Hypoglycemia poses a significant threat to neurological function as neurons require a continuous glucose supply to sustain vital high-energy functions but have access to limited fuel reserves. Neuroglycopenia triggers an integrated array of counter-regulatory autonomic, neuroendocrine, and behavioral responses that enhance systemic glucose availability. Conventional therapeutic strategies involving treatment with intermediate-release insulin formulations for mandatory strict glycemic control in type I diabetes mellitus regularly produce iatrogenic hypoglycemia. In diabetic patients, antecedent hypoglycemia is a primary cause of hypoglycemia-associated autonomic failure (HAAF), which exacerbates the risk of neurological dysfunction and injury due to diminished hypoglycemic awareness and suppressed counter-regulatory outflow.
Glucose counter-regulatory collapse correlates with impaired activation of the hypothalamic metabolic sensor adenosine 5′monophosphate-activated protein kinase (AMPK). Hindbrain energy status controls hypothalamic AMPK. Results show that recurrent insulin-induced hypoglycemia (RIIH) elicited compound C-reversible augmentation of ventromedial hypothalamic nucleus (VMN) glutamate decarboxylase, arcuate pro-opiomelanocortin, and lateral hypothalamic orexin-A proteins or reductions
in VMH nitric oxide synthase profiles but caused adaptation of other hypothalamic metabolic neurotransmitter proteins without hindbrain sensor involvement. Data also show acclimated up-regulation of total AMPK protein expression in multiple hypothalamic loci during RIIH, and document hindbrain sensor contribution to upregulation of AMPK in ARH, VMH. Hindbrain AMPK required for acute hypoglycemic intensification of norepinephrine (NE) activity in characterized hypothalamic gluco-regulatory structures. Outcomes here indicate that hindbrain lactoprivic-driven NE signaling to those hypothalamic loci may acclimate to RIIH because of lessened A2 neuron reactivity to hypoglycemia-related decrements in this oxidizable glycolytic-derived energy fuel. Lastly, VMN metabolic-sensory nitrergic neurons exhibit significantly up-regulated expression of characterized biomarkers for pyruvate recycling pathway activity, e.g., glutaminase and malic enzyme-1, alongside diminished AMPK activation and altered patterns of adrenergic receptor expression. These findings show that habituated receptor-specific sensitivity of VMN sensing neurons to NE may correlate with augmented utilization of amino acids as a non-glucose energy substrate and decreased the reactivity of these cells to hypoglycemia.
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|Advisor:||Briski, Karen P.|
|Commitee:||Sylvester, Paul W., Liu, Yong Yu, Jackson, Keith E.|
|School:||University of Louisiana at Monroe|
|School Location:||United States -- Louisiana|
|Source:||DAI-B 81/2(E), Dissertation Abstracts International|
|Subjects:||Nanoscience, Pharmaceutical sciences|
|Keywords:||Hypoglycemia, Neuroglycopenia, AMPK|
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