title: Hypothalamic glucagon signaling in fasting hypoglycemia.
abstract: OBJECTIVE
  Sustained glucagon infusion increases hepatic glucose production, but this effect is transient due to hypothalamic glucagon signaling. In hypoglycemia, glucagon acts as a major defense to sustain the blood glucose level and this raises the question regarding glucagon signaling associated glucose production in prolonged fasting hypoglycemia. In this study, we investigated the proteins associated with hypothalamic glucagon signaling and liver gluconeogenesis during fasting hypoglycemia.
  
  
  METHODS
  8-9week old, male C57BL6/J mice were fasted for 4, 8, 12, 18, 24, 30, 36 or 42h. In the hypothalamus, we investigated glucagon signaling by analyzing the glucagon receptor and its downstream protein, peroxisome proliferator-activated receptor-gamma coactivator 1 (PGC-1) expression. In the liver, we investigated gluconeogenesis by analyzing p-protein kinase A (PKA)(Ser/Thr) substrate and phosphoenolpyruvate carboxykinase - cytosolic (PEPCK-C) expression using the western blotting technique.
  
  
  RESULTS
  The elevated or trended higher hypothalamic glucagon receptor and PGC-1 expressions at 18 and 42h were correlated with the attenuated liver p-PKA(Ser/Thr) substrate expression. The attenuated hypothalamic glucagon receptor and PGC-1 expressions at 12, 24, 30 and 36h were correlated with the elevated or trended higher liver p-PKA(Ser/Thr) substrate expression.
  
  
  CONCLUSIONS
  The hypothalamic glucagon signaling during fasting hypoglycemia might have been modulated by circadian rhythm and this possibly attenuates the liver p-PKA(Ser/Thr) substrate to modify the gluconeogenesis pathway. This mechanism will help to understand the hyperglucagonemia associated complications in diabetes.
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan.
authors.forename: Vigneshwaran
authors.initials: V
authors.lastname: Pitchaimani
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan.
authors.forename: Somasundaram
authors.initials: S
authors.lastname: Arumugam
authors.affiliation: Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX 77030, USA.
authors.forename: Rajarajan Amirthalingam
authors.initials: RA
authors.lastname: Thandavarayan
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan.
authors.forename: Vengadeshprabhu
authors.initials: V
authors.lastname: Karuppagounder
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan.
authors.forename: Mst Rejina
authors.initials: MR
authors.lastname: Afrin
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan.
authors.forename: Remya
authors.initials: R
authors.lastname: Sreedhar
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan.
authors.forename: Meilei
authors.initials: M
authors.lastname: Harima
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan.
authors.forename: Shizuka
authors.initials: S
authors.lastname: Miyashita
authors.affiliation: Department of Gastroenterology, Niigata University of Graduate School of Medicine and Dental Sciences, Niigata City 951-8510, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Cardiology, Yamanashi Prefectural Central Hospital, Kofu, Yamanashi 400-8506, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Department of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Ueno
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan. Electronic address: watanabe@nupals.ac.jp.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005934:Glucagon / Q000378:metabolism*; D007003:Hypoglycemia / Q000378:metabolism*; D007031:Hypothalamus / Q000378:metabolism*; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000378:metabolism; D015398:Signal Transduction; D013379:Substrate Specificity; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D005934:Glucagon; D017868:Cyclic AMP-Dependent Protein Kinases; D019764:Phosphoenolpyruvate Carboxykinase (ATP)
keywords: Fasting; Glucagon; Gluconeogenesis; Hypoglycemia; Hypothalamus; Liver