation caused by GPbb or GPmm siRNA, but suppressed non-targeted GP variant expression in a VMN region-specific manner. Hypoglycemic up-regulation of neuronal nitric oxide synthase was enhanced in rostral and caudal VMN by GPbb knockdown, yet attenuated by GPMM siRNA in the middle VMN; lactate or LV-1075 reversed these silencing effects. Hypoglycemic inhibition of glutamate decarboxylase65/67 was magnified by GPbb (middle and caudal VMN) or GPmm (middle VMN) knockdown, responses that were negated by lactate or LV-1075. GPbb or GPmm siRNA enlarged hypoglycemic VMN glycogen profiles in rostral and middle VMN. Lactate and LV-1075 elicited progressive rostral VMN glycogen augmentation in GPbb knockdown rats, but stepwise-diminution of rostral and middle VMN glycogen after GPmm silencing. GPbb, not GPmm, knockdown caused lactate or LV-1075 - reversible amplification of hypoglycemic hyperglucagonemia and hypercorticosteronemia. Results show that lactate and octadecaneuropeptide exert opposing control of GPbb protein in distinct VMN regions, while the latter stimulates GPmm. During hypoglycemia, GPbb and GPmm may respectively diminish (rostral, caudal VMN) or enhance (middle VMN) nitrergic transmission and each oppose GABAergic signaling (middle VMN) by lactate- and octadecaneuropeptide-dependent mechanisms.

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

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.