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Abstract
Background: The relationship between urokinase-type plasminogen activator (uPA) and the development of type 2 diabetes mellitus (T2DM) was investigated in the study by using mice and cell models, as well as patients with T2DM. Methods: In mice models, wild-type and uPA knockout (uPA-/-) BALB/c mice were used for induction of T2DM. In cell models, insulin secretion rate and β cell proliferation were assessed in normal and high glucose after treating uPA siRNA, uPA, or anti-uPA antibody. In our clinical study, patients with T2DM received an oral glucose-tolerance test, and the relationship between uPA and insulin secretion was assessed. Results: Insulin particles and insulin secretion were mildly restored one month after induction in wild-type mice, but not in uPA-/- mice. In cell models, insulin secretion rate and cell proliferation declined in high glucose after uPA silencing either by siRNA or by anti-uPA antibody. After treatment with uPA, β cell proliferation increased in normal glucose. In clinical study, patients with T2DM and higher uPA levels had better ability of insulin secretion than those with lower uPA levels. Conclusion: uPA may play a substantial role in insulin secretion, β cell regeneration, and progressive development of T2DM. Supplementation of uPA might be a novel approach for prevention and treatment of T2DM in the future.
Highlights
In recent decades, cases of type 2 diabetes mellitus (T2DM) have been rapidly increasing worldwide.While the causes of T2DM include insulin resistance and impaired insulin secretion, some clinical evidence has shown progressive insulin secretion impairment over time in patients with T2DM [1,2,3].Molecules 2019, 24, 4208; doi:10.3390/molecules24234208 www.mdpi.com/journal/moleculesThe causality of mass declination of β cells in T2DM is the increasing rate of apoptosis rather than neogenesis [4]
2.1. urokinase-type plasminogen activator (uPA)-/- Mice Were Prone to HyperGlycemia and Development of T2DM
The uPA-/- mice developed significantly higher hyperglycemia after induction, and the level difference persisted for one month (Figure 1B)
Summary
The causality of mass declination of β cells in T2DM is the increasing rate of apoptosis rather than neogenesis [4]. The relationship between urokinase-type plasminogen activator (uPA) and the development of type 2 diabetes mellitus (T2DM) was investigated in the study by using mice and cell models, as well as patients with T2DM. Insulin secretion rate and β cell proliferation were assessed in normal and high glucose after treating uPA siRNA, uPA, or anti-uPA antibody. Patients with T2DM received an oral glucose-tolerance test, and the relationship between uPA and insulin secretion was assessed. Insulin secretion rate and cell proliferation declined in high glucose after uPA silencing either by siRNA or by anti-uPA antibody. Supplementation of uPA might be a novel approach for prevention and treatment of T2DM in the future
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