title: Partial blockade of nicotinic acetylcholine receptors improves the counterregulatory response to hypoglycemia in recurrently hypoglycemic rats.
abstract: Recurrent exposure to hypoglycemia can impair the normal counterregulatory hormonal responses that guard against hypoglycemia, leading to hypoglycemia unawareness. This pathological condition known as hypoglycemia-associated autonomic failure (HAAF) is the main adverse consequence that prevents individuals with type 1 diabetes mellitus from attaining the long-term health benefits of tight glycemic control. The underlying molecular mechanisms responsible for the progressive loss of the epinephrine response to subsequent bouts of hypoglycemia, a hallmark sign of HAAF, are largely unknown. Normally, hypoglycemia triggers both the release and biosynthesis of epinephrine through activation of nicotinic acetylcholine receptors (nAChR) on the adrenal glands. We hypothesize that excessive cholinergic stimulation may contribute to impaired counterregulation. Here, we tested whether administration of the nAChR partial agonist cytisine to reduce postganglionic synaptic activity can preserve the counterregulatory hormone responses in an animal model of HAAF. Compared with nicotine, cytisine has limited efficacy to activate nAChRs and stimulate epinephrine release and synthesis. We evaluated adrenal catecholamine production and secretion in nondiabetic rats subjected to two daily episodes of hypoglycemia for 3 days, followed by a hyperinsulinemic hypoglycemic clamp on day 4. Recurrent hypoglycemia decreased epinephrine responses, and this was associated with suppressed TH mRNA induction (a measure of adrenal catecholamine synthetic capacity). Treatment with cytisine improved glucagon responses as well as epinephrine release and production in recurrently hypoglycemic animals. These data suggest that pharmacological manipulation of ganglionic nAChRs may be promising as a translational adjunctive therapy to avoid HAAF in type 1 diabetes mellitus.
authors.affiliation: Division of Newborn Medicine, Departments of Pediatrics, Biochemistry, and Molecular Biology, New York Medical College, Valhalla, New York; Regional Neonatal Center, Maria Fareri Children's Hospital at Westchester Medical Center, Valhalla, New York; and.
authors.forename: Edmund F
authors.initials: EF
authors.lastname: LaGamma
authors.affiliation: Regional Neonatal Center, Maria Fareri Children's Hospital at Westchester Medical Center, Valhalla, New York; and.
authors.forename: Necla
authors.initials: N
authors.lastname: Kirtok
authors.affiliation: Department of Internal Medicine, Section of Endocrinology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Owen
authors.initials: O
authors.lastname: Chan
authors.affiliation: Division of Newborn Medicine, Departments of Pediatrics, Biochemistry, and Molecular Biology, New York Medical College, Valhalla, New York; Bistra_Nankova@nymc.edu.
authors.forename: Bistra B
authors.initials: BB
authors.lastname: Nankova
mesh_terms: D000311:Adrenal Glands / Q000187:drug effects* / Q000378:metabolism; D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects* / Q000378:metabolism; D001392:Azocines / Q000494:pharmacology; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004837:Epinephrine / Q000096:biosynthesis / Q000378:metabolism*; D020869:Gene Expression Profiling; D015309:Glucose Clamp Technique; D007003:Hypoglycemia / Q000378:metabolism*; D008297:Male; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D011807:Quinolizines / Q000494:pharmacology; D012333:RNA, Messenger; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic; D012008:Recurrence; D014446:Tyrosine 3-Monooxygenase / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000093843:Quinolizidine Alkaloids
chemical_list: D000470:Alkaloids; D001392:Azocines; D001786:Blood Glucose; D004837:Epinephrine; D018733:Nicotinic Antagonists; D011807:Quinolizines; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D014446:Tyrosine 3-Monooxygenase; C004712:cytisine; D000093843:Quinolizidine Alkaloids
keywords: cytisine; epinephrine release; hypoglycemia-associated autonomic failure; partial nicotinic acetylcholine receptor agonists; tyrosine hydroxylase