title: Hypothalamic AMP-Activated Protein Kinase Regulates Biphasic Insulin Secretion from Pancreatic β Cells during Fasting and in Type 2 Diabetes.
abstract: Glucose-stimulated insulin secretion (GSIS) by pancreatic β cells is biphasic. However, the physiological significance of biphasic GSIS and its relationship to diabetes are not yet fully understood. This study demonstrated that impaired first-phase GSIS follows fasting, leading to increased blood glucose levels and brain glucose distribution in humans. Animal experiments to determine a possible network between the brain and β cells revealed that fasting-dependent hyperactivation of AMP-activated protein kinase in the hypothalamus inhibited first-phase GSIS by stimulating the β-adrenergic pancreatic nerve. Furthermore, abnormal excitability of this brain-β cell neural axis was involved in diabetes-related impairment of first-phase GSIS in diabetic animals. Finally, pancreatic denervation improved first-phase GSIS and glucose tolerance and ameliorated severe diabetes by preventing β cell loss in diabetic animals. These results indicate that impaired first-phase GSIS is critical for brain distribution of dietary glucose after fasting. Furthermore, β cells in individuals with diabetes mistakenly sense that they are under conditions that mimic prolonged fasting. The present study provides additional insight into both β cell physiology and the pathogenesis of β cell dysfunction in type 2 diabetes.
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan. Electronic address: skume@belle.shiga-med.ac.jp.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kume
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan.
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Kondo
authors.affiliation: Laboratory for Endocrinology and Metabolism, RIKEN Center for Genomic Medicine, Yokohama, Kanagawa 230-0045, Japan; Department of Advanced Genomic and Laboratory Medicine, Graduate School of Medicine, University of the Ryukyus, Uehara, Nishihara-cho, Nakagami-gun, Okinawa 903-0215, Japan; Division of Clinical Laboratory and Blood Transfusion, University of the Ryukyus Hospital, Uehara, Nishihara-cho, Nakagami-gun, Okinawa 903-0215, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Maeda
authors.affiliation: Division of Diabetes, Metabolism and Endocrinology, Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka, Kagoshima 890-8580, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Nishio
authors.affiliation: Division of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido 078-8510, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yanagimachi
authors.affiliation: Division of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido 078-8510, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Fujita
authors.affiliation: Division of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido 078-8510, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Haneda
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan; Department of Public Health, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Kondo
authors.affiliation: Chiba University, Center for Preventive Medical Science. 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, 260-0856, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Sekine
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan.
authors.forename: Shin-Ich
authors.initials: SI
authors.lastname: Araki
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan.
authors.forename: Hisazumi
authors.initials: H
authors.lastname: Araki
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Chin-Kanasaki
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ugi
authors.affiliation: Division of Diabetology & Endocrinology, Kanazawa Medical University, Kahoku-gun, Ishikawa 920-1192, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Koya
authors.affiliation: Kusatsu General Hospital, Kusatsu, Shiga 525-0066, Japan.
authors.forename: Sawako
authors.initials: S
authors.lastname: Kitahara
authors.affiliation: Kusatsu General Hospital, Kusatsu, Shiga 525-0066, Japan.
authors.forename: Kiyosumi
authors.initials: K
authors.lastname: Maeda
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan; Kusatsu General Hospital, Kusatsu, Shiga 525-0066, Japan.
authors.forename: Atsunori
authors.initials: A
authors.lastname: Kashiwagi
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Uzu
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan. Electronic address: maegawa@belle.shiga-med.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maegawa
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D003714:Denervation; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000378:metabolism* / Q000628:therapy; D004195:Disease Models, Animal; D005215:Fasting / Q000378:metabolism*; D019788:Fluorodeoxyglucose F18; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test / Q000379:methods; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism; D061385:Insulins / Q000378:metabolism*; D008297:Male; D009928:Organ Specificity; D010179:Pancreas / Q000294:innervation; D049268:Positron-Emission Tomography; D051381:Rats; D013564:Sympathetic Nervous System / Q000378:metabolism; D013997:Time Factors; D014057:Tomography, X-Ray Computed
chemical_list: D061385:Insulins; D019788:Fluorodeoxyglucose F18; D055372:AMP-Activated Protein Kinases; D005947:Glucose
keywords: Diabetes; First-phase GSIS; Insulin secretion; Pancreatic ? cell; Starvation