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

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 gl...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5264491/
https://www.ncbi.nlm.nih.gov/pubmed/28005533
http://dx.doi.org/10.1016/j.ebiom.2016.10.038
Descripción
Sumario: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.