Activation of the osteoblastic HIF-1α pathway partially alleviates the symptoms of STZ-induced type 1 diabetes mellitus via RegIIIγ

Abstract

The hypoxia-inducible factor-1α (HIF-1α) pathway coordinates skeletal bone homeostasis and endocrine functions. Activation of the HIF-1α pathway increases glucose uptake by osteoblasts, which reduces blood glucose levels. However, it is unclear whether activating the HIF-1α pathway in osteoblasts can help normalize glucose metabolism under diabetic conditions through its endocrine function. In addition to increasing bone mass and reducing blood glucose levels, activating the HIF-1α pathway by specifically knocking out Von Hippel‒Lindau (Vhl) in osteoblasts partially alleviated the symptoms of streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM), including increased glucose clearance in the diabetic state, protection of pancreatic β cell from STZ-induced apoptosis, promotion of pancreatic β cell proliferation, and stimulation of insulin secretion. Further screening of bone-derived factors revealed that islet regeneration-derived protein III gamma (RegIIIγ) is an osteoblast-derived hypoxia-sensing factor critical for protection against STZ-induced T1DM. In addition, we found that iminodiacetic acid deferoxamine (SF-DFO), a compound that mimics hypoxia and targets bone tissue, can alleviate symptoms of STZ-induced T1DM by activating the HIF-1α-RegIIIγ pathway in the skeleton. These data suggest that the osteoblastic HIF-1α-RegIIIγ pathway is a potential target for treating T1DM. The skeleton isn’t just for support, it also helps control body functions. This research looked at how a specific process in bone-forming cells, called the hypoxia-inducible factor-1 alpha (HIF-1α) pathway, affects sugar breakdown and diabetes. The scientists discovered that triggering this process in these cells can help manage sugar levels in diabetes through a protein named RegIIIγ. They also found that a substance named SF-DFO, which imitates low oxygen conditions and focuses on bone tissue, can somewhat ease type 1 diabetes symptoms by triggering the HIF-1α-RegIIIγ process in the skeleton. This implies that this specific process in bone-forming cells could be a possible treatment for type 1 diabetes. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.