Treatment with Mammalian Ste-20-like Kinase 1/2 (MST1/2) Inhibitor XMU-MP-1 Improves Glucose Tolerance in Streptozotocin-Induced Diabetes Mice

Molecules. 2020 Sep 24;25(19):4381. doi: 10.3390/molecules25194381.

Abstract

Diabetes mellitus (DM) is one of the major causes of death in the world. There are two types of DM-type 1 DM and type 2 DM. Type 1 DM can only be treated by insulin injection whereas type 2 DM is commonly treated using anti-hyperglycemic agents. Despite its effectiveness in controlling blood glucose level, this therapeutic approach is not able to reduce the decline in the number of functional pancreatic β cells. MST1 is a strong pro-apoptotic kinase that is expressed in pancreatic β cells. It induces β cell death and impairs insulin secretion. Recently, a potent and specific inhibitor for MST1, called XMU-MP-1, was identified and characterized. We hypothesized that treatment with XMU-MP-1 would produce beneficial effects by improving the survival and function of the pancreatic β cells. We used INS-1 cells and STZ-induced diabetic mice as in vitro and in vivo models to test the effect of XMU-MP-1 treatment. We found that XMU-MP-1 inhibited MST1/2 activity in INS-1 cells. Moreover, treatment with XMU-MP-1 produced a beneficial effect in improving glucose tolerance in the STZ-induced diabetic mouse model. Histological analysis indicated that XMU-MP-1 increased the number of pancreatic β cells and enhanced Langerhans islet area in the severe diabetic mice. Overall, this study showed that MST1 could become a promising therapeutic target for diabetes mellitus.

Keywords: Hippo pathway; MST1/2; XMU-MP-1; diabetes mellitus.

MeSH terms

  • Animals
  • Cell Line
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / enzymology
  • Diabetes Mellitus, Experimental / pathology
  • Glucose Intolerance / chemically induced
  • Glucose Intolerance / drug therapy*
  • Glucose Intolerance / enzymology
  • Glucose Intolerance / pathology
  • Insulin-Secreting Cells / enzymology*
  • Insulin-Secreting Cells / pathology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Serine-Threonine Kinase 3
  • Sulfonamides / pharmacology*

Substances

  • Sulfonamides
  • XMU-MP-1
  • Stk4 protein, mouse
  • Protein Serine-Threonine Kinases
  • Serine-Threonine Kinase 3
  • Stk3 protein, mouse