Abstract
Objective: To clarify the role and mechanism of miR-17-92 cluster in islet beta-cell repair after streptozotocin intervention.Methods: Genetically engineered mice (miR-17-92βKO) and control RIP-Cre mice were intraperitoneally injected with multiple low dose streptozotocin. Body weight, random blood glucose (RBG), fasting blood glucose, and intraperitoneal glucose tolerance test (IPGTT) were monitored regularly. Mice were sacrificed for histological analysis 8 weeks later. Morphological changes of pancreas islets, quantity, quality, apoptosis, and proliferation of beta-cells were measured. Islets from four groups were isolated. MiRNA and mRNA were extracted and quantified.Results: MiR-17-92βKO mice showed dramatically elevated fasting blood glucose and impaired glucose tolerance after streptozotocin treatment in contrast to control mice, the reason of which is reduced beta-cell number and total mass resulting from reduced proliferation, enhanced apoptosis of beta-cells. Genes related to cell proliferation and insulin transcription repression were significantly elevated in miR-17-92βKO mice treated with streptozotocin. Furthermore, genes involved in DNA biosynthesis and damage repair were dramatically increased in miR-17-92βKO mice with streptozotocin treatment.Conclusion: Collectively, our results demonstrate that homozygous deletion of miR-17-92 cluster in mouse pancreatic beta-cells promotes the development of experimental diabetes, indicating that miR-17-92 cluster may be positively related to beta-cells restoration and adaptation after streptozotocin-induced damage.
Highlights
Defective beta-cell function is one of the key reasons underlying the pathological process of both type 1 and 2 diabetes mellitus
Our studies suggested conditional knockout of miR-17-92 cluster in mouse pancreatic beta-cells impaired glucose tolerance and the first phase insulin secretion during intraperitoneal glucose tolerance test (IPGTT), which was further deteriorated by chronic highfat diet feeding [30], suggesting that miR-17-92 cluster may be involved in the adaptation and proliferation of pancreatic beta-cells in response to chronic metabolic challenges
The miR-17-92 Cluster Is Induced by Streptozotocin
Summary
Defective beta-cell function is one of the key reasons underlying the pathological process of both type 1 and 2 diabetes mellitus. Normal insulin-producing pancreatic beta-cells possess the powerful ability of adaptation and proliferation in response to chronic metabolic challenges such as obesity and gestation. At the end of pregnancy, the beta-cell mass in normal rodents is increased by about 50% compared with non-pregnant female rodents [1, 2]. Long-term high-fat diet feeding for 4 months leads to a threefold increase in beta-cell mass and more insulin secretion in response to glucose stimulation [3]. Individuals with the failed beta-cell function will. Exploring the molecular and cellular mechanisms underlying the beta-cell adaptation and proliferation is critical for the intervention of diabetes
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