TDP-43 Regulates Early-Phase Insulin Secretion Via Cav1.2-Mediated Exocytosis in Pancreatic Islets

Nuclear depletion of TAR DNA-binding protein 43 kDa (TDP-43), encoded by TARDBP, is the histopathological hallmark of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder affecting motor neurons. Besides motor symptoms, ALS patients often develop non-neuronal signs including glucose intolerance, but the underlying pathomechanism is still controversial, i.e., impaired insulin and/or insulin resistance. Here, we show that ALS subjects have reduced early-phase insulin secretion and loss of TDP-43 in the nuclei of pancreatic islets. Loss of TDP-43 inhibited exocytosis by down-regulating Cav1.2 calcium channels, thereby reducing early-phase insulin secretion in a cultured β cell line (MIN6). Furthermore, β cell-specific TDP-43 knock-out induced glucose intolerance via suppression of early-phase insulin secretion in mice. These results suggest that TDP-43 regulates cellular exocytosis mediated by L-type voltage dependent calcium channels and thus plays an important role in the early-phase of insulin secretion by pancreatic islets. Funding: This work was supported by Grants-in-Aid (KAKENHI) from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan: Nos. 16K09742, 16K15480, 17H04195, and 17K08547 (M.K.); and 16K09392 and 16K09393 (H.I.). This work was partly supported by grants from the Japan Agency of Medical Research and Development (AMED): JP17dm0107105h0002 and JP16kk0205009h0001 (M.Y.). This work was also supported by Grants-in-Aid from the Research Committee of CNS Degenerative Diseases, Research on Policy Planning and Evaluation for Rare and Intractable Diseases, Health, Labor and Welfare Sciences Research Grants, the Ministry of Health, Labor and Welfare, Japan (M.Y.), a grant from the Naito Foundation (M.K.), and a grant from Hori Sciences & Arts Foundation (M.K.). Declaration of Interest: S.M. owns equity in a gene therapy company (Gene Therapy Research Institution) that commercializes the use of AAV vectors for gene therapy applications. To the extent that the work in this manuscript increases the value of these commercial holdings, S.M. has a conflict of interest. Ethical Approval: This study adhered to the Ethics Guidelines for Human Genome/gene Analysis Research and those for Medical and Health Research Involving Human Subjects endorsed by the Japanese government, and approved by the Ethics Committees of Nagoya University Graduate School of Medicine. All participants provided their written informed consent. Experimental procedures involving human subjects were conducted in conformance with the principles expressed in the Declaration of Helsinki.