黃建寧;林志立Chien-Ning Huang;Chih-Li Lin林聖傑Sheng-chieh Lin醫學研究所博士班2026-03-132027-02-1720242024-01-30https://handle.ncl.edu.tw/11296/rd3mu9https://scholars.csmu.edu.tw/handle/123456789/5466研究背景：慢性病治療中目前多強調次群體藥物選擇，而骨質疏鬆症用藥在糖尿病的次群體中，目前尚未有明確建議。而Denosumab可透過抑制細胞核κB受體活化因子配體（Receptor activator of nuclear factor kappa-B ligand，RANKL），阻礙破骨細胞後續的成熟和功能，是目前骨質疏鬆症用藥中很常用的選擇。而肥胖與第二型糖尿病中的胰島素敏感性高度相關，尤其是高脂肪酸及血糖的環境會導致明顯的糖脂毒性，並會因此損害胰臟β細胞，加速第2型糖尿病的病程進程，然而目前仍未有臨床策略可保護β細胞。因此，在本研究中，我們試圖證明Denosumab於糖尿病次群體的優勢：健保資料庫對於糖尿病保護力，細胞實驗則探討在β細胞受到高糖高脂的傷害後，能否經由Denosumab減少糖脂毒性，並因此提高β細胞的存活率並對抗凋亡，並進一步研究保護過程中的信號傳遞途徑，以期對於未來骨質疏鬆次群體或是糖尿病治療做出進展。研究方法：在健保資料庫部分，我們利用巢式病例對照研究。收集2000年至2014年診斷為骨質疏鬆症的病人，將其區分為使用口服雙磷酸鹽組與使用Denosumab組，並探討使用藥物後病人產生糖尿病診斷的差別及相關性。而在細胞實驗部分，本研究使用人類1.4E7 β細胞，在高糖和高脂肪酸的第二型糖尿病環境下誘發細胞凋亡，並觀察加入Denosumab藥物後能否產生對抗糖脂毒性的能力。研究結果：健保資料庫研究的結果顯示，對比使用Denosumab及口服雙磷酸鹽類藥物，在使用Denosumab與降低罹患第二型糖尿病有顯著相關性，尤其是在藥物使用後一至兩年時。同時，我們在細胞實驗亦發現 Denosumab能有效減輕高糖和高脂肪酸導致的β細胞功能障礙和凋亡，且其機制可能是透過阻斷RANK/RANKL途徑，降低了Ｍammalian sterile 20-like kinase 1（MST1）的活化，並間接增加了Pancreatic and duodenal homeobox-1（PDX-1）的表達。此外，Denosumab亦能降低RANK/RANKL途徑所引起的發炎性細胞激素（Inflammatory cytokines）和活性氧化物質（Reactive oxygen species, ROS）的增加，並因此來保護β細胞對抗糖脂毒性的傷害。結論與建議：我們的結果證明Denosumab對於β細胞在第二型糖尿病的高糖和高脂肪酸的環境下可提供有效保護，並提供了可能的作用分子機制，因此Denosumab可作為骨質疏鬆症中第二型糖尿病次群體患者的藥物優先選擇。Background：Drug selection for subgroups is currently a major focus in the treatment of chronic diseases; however, there are currently no established guidelines for osteoporosis medication in the diabetes subgroup. One common osteoporosis medication is denosumab, which works by inhibiting the receptor activator of nuclear factor kappa-B ligand (RANKL), which in turn prevents osteoclasts from maturing and functioning. Insulin sensitivity and obesity are closely associated with type 2 diabetes. Specifically, a high blood glucose and free fatty acid (FFA) environment can cause a substantial amount of glucolipotoxicity, which can harm pancreatic β-cells and hasten the onset of type 2 diabetes. Nevertheless, no clinical methods exist at this time to safeguard β-cells. Therefore, we try to prove the superiority of choosing Denosumab for such a subgroup. The possible protection ability after using Denosumab in the database. Also, after β-cells are injured by high glucose and high FFA, we investigate in this study whether Denosumab can improve β-cell survival rate and resist apoptosis by reducing glucolipotoxicity. We also look into the possible function of denosumab in protecting β-cells. Additionally, investigate the denosumab signaling pathway in the process of β-cell protection in more detail in order to advance treatment options in the future. Materials and Methods： We employed a nested case-control study in the Taiwan National Health Insurance Research Database (NHIRD) section. Osteoporosis patients diagnosed between 2000 and 2014 were gathered and split into two groups (Oral bisphosphonate and Denosumab group). Their diabetes diagnoses were followed up on to examine any differences or correlations. In addition, using human 1.4E7 β-cells in a type 2 diabetes environment with high glucose and fatty acids, the in vitro experiments examined whether denosumab could attenuate glucolipotoxicity.Results：The NHIRD study's findings demonstrated that using denosumab, as opposed to oral bisphosphonates, was substantially linked to a decreased risk of type 2 diabetes, particularly during the first two years of the medication’s use. Simultaneously, we observed in in vitro experiments that denosumab can effectively reduce β-cell dysfunction and apoptosis caused by high fatty acid and glucose levels. This could be because it indirectly increases the expression of pancreatic and duodenal homeobox-1 (PDX-1), blocks the RANK/RANKL pathway, and reduces mammalian sterile 20-like kinase 1 (MST1) activation. Furthermore, denosumab can suppress the rise in reactive oxygen species (ROS) and inflammatory cytokines brought on by the RANK/RANKL pathway, protecting β-cells from glucolipotoxicity.Conclusion and suggestion：Our findings imply that denosumab can shield β-cells from the high-FFA, high-glucose environment of type 2 diabetes and offer a potential molecular mechanism of action. Consequently, denosumab may be the medication of choice for patients in subgroups of osteoporosis who also have type 2 diabetes.Denosumab（藥物名：保骼麗）糖脂毒性胰島β細胞細胞核κB受體活化因子配體路徑（RANK/RANKL pathway）第二型糖尿病健保資料庫研究Denosumabglucolipotoxicitypancreatic β-cellRANK/RANKL pathwaytype 2 diabetesNHI-database studythesis