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J Clin Invest. 2018 Aug 1;128(8):3369-3381. doi: 10.1172/JCI120115. Epub 2018 Jul 9.

Neuronatin regulates pancreatic β cell insulin content and secretion.

Author information

MRC London Institute of Medical Sciences, London, United Kingdom.
Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom.
Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, United Kingdom.
Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom.
Computational Cell and Molecular Biology Laboratory, Francis Crick Institute, London, United Kingdom.
European Genomic Institute for Diabetes, UMR 1190 Translational Research for Diabetes, INSERM, CHU Lille, University of Lille, Lille, France.
Beta Cell Genome Regulation Laboratory, Department of Medicine, Imperial College London, London, United Kingdom.
Institute of Reproductive and Developmental Biology, Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
School of Biosciences, Cardiff University, Cardiff, United Kingdom.
Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China.
National Heart and Lung Institute, Department of Medicine, Imperial College London, London, United Kingdom.


Neuronatin (Nnat) is an imprinted gene implicated in human obesity and widely expressed in neuroendocrine and metabolic tissues in a hormone- and nutrient-sensitive manner. However, its molecular and cellular functions and precise role in organismal physiology remain only partly defined. Here we demonstrate that mice lacking Nnat globally or specifically in β cells display impaired glucose-stimulated insulin secretion leading to defective glucose handling under conditions of nutrient excess. In contrast, we report no evidence for any feeding or body weight phenotypes in global Nnat-null mice. At the molecular level neuronatin augments insulin signal peptide cleavage by binding to the signal peptidase complex and facilitates translocation of the nascent preprohormone. Loss of neuronatin expression in β cells therefore reduces insulin content and blunts glucose-stimulated insulin secretion. Nnat expression, in turn, is glucose-regulated. This mechanism therefore represents a novel site of nutrient-sensitive control of β cell function and whole-animal glucose homeostasis. These data also suggest a potential wider role for Nnat in the regulation of metabolism through the modulation of peptide processing events.


Beta cells; Cell Biology; Diabetes; Genetics; Insulin

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