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Hypothalamic AMP-Activated Protein Kinase Regulates Biphasic Insulin Secretion from Pancreatic β Cells during Fasting and in Type 2 Diabetes

Kume, Shinji ; Kondo, Motoyuki ; Maeda, Shiro ; Nishio, Yoshihiko ; Yanagimachi, Tsuyoshi ; Fujita, Yukihiro ; Haneda, Masakazu ; Kondo, Keiko ; Sekine, Akihiro ; Araki, Shin-Ich ; Araki, Hisazumi ; Chin-Kanasaki, Masami ; Ugi, Satoshi ; Koya, Daisuke ; Kitahara, Sawako ; Maeda, Kiyosumi ; Kashiwagi, Atsunori ; Uzu, Takashi ; Maegawa, Hiroshi

EBioMedicine, November 2016, Vol.13, pp.168-180 [Peer Reviewed Journal]

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  • Title:
    Hypothalamic AMP-Activated Protein Kinase Regulates Biphasic Insulin Secretion from Pancreatic β Cells during Fasting and in Type 2 Diabetes
  • Author: Kume, Shinji ; Kondo, Motoyuki ; Maeda, Shiro ; Nishio, Yoshihiko ; Yanagimachi, Tsuyoshi ; Fujita, Yukihiro ; Haneda, Masakazu ; Kondo, Keiko ; Sekine, Akihiro ; Araki, Shin-Ich ; Araki, Hisazumi ; Chin-Kanasaki, Masami ; Ugi, Satoshi ; Koya, Daisuke ; Kitahara, Sawako ; Maeda, Kiyosumi ; Kashiwagi, Atsunori ; Uzu, Takashi ; Maegawa, Hiroshi
  • Description: 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 α-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. Glucose-stimulated insulin secretion (GSIS) from pancreatic β cells is biphasic. Furthermore, first-phase GSIS is inhibited in type 2 diabetes. This study revealed that fasting reduced first-phase GSIS by signaling via the brain-pancreatic β cell neural axis, which is essential for maintaining glucose supply to the brain at re-feeding after fasting. Abnormal excitability of this neural axis was also associated with impaired first-phase GSIS in type 2 diabetes. Surgical pancreatic denervation improved diabetes in an animal study. The present data reveal that diabetic β cells exist under conditions that mimic starvation and provide a therapeutic potency of pancreatic denervation against diabetes.
  • Is Part Of: EBioMedicine, November 2016, Vol.13, pp.168-180
  • Identifier: ISSN: 2352-3964 ; E-ISSN: 2352-3964 ; DOI: 10.1016/j.ebiom.2016.10.038
  • Subjects: First-Phase Gsis ; Pancreatic Β Cell ; Starvation ; Diabetes ; Insulin Secretion ; Biology
  • Language: English

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