miR-10b-5p Rescues Type 1 Diabetes in Mice, Rats, and Dogs
Loading...
Authors
CHO, HAYEONG
Issue Date
2023
Type
Thesis
Language
Keywords
Autoimmune disease , Diabetes , miR-10b-5p , miRNAs , Type 1 diabetes
Alternative Title
Abstract
Type 1 diabetes (T1D) is characterized by insulin deficiency and hyperglycemia via destruction of insulin-producing pancreatic β cells. Degeneration of pancreatic β cells arises from diverse elements like autoimmune systems, genetic problems, and infection of viruses. Therefore, the molecular mechanism of T1D onset remains poorly understood. Our previous study showed that anti-diabetic miRNAs, miR-10b-5p is a key factor of growth and survival of pancreatic β cells via targeting KLF11. The reduction of miR-10b-5p induced diabetes with the dysfunction of pancreatic β cells, but restoration of miR-10b-5p rescued diabetes with regeneration of pancreatic β cells. In the present study, we found that a global mir-10b knock-out (KO) mouse model had decreased insulin level with developing diabetes. Also, we found that miR-10b-5p was substantially reduced in pancreatic islet cells or pancreatic islet as well as blood in both the autoimmune non-obese T1D (NOD) mice and streptozotocin (STZ)-induced T1D mice with insulin deficiency and hyperglycemia. Surprisingly, we also identified that miR-10b-5p is prominently down-regulated in peripheral blood mononuclear cells (PBMC) and serum from T1D patients. Additionally, STZ-alloxan (ALX)-induced or spontaneously developing diabetic dogs had remarkedly an decrease in insulin levels with the reduction of miR-10b-5p. Furthermore, restoration of miR-10b-5p led to decreased blood glucose and increased insulin levels to healthy conditions in NOD and STZ-induced mice with recovery of degenerated pancreatic islets. Injection of the miR-10b-5p mimic rescued hyperglycemia with STZ-induced T1D rats as well as mice. STZ-ALX-induced or spontaneously developing diabetic dogs had a marked decrease in insulin expression with the reduction of miR-10b-5p. Taken together, the reduced miR-10b-5p leads to insulin-dependent diabetes. Moreover, the deficiency of insulin induced the reduction of miR-10b-5 inversely. Our previous study showed that Krüppel-like factor 11 (KLF11) was up-regulated in KIT+ cell specific-mir-10b KO mice. In addition, miR-10b-5p mimic reduced KLF11 expression in pancreatic β cells and showed the targeting effects of miR-10b-5p on KLF11 by regulating insulin expression directly. KLF11 is known as a major factor in promoting apoptosis and inhibiting cell growth. It also regulated the activity of insulin by binding its promoter in β cells. Finally, we also identified that miR-10b-5p is significantly down-regulated in peripheral blood mononuclear cells (PBMC) and serum from T1D patients. In summary, we uncovered that the lack of miR-10b-5p triggered T1D via the KLF11 pathway in pancreatic β cells. Moreover, restoration of miR-10b-5p reversed T1D phenotypes like hyperglycemia and insulin deficiency in T1D mice, rats, and dogs. Here, we report a new therapeutic nomination for T1D with novel insight into the destruction of pancreatic β cells by figuring out the role of miR-10b-5p in T1D.