title: Impairment of vesicular ATP release affects glucose metabolism and increases insulin sensitivity.
abstract: Neuroendocrine cells store ATP in secretory granules and release it along with hormones that may trigger a variety of cellular responses in a process called purinergic chemical transmission. Although the vesicular nucleotide transporter (VNUT) has been shown to be involved in vesicular storage and release of ATP, its physiological relevance in vivo is far less well understood. In Vnut knockout (Vnut(-/-)) mice, we found that the loss of functional VNUT in adrenal chromaffin granules and insulin granules in the islets of Langerhans led to several significant effects. Vesicular ATP accumulation and depolarization-dependent ATP release were absent in the chromaffin granules of Vnut(-/-) mice. Glucose-responsive ATP release was also absent in pancreatic β-cells in Vnut(-/-) mice, while glucose-responsive insulin secretion was enhanced to a greater extent than that in wild-type tissue. Vnut(-/-) mice exhibited improved glucose tolerance and low blood glucose upon fasting due to increased insulin sensitivity. These results demonstrated an essential role of VNUT in vesicular storage and release of ATP in neuroendocrine cells in vivo and suggest that vesicular ATP and/or its degradation products act as feedback regulators in catecholamine and insulin secretion, thereby regulating blood glucose homeostasis.
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, JAPAN.
authors.forename: Shohei
authors.initials: S
authors.lastname: Sakamoto
authors.affiliation: Advanced Research Science Center, Okayama University, Okayama 700-8530, JAPAN.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Miyaji
authors.affiliation: Department of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8530, JAPAN.
authors.forename: Miki
authors.initials: M
authors.lastname: Hiasa
authors.affiliation: Institute for Innovation, Ajinomoto Co., Inc. Kawasaki 210-5893, JAPAN.
authors.forename: Reiko
authors.initials: R
authors.lastname: Ichikawa
authors.affiliation: Institute for Innovation, Ajinomoto Co., Inc. Kawasaki 210-5893, JAPAN.
authors.forename: Akira
authors.initials: A
authors.lastname: Uematsu
authors.affiliation: Institute for Innovation, Ajinomoto Co., Inc. Kawasaki 210-5893, JAPAN.
authors.forename: Ken
authors.initials: K
authors.lastname: Iwatsuki
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, JAPAN.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shibata
authors.affiliation: Institute for Innovation, Ajinomoto Co., Inc. Kawasaki 210-5893, JAPAN.
authors.forename: Hisayuki
authors.initials: H
authors.lastname: Uneyama
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, JAPAN.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Takayanagi
authors.affiliation: Faculty of Bioscience, Nagahama Institute of Bio-science and Technology, Nagahama 526-0829, JAPAN.
authors.forename: Akitsugu
authors.initials: A
authors.lastname: Yamamoto
authors.affiliation: Department of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8530, JAPAN.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Omote
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, JAPAN.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Nomura
authors.affiliation: 1] Advanced Research Science Center, Okayama University, Okayama 700-8530, JAPAN [2] Department of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8530, JAPAN.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Moriyama
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D001786:Blood Glucose / Q000235:genetics; D002395:Catecholamines / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D000078790:Insulin Secretion; D051379:Mice; D018345:Mice, Knockout; D033704:Nucleotide Transport Proteins / Q000235:genetics* / Q000378:metabolism; D009711:Nucleotides / Q000378:metabolism*; D022142:Secretory Vesicles / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D002395:Catecholamines; D007328:Insulin; D033704:Nucleotide Transport Proteins; D009711:Nucleotides; C578984:Slc17a9 protein, mouse; D000255:Adenosine Triphosphate; D005947:Glucose