Understanding the mechanism governing β cell proliferation is essential for the in vitro expansion of β cells and the replacement therapy for patients with diabetes. We recently found that deletion of Smad3, a downstream effector of TGF-β signaling, promoted β cell proliferation, while the underlying mechanisms remain elusive. It’s reported that high glucose stimulates β cell proliferation through unfold protein response (UPR). In this study, we tested the hypothesis that whether deficiency of Smad3 promotes β cell proliferation by regulating UPR. As a result, we found that knockout of Smad3 promoted β cell proliferation in diabetic db/db mice, but not in healthy db/m mice. Interestingly, islets from db/db mice of Smad3 knockout presented increased UPR compared with db/m mice of Smad3 knockout. In cultured islet cells, deletion of Smad3 increased β cell proliferation under high glucose (20mM) conditions, which was associated with up-regulated and non-decompensated UPR. Further studies showed that inhibition of UPR with an inhibitor 4-PBA abolished the pro-proliferative effect of Smad3 deficiency in β cells.
In conclusion, Smad3 deficiency increases β cell proliferation by augmenting UPR. Therefore, targeting Smad3 may be an effective therapy for diabetes.
H. Wang: None. H. He: None. X. Huang: None. L. Wang: None. R.C. Ma: Advisory Panel; Self; AstraZeneca. Stock/Shareholder; Self; GemVCare. Other Relationship; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis, Tricida Inc. H. Lan: None.
Research Grants Council of Hong Kong (C7018-16G, R4012-18); Health and Medical Research Fund of Hong Kong (14152321, 05161326, 06173986)
