National Clinical Research Center for Metabolic Diseases, Key Laboratory of Cardiometabolic Medicine of Hunan Province, Metabolic Syndrome Research Center, Department of Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
Departments of Liver Organ Transplantation, the Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China.
Metabolism. 2024 Aug;157:155933. doi: 10.1016/j.metabol.2024.155933. Epub 2024 May 9.
AIMS/HYPOTHESIS: cGAS (cyclic GMP-AMP synthase) has been implicated in various cellular processes, but its role in β-cell proliferation and diabetes is not fully understood. This study investigates the impact of cGAS on β-cell proliferation, particularly in the context of diabetes.
Utilizing mouse models, including cGAS and STING (stimulator of interferon genes) knockout mice, we explored the role of cGAS in β-cell function. This involved β-cell-specific cGAS knockout (cGAS) mice, created by breeding cGAS floxed mice with transgenic mice expressing Cre recombinase under the insulin II promoter. We analyzed cGAS expression in diabetic mouse models, evaluated the effects of cGAS deficiency on glucose tolerance, and investigated the molecular mechanisms underlying these effects through RNA sequencing.
cGAS expression is upregulated in the islets of diabetic mice and by high glucose treatment in MIN6 cells. Both global cGAS deficiency and β-cell-specific cGAS knockout mice lead to improved glucose tolerance by promoting β-cell mass. Interestingly, STING knockout did not affect pancreatic β-cell mass, suggesting a STING-independent mechanism for cGAS's role in β-cells. Further analyses revealed that cGAS- but not STING-deficiency leads to reduced expression of CEBPβ, a known suppressor of β-cell proliferation, concurrently with increased β-cell proliferation. Moreover, overexpression of CEBPβ reverses the upregulation of Cyclin D1 and D2 induced by cGAS deficiency, thereby regulating β-cell proliferation. These results confirm that cGAS regulation of β-cell proliferation via a CEBPβ-dependent but STING-independent mechanism.
CONCLUSIONS/INTERPRETATION: Our findings highlight the pivotal role of cGAS in promoting β-cell proliferation and maintaining glucose homeostasis, potentially by regulating CEBPβ expression in a STING-independent manner. This study uncovers the significance of cGAS in controlling β-cell mass and identifies a potential therapeutic target for enhancing β-cell proliferation in the treatment of diabetes.
目的/假设：环鸟苷酸-腺苷酸合酶（cGAS）参与了多种细胞过程，但它在β细胞增殖和糖尿病中的作用尚不完全清楚。本研究旨在探讨 cGAS 对β细胞增殖的影响，特别是在糖尿病背景下。
我们利用包括 cGAS 和 STING（干扰素基因刺激蛋白）敲除小鼠在内的小鼠模型，研究了 cGAS 在β细胞功能中的作用。这涉及到β细胞特异性 cGAS 敲除（cGAS）小鼠，该小鼠通过将 cGAS 基因 floxed 小鼠与胰岛素 II 启动子下表达 Cre 重组酶的转基因小鼠杂交而产生。我们分析了糖尿病小鼠模型中 cGAS 的表达，评估了 cGAS 缺失对葡萄糖耐量的影响，并通过 RNA 测序研究了这些影响的分子机制。
cGAS 在糖尿病小鼠胰岛和 MIN6 细胞高葡萄糖处理中表达上调。全身性 cGAS 缺失和β细胞特异性 cGAS 敲除小鼠均通过促进β细胞质量改善葡萄糖耐量。有趣的是，STING 敲除并不影响胰腺β细胞质量，提示 cGAS 在β细胞中的作用存在 STING 非依赖性机制。进一步分析表明，cGAS 缺失而非 STING 缺失导致已知抑制β细胞增殖的 CEBPβ表达降低，同时β细胞增殖增加。此外，CEBPβ 的过表达逆转了 cGAS 缺失引起的 Cyclin D1 和 D2 的上调，从而调节β细胞增殖。这些结果证实，cGAS 通过 CEBPβ 依赖性但 STING 非依赖性机制调节β细胞增殖。
结论/解释：我们的研究结果强调了 cGAS 在促进β细胞增殖和维持葡萄糖稳态中的关键作用，可能通过 STING 非依赖性机制调节 CEBPβ 表达。本研究揭示了 cGAS 在控制β细胞质量方面的重要性，并确定了一个潜在的治疗靶点，以增强β细胞增殖在糖尿病治疗中的作用。
