title: Whole genome expression profiling associates activation of unfolded protein response with impaired production and release of epinephrine after recurrent hypoglycemia.
abstract: Recurrent hypoglycemia can occur as a major complication of insulin replacement therapy, limiting the long-term health benefits of intense glycemic control in type 1 and advanced type 2 diabetic patients. It impairs the normal counter-regulatory hormonal and behavioral responses to glucose deprivation, a phenomenon known as hypoglycemia associated autonomic failure (HAAF). The molecular mechanisms leading to defective counter-regulation are not completely understood. We hypothesized that both neuronal (excessive cholinergic signaling between the splanchnic nerve fibers and the adrenal medulla) and humoral factors contribute to the impaired epinephrine production and release in HAAF. To gain further insight into the molecular mechanism(s) mediating the blunted epinephrine responses following recurrent hypoglycemia, we utilized a global gene expression profiling approach. We characterized the transcriptomes during recurrent (defective counter-regulation model) and acute hypoglycemia (normal counter-regulation group) in the adrenal medulla of normal Sprague-Dawley rats. Based on comparison analysis of differentially expressed genes, a set of unique genes that are activated only at specific time points after recurrent hypoglycemia were revealed. A complementary bioinformatics analysis of the functional category, pathway, and integrated network indicated activation of the unfolded protein response. Furthermore, at least three additional pathways/interaction networks altered in the adrenal medulla following recurrent hypoglycemia were identified, which may contribute to the impaired epinephrine secretion in HAAF: greatly increased neuropeptide signaling (proenkephalin, neuropeptide Y, galanin); altered ion homeostasis (Na+, K+, Ca2+) and downregulation of genes involved in Ca2+-dependent exocytosis of secretory vesicles. Given the pleiotropic effects of the unfolded protein response in different organs, involved in maintaining glucose homeostasis, these findings uncover broader general mechanisms that arise following recurrent hypoglycemia which may afford clinicians an opportunity to modulate the magnitude of HAAF syndrome.
authors.affiliation: The Regional Neonatal Center, Maria Fareri Children's Hospital at Westchester Medical Center, Valhalla, New York, United States of America.
authors.forename: Juhye Lena
authors.initials: JL
authors.lastname: Kim
authors.affiliation: The Regional Neonatal Center, Maria Fareri Children's Hospital at Westchester Medical Center, Valhalla, New York, United States of America.|Departments of Pediatrics, Biochemistry and Molecular Biology, Division of Newborn Medicine, New York Medical College, Valhalla, New York, United States of America.
authors.forename: Edmund F
authors.initials: EF
authors.lastname: La Gamma
authors.affiliation: New York Medical College School of Medicine, Valhalla, New York, United States of America.
authors.forename: Todd
authors.initials: T
authors.lastname: Estabrook
authors.affiliation: The Regional Neonatal Center, Maria Fareri Children's Hospital at Westchester Medical Center, Valhalla, New York, United States of America.
authors.forename: Necla
authors.initials: N
authors.lastname: Kudrick
authors.affiliation: Departments of Pediatrics, Biochemistry and Molecular Biology, Division of Newborn Medicine, New York Medical College, Valhalla, New York, United States of America.
authors.forename: Bistra B
authors.identifier: http://orcid.org/0000-0002-3997-4369
authors.initials: BB
authors.lastname: Nankova
mesh_terms: D000818:Animals; D001342:Autonomic Nervous System Diseases / Q000503:physiopathology; D001786:Blood Glucose; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004837:Epinephrine / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000235:genetics*; D016678:Genome; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007003:Hypoglycemia / Q000235:genetics* / Q000473:pathology; D007328:Insulin / Q000378:metabolism*; D051381:Rats; D056811:Unfolded Protein Response / Q000235:genetics
chemical_list: D001786:Blood Glucose; D007328:Insulin; D005947:Glucose; D004837:Epinephrine