Yu Josephine, Lalwani Amit, Gunton Jenny E
Centre for Diabetes, Obesity and Endocrinology (CDOE), The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW 2145, Australia.
Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2145, Australia.
Int J Mol Sci. 2024 Dec 15;25(24):13451. doi: 10.3390/ijms252413451.
Type 1 diabetes (T1D) is caused by the immune-mediated loss of pancreatic β-cells. Hypoxia-inducible factor 1α (HIF-1α) is a transcription factor which is crucial for cellular responses to low oxygen. Here, we investigate the role of β-cell HIF-1α in β-cell death and diabetes after exposure to multiple low-dose streptozotocin (MLDS). MDLS triggers auto-immunity in susceptible animal models, such as non-obese diabetic (NOD) mice. These experiments used a novel mouse model with β-cell-specific deletion of HIF-1α on a NOD background (BIN mice). Mice were given 20 mg/kg MLDS for 5 consecutive days. Following MLDS, 100% of BIN mice developed frank diabetes versus 33% of floxed-control (FC) littermates and 17% of NOD controls ( < 0.001). BIN mice had obvious loss of β-cell mass ( < 0.0001) and increased necrotic areas within islets ( < 0.001). To confirm that diabetes was T1D, adoptive transfers of splenocytes from diabetic BIN and FC mice were performed on NOD-SCID (Severe Combined ImmunoDeficiency) recipients. All mice receiving BIN-splenocytes developed frank diabetes, confirming that MLDS induced true T1D. Interestingly, diabetes developed significantly faster in BIN-adoptive transfer mice compared to mice which developed diabetes after receiving an FC-adoptive transfer. These studies demonstrate the importance of β-cell HIF-1α in the preservation of β-cell mass and avoidance of auto-immunity.
1型糖尿病（T1D）是由免疫介导的胰腺β细胞丢失所致。缺氧诱导因子1α（HIF-1α）是一种转录因子，对细胞对低氧的反应至关重要。在此，我们研究了β细胞HIF-1α在暴露于多次低剂量链脲佐菌素（MLDS）后β细胞死亡和糖尿病中的作用。MLDS在易感动物模型（如非肥胖糖尿病（NOD）小鼠）中引发自身免疫。这些实验使用了一种新型小鼠模型，即在NOD背景下β细胞特异性缺失HIF-1α的小鼠（BIN小鼠）。给小鼠连续5天给予20mg/kg的MLDS。MLDS处理后，100%的BIN小鼠出现明显糖尿病，而floxed对照（FC）同窝小鼠为33%，NOD对照为17%（<0.001）。BIN小鼠的β细胞数量明显减少（<0.0001），胰岛内坏死区域增加（<0.001）。为了证实糖尿病是T1D，对NOD-SCID（严重联合免疫缺陷）受体进行了来自糖尿病BIN和FC小鼠的脾细胞过继转移。所有接受BIN脾细胞的小鼠均出现明显糖尿病，证实MLDS诱导了真正的T1D。有趣的是，与接受FC过继转移后发生糖尿病的小鼠相比，BIN过继转移小鼠的糖尿病发展明显更快。这些研究证明了β细胞HIF-1α在维持β细胞数量和避免自身免疫方面的重要性。
