NAG-1/GDF15 protects against streptozotocin-induced type 1 diabetes by inhibiting apoptosis, preserving beta-cell function, and suppressing inflammation in pancreatic islets.

Abstract

The loss of functional insulin-producing β-cells is a hallmark of type 1 diabetes mellitus (T1DM). Previously, we reported that the non-steroidal anti-inflammatory drug activated gene-1, or growth differentiation factor-15 (NAG-1/GDF15) inhibits obesity and improves insulin sensitivity in both genetic and dietary-induced obese mice. However, the regulatory role of NAG-1/GDF15 in the structure and function of β-cells and the prevention of T1DM is largely unknown. In the current study, we reported that NAG-1/GDF15 transgenic (Tg) mice are resistant to diabetogenesis induced by multiple low-dose streptozotocin (MLD-STZ) treatment. NAG-1/GDF15 overexpression significantly reduced diabetes incidence, alleviated symptoms of T1DM, and improved MLD-STZ-induced glucose intolerance and insulin resistance. Both the mass and function of pancreatic β cells were preserved in the NAG-1/GDF15 Tg mice as evidenced by significantly increased islet area and insulin production. The mechanistic study revealed that NAG-1/GDF15 significantly inhibited STZ-induced apoptosis and preserved the reduction of proliferation in the islets of the Tg mice as compared to the wild-type (WT) mice upon MLD-STZ treatment. Additionally, NAG-1/GDF15 significantly reduced both the serum and islet levels of the inflammatory cytokines (IL-1β, IL-6, and TNFα), and reduced the expression of NF-κB expression and immune cells infiltration in the islets. Collectively, these results indicate that NAG-1/GDF15 is effective in improving STZ-induced glucose intolerance, probably was mediated via suppressing inflammation, inhibiting apoptosis, and preserving β-cell mass and function.

• Authors: Ying Wang, Jiajun Chen, Tingting Sang, Chaojie Chen, He Peng, Xiaojian Lin, Qian Zhao, Shengjia Chen, Thomas Eling, Xingya Wang
• Journal: Molecular and cellular endocrinology (Mol Cell Endocrinol) Vol. 549 Pg. 111643 (06 01 2022) ISSN: 1872-8057 [Electronic] Ireland
• PMID: 35398052 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier B.V. All rights reserved.

Chemical References

• Insulin
• Streptozocin

Topics

• Animals
• Apoptosis
• Diabetes Mellitus, Experimental (metabolism)
• Diabetes Mellitus, Type 1 (metabolism)
• Glucose Intolerance (metabolism)
• Inflammation (metabolism)
• Insulin (metabolism)
• Insulin Resistance
• Insulin-Secreting Cells (metabolism)
• Islets of Langerhans (metabolism)
• Mice
• Mice, Transgenic
• Streptozocin (adverse effects)