GDF15 is a Critical Renostat in the Defense Against Hypoglycemia
GDF15 is a Critical Renostat in the Defense Against Hypoglycemia
Summary Episodic hypoglycemia is one of the best honed, evolutionary conserved phenomena in biology, because of the constant feast-fast cycles that have characterized most of history. The counterregulatory response to hypoglycemia, mobilizing substrate stores to produce glucose, is the primary adaptive mechanism to enable survival. Catecholamines and glucagon have long been considered the key hypoglycemia counterregulatory hormones, but here we identify a new hypoglycemia counterregulatory factor. We employed the insulin tolerance test (ITT) and hyperinsulinemic-hypoglycemic clamp to mimic the two common settings in which hypoglycemia can occur in patients: postprandial insulin overdose and elevated basal insulin administration, respectively. We found that Growth Differentiation Factor 15 (GDF15) production is induced in the S3 segment of the renal proximal tubules and its release increases hepatic gluconeogenesis by increasing intrahepatic lipolysis in a beta-adrenergic receptor-2 (Adrb2)-dependent manner. In addition, mice exposed to recurrent hypoglycemia and patients with T1D exhibit impaired GDF15 production in the setting of hypoglycemia. These data demonstrate that GDF15 acts acutely as a gluco-counterregulatory hormone and identify a critical role for kidney-derived GDF15 in glucose homeostasis under physiological and pathophysiological conditions.
Xu Qian、Li Xiruo、Israni-Winger Kavita、Caplan Michael J.、Wang Andrew、Belfort de Aguiar Renata、Hwang Janice J.、Zhao Qiancheng、Siebel Stephan、Perry Rachel J.、Yu Chuyue、Nasiri Ali R.、Chang Rui B.、Zhu Wanling、Costa Lima Bruna Genisa、Li Zongyu、Zhang Cuiling、Zhang Xinyi
Departments of Neuroscience Yale School of MedicineDepartments of Cellular & Molecular Physiology Yale School of Medicine||Departments of Internal Medicine Yale School of MedicineDepartments of Internal Medicine Yale School of Medicine||Departments of Immunobiology Yale School of MedicineDepartments of Cellular & Molecular Physiology Yale School of Medicine||Departments of Cell Biology Yale School of MedicineDepartments of Internal Medicine Yale School of Medicine||Departments of Immunobiology Yale School of MedicineDepartments of Internal Medicine Yale School of MedicineDepartments of Internal Medicine Yale School of MedicineDepartments of Neuroscience Yale School of MedicineDepartments of Cellular & Molecular Physiology Yale School of Medicine||Departments of Internal Medicine Yale School of Medicine||Departments of Pediatrics Yale School of MedicineDepartments of Cellular & Molecular Physiology Yale School of Medicine||Departments of Internal Medicine Yale School of MedicineDepartments of Neuroscience Yale School of MedicineDepartments of Cellular & Molecular Physiology Yale School of Medicine||Departments of Internal Medicine Yale School of MedicineDepartments of Cellular & Molecular Physiology Yale School of Medicine||Departments of Neuroscience Yale School of MedicineDepartments of Cellular & Molecular Physiology Yale School of Medicine||Departments of Internal Medicine Yale School of MedicineDepartments of Cell Biology Yale School of MedicineDepartments of Cellular & Molecular Physiology Yale School of MedicineDepartments of Internal Medicine Yale School of Medicine||Departments of Immunobiology Yale School of MedicineDepartments of Cellular & Molecular Physiology Yale School of Medicine
基础医学生理学生物化学
Xu Qian,Li Xiruo,Israni-Winger Kavita,Caplan Michael J.,Wang Andrew,Belfort de Aguiar Renata,Hwang Janice J.,Zhao Qiancheng,Siebel Stephan,Perry Rachel J.,Yu Chuyue,Nasiri Ali R.,Chang Rui B.,Zhu Wanling,Costa Lima Bruna Genisa,Li Zongyu,Zhang Cuiling,Zhang Xinyi.GDF15 is a Critical Renostat in the Defense Against Hypoglycemia[EB/OL].(2025-03-28)[2025-06-12].https://www.biorxiv.org/content/10.1101/2023.06.22.546095.点此复制
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