Abstract
Diabetes mellitus is a global threat to human health. The ultimate cause of diabetes mellitus is insufficient insulin production and secretion associated with reduced pancreatic β-cell mass. Apoptosis is an important and well-recognized mechanism of the progressive loss of functional β-cells. However, there are currently no available antiapoptotic drugs for diabetes mellitus. This study evaluated whether recombinant human thrombomodulin can inhibit β-cell apoptosis and improve glucose intolerance in a diabetes mouse model. A streptozotocin-induced diabetes mouse model was prepared and treated with thrombomodulin or saline three times per week for eight weeks. The glucose tolerance and apoptosis of β-cells were evaluated. Diabetic mice treated with recombinant human thrombomodulin showed significantly improved glucose tolerance, increased insulin secretion, decreased pancreatic islet areas of apoptotic β-cells, and enhanced proportion of regulatory T cells and tolerogenic dendritic cells in the spleen compared to counterpart diseased mice treated with saline. Non-diabetic mice showed no changes. This study shows that recombinant human thrombomodulin, a drug currently used to treat patients with coagulopathy in Japan, ameliorates glucose intolerance by protecting pancreatic islet β-cells from apoptosis and modulating the immune response in diabetic mice. This observation points to recombinant human thrombomodulin as a promising antiapoptotic drug for diabetes mellitus.
Highlights
The growing number of patients with diabetes mellitus (DM) is a serious human health concern worldwide [1]
The IPGT test disclosed a significant decrease in the blood glucose levels in diabetic mice treated with recombinant human thrombomodulin (rhTM) (STZ/rhTM) 60 min after glucose injection compared to mouse counterparts treated with saline (STZ/SAL)
The blood glucose levels were decreased in mice receiving rhTM after 120 min of glucose injection compared to controls, the decrease did not reach statistical significance
Summary
The growing number of patients with diabetes mellitus (DM) is a serious human health concern worldwide [1]. The global diabetic population is estimated to be about. Type 2 DM is associated with lifestyle and genetic factors that cause insulin resistance, impaired biosynthesis and secretion of insulin, and reduced β-cell mass, resulting in a relative insufficiency of insulin activity [8]. In both types of DM, a persistent hyperglycemic condition leads to excessive oxidative stress, endoplasmic reticulum stress, and autophagy dysregulation that result in the apoptosis of β-cells [9,10]. The death of β-cells triggers a vicious cycle of reduced insulin secretion, hyperglycemia, and increased oxidative stress that results in vasculopathy [9,10]
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