Abstract
ObjectivePrevious studies demonstrated that circulating microRNA-375 (miR-375) is a suitable plasma biomarker for real-time detection of beta cell death. The present study evaluated the use of this biomarker to assess the beta cytoprotective effect of phenylpropenoic acid glucoside (PPAG), which was previously demonstrated to protect beta cells against various types of injury, and of exendin-4, which is an established antidiabetic drug.MethodsPPAG or exendin-4 were administered in mice treated with streptozotocin (STZ) to acutely induce beta cell death. Beta cell mass and apoptotic death were measured in pancreatic tissue sections. Circulating miR-375 was measured in blood plasma by RT-qPCR. The release of miR-375 was also measured in vitro by MIN-6 beta cells.ResultsAdministration of STZ resulted in measurable circulating levels of miR-375, a decrease in beta cell mass and increase in frequency of apoptotic beta cells. In vitro, there was a good correlation between miR-375 release and the extent of beta cell death. Treatment of mice with PPAG or exendin-4 significantly attenuated STZ-induced loss of beta cell mass and beta cell apoptosis, and normalized the blood level of miR-375.ConclusionsThese findings show the potential use of serological miR-375 measurements to evaluate the beta cytoprotective effect of (potential) antidiabetic drugs in vivo.
Highlights
Type 2 diabetes and prediabetes are two of the top pressing health issues worldwide and there is an important unmet need in new medication to prevent or halt the disease.Besides dysregulated blood sugar levels and the devastating effects of chronic hyperglycemia, diabetes is characterized by progressive failure and loss of pancreatic beta cells [1,2,3,4]
phenylpropenoic acid glucoside (PPAG) or exendin-4 were administered in mice treated with streptozotocin (STZ) to acutely induce beta cell death
Treatment of mice with PPAG or exendin-4 significantly attenuated STZ-induced loss of beta cell mass and beta cell apoptosis, and normalized the blood level of miR-375. These findings show the potential use of serological miR-375 measurements to evaluate the beta cytoprotective effect of antidiabetic drugs in vivo
Summary
Type 2 diabetes and prediabetes are two of the top pressing health issues worldwide and there is an important unmet need in new medication to prevent or halt the disease.Besides dysregulated blood sugar levels and the devastating effects of chronic hyperglycemia, diabetes is characterized by progressive failure and loss of pancreatic beta cells [1,2,3,4]. Normal postnatal maintenance or growth of the pancreatic beta cell mass is considered to result exclusively from mitotic division of existing beta cells [9]. This mechanism can be counterbalanced or outweighed by beta cell loss resulting from cell death. Streptozotocin (STZ) treatment of mice represents a convenient model for rapid pharmacological screening of potential antidiabetic, beta cell protecting drugs. In this short-term model, changes in beta cell mass and apoptotic index that are caused by injury or by cytoprotective compounds can be measured with immunohistochemical methods in pancreatic tissue. Measuring changes in the beta cell mass by imaging methods like positron emission tomography (PET) is a key tool for optimizing diabetes prevention and treatment but is still in its infancy due to lack of highly specific and sensitive beta cell tracers as well as technical limitations of the imaging tools [13]
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