title: Posttranscriptional regulation of adrenal TH gene expression contributes to the maladaptive responses triggered by insulin-induced recurrent hypoglycemia.
abstract: Acute metabolic stress such as insulin-induced hypoglycemia triggers a counterregulatory response during which the release of catecholamines (epinephrine), the activation of tyrosine hydroxylase (TH) enzyme and subsequent compensatory catecholamine biosynthesis occur in the adrenal medulla. However, recurrent exposure to hypoglycemia (RH), a consequence of tight glycemic control in individuals with type 1 and type 2 diabetes compromises this physiological response. The molecular mechanisms underlying the maladaptive response to repeated glucose deprivation are incompletely understood. We hypothesize that impaired epinephrine release following RH reflects altered regulation of adrenal catecholamine biosynthesis. To test this hypothesis, we compared the effect of single daily (RH) and twice-daily episodes of insulin-induced hypoglycemia (2RH) on adrenal epinephrine release and production in normal rats. Control animals received saline injections under similar conditions (RS and 2RS, respectively). Following 3 days of treatment, we assessed the counterregulatory hormonal responses during a hypoglycemic clamp. Changes in adrenal TH gene expression were also analyzed. The counterregulatory responses, relative TH transcription and TH mRNA levels and Ser40-TH phosphorylation (marker for enzyme activation) were induced to a similar extent in RS, 2RS, and RH groups. In contrast, epinephrine and glucagon responses were attenuated in the 2RH group and this was associated with a limited elevation of adrenal TH mRNA, rapid inactivation of TH enzyme and no significant changes in TH protein. Our results suggest that novel posttranscriptional mechanisms controlling TH mRNA and activated TH enzyme turnover contribute to the impaired epinephrine responses and may provide new therapeutic targets to prevent HAAF.
authors.affiliation: The Regional Neonatal Center, Maria Fareri Children's Hospital at Westchester Medical Center, Valhalla, New York.
authors.forename: Necla
authors.initials: N
authors.lastname: Kudrick
authors.affiliation: Department of Internal Medicine, Section of Endocrinology and Metabolism, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Owen
authors.initials: O
authors.lastname: Chan
authors.affiliation: The Regional Neonatal Center, Maria Fareri Children's Hospital at Westchester Medical Center, Valhalla, New York Division of Newborn Medicine, Departments of Pediatrics, Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York.
authors.forename: Edmund F
authors.initials: EF
authors.lastname: La Gamma
authors.affiliation: The Regional Neonatal Center, Maria Fareri Children's Hospital at Westchester Medical Center, Valhalla, New York.
authors.forename: Juhye Lena
authors.initials: JL
authors.lastname: Kim
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York.
authors.forename: Arnold William
authors.initials: AW
authors.lastname: Tank
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York.
authors.forename: Carol
authors.initials: C
authors.lastname: Sterling
authors.affiliation: Division of Newborn Medicine, Departments of Pediatrics, Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York.
authors.forename: Bistra B
authors.initials: BB
authors.lastname: Nankova
keywords: Adrenal medulla; epinephrine; hypoglycemia‐associated autonomic failure; tyrosine hydroxylase gene expression