血糖調控異常之高齡族群：橫斷式研究及阻力運動訓練效益

Abstract

背景：隨著老化的進程，肌肉量減少、體脂率上升、血脂異常以及細胞激素增加，罹患糖尿病的風險因而升高。然而糖尿病發病因素繁雜且尚未被完全闡明，除了老化身體組成改變的因素外，近期研究顯示循環免疫與內皮細胞受到循環中升高的脂質與細胞激素刺激，增加細胞內發炎相關路徑的活化，進而導致免疫細胞黏附於內皮細胞上損害血管功能；同時增加發炎細胞激素的釋放，造成胰島素阻抗與動脈粥狀硬化的發展。周邊血液單核細胞 (peripheral blood mononuclear cells, PBMC) 為易於從血液中分離之細胞檢體，先前研究已通過病例對照研究，分析比較PBMC中發炎相關mRNA、蛋白質含量，以作為疾病預測之生物指標，並且建立免疫細胞發炎與其他發病機制之間的可能因果連結。然而目前仍未有研究對於糖尿病進程中PBMC之NF-κB發炎相關路徑與身體組成及血液指標進行分析比較。另一方面，糖尿病前期族群若積極改善生活型態，血糖有機會回到正常值。目前未有研究探討阻力訓練對改善糖尿病前期免疫細胞發炎與血糖狀態之效益。研究目的：一、探討老化發炎、身體組成改變與PBMC中NF-κB發炎相關激酶的含量在糖尿病發病過程中相互影響的可能作用機制。二、探討阻力訓練對於糖尿病前期高齡者在血脂數值、細胞激素以及PBMC中NF-κB發炎相關激酶含量的影響。方法：一、35名60歲以上高齡者依口服葡萄糖耐受度測驗結果進行糖類代謝能力分組，分別為正常血糖13名；糖尿病前期14名；糖尿病8名。並使用西方墨點法分析PBMC中NF-κB發炎相關激酶含量，以對照身體組成與血液指標。二、從研究一中召募有意願參加運動訓練之10名糖尿病前期受試者，進行10週70-80% 1RM之高強度阻力訓練，並分析訓練前後PBMC中NF-κB發炎相關激酶含量、身體組成與血液指標數值。結果：一、不同血糖狀況之高齡者在身體組成數值均未達顯著差異 (p> .05)；血脂相關指標僅TG數值糖尿病組顯著高於正常血糖組 (p < .05)；血液細胞激素TNF-α、MCP-1與IL-10達顯著差異，糖尿病組之TNF-α與MCP-1顯著高於正常血糖組 (p < .05)，糖尿病前期IL-10顯著低於正常血糖組 (p < .05)；PBMC中NF-κB發炎相關路徑結果顯示，糖尿病組phos-IKKαβ、phos-IκBα與phos-p65含量顯著高於正常血糖組 (p < .05)，另外在SIRT1與IκBα部分，正常血糖組含量顯著高於其他兩組 (p < .05)；相關性分析結果顯示PBMC中SIRT1、IκBα及phos-p65與血糖調控數值、TNF-α及IL-10濃度數值呈顯著相關 (p < .05)，而phos-IκBα與TG數值呈現顯著正相關 (p < .05)。二、訓練前後之身體組成、血糖與血脂數值皆未有顯著變化 (p < .05)。訓練後TNF-α與MCP-1以及PBMC中phos-IKKαβ、phos-IκBα、phos-p65與acetyl-p65等促發炎指標皆顯著下降 (p < .05)；同時抗發炎激素IL-10與PBMC中SIRT1顯著上升 (p < .05)。結論：一、身體組成數值無法有效辨別高齡者之血糖調控狀態。糖尿病組別血液中TNF-α、MCP-1與TG濃度顯著上升與PBMC中發炎相關路徑交互影響，為導致血糖調控異常的因素；糖尿病前期血液IL-10濃度與PBMC中SIRT1含量下降，造成抗發炎與提升胰島素敏感性的作用減弱，為導致血糖數值惡化往糖尿病發展之危險因子。二、10週高強度阻力訓練可有效降低血液TNF-α、MCP-1濃度與PBMC中NF-κB發炎相關激酶含量；同時增加PBMC中SIRT1的含量，並提升抗發炎IL-10濃度，顯示阻力訓練對抗循環發炎程度的效益。

Introduction: Diabetes is a complex disease. Aging-associated disorders such as losing muscle mass and developing obesity, may result in insulin resistance and increased risks of type 2 diabetes. On the other hand, previous evidences showed that dyslipidemia and increased cytokines stimulates inflammatory signaling pathways in endothelial and immune cells. Atherosclerotic plaque formation and impaired insulin sensitivity are associated with elevated pro-inflammation cytokines and adhesion molecules which are produced by activated immune and endothelial cells. Peripheral blood mononuclear cells (PBMCs) are frequently used in preclinical research as a source of biomarkers in infectious, chronic diseases, epidemiological studies, and clinical trials. However, the relationship between NF-κB signaling pathway in PBMCs and abnormal glucose metabolism remains elusive in older adults. In addition, effects of resistance exercise on anti-inflammation and glycemic control were still unknow. Purpose: The present study investigates Ⅰ. the relationship between NF-κB signaling pathway in PBMCs and abnormal glucose metabolism in older adults. Ⅱ. The effects of high-intensity resistance training on glycemic control and inflammation of immune cell in older adults with prediabetes. Methods: Ⅰ. The glucose metabolism status of 45 older adults were determined by a standardized 75-g oral glucose tolerance test (OGTT). Upon OGTT, 13 subjects were identified as normal glucose tolerance (NGT), 14 with pre-diabetes (PDM), and 8 with diabetes (DM). Protein levels of TNFR, IKK, IκB, p65, and SIRT1 were assessed by Western blot which are used to compare with anthropometrical, cytokine, and lipid profile variables. Ⅱ. 10 older adults with prediabetes completed a 10-week of resistance training (70-80% 1RM). Glycemic control, markers of inflammation, and body composition differences were determined between pre- and post-training. Results: Ⅰ. No significant difference was observed in body composition among groups (p> .05). The higher serum TG, TNF-α, and MCP-1 levels were observed in the DM group comparing with the NGT group. The lower IL-10 levels were observed in the PDM group comparing with the NGT group (p < .05). Compared with NGT group, PBMC in the DM group indicated an activation in phos-IKKαβ, phos-IκB, and phos-p65 (p < .05). Decreased SIRT1 and IκB expression were observed in PDM and DM groups comparing with NGT group (p < .05). SIRT1, IκBα, and phos-p65 expression was significantly correlated with glycemia index, TNF-α, and IL-10 level (p< .05). Significant positive correlation between phos-IκBα and serum TG level was also found (p < .05). Ⅱ. Resistance training reduced serum TNF-α, MCP-1 level, and phos-IKKαβ, phos-IκBα, phos-p65, and acetyl-p65 activation in PBMC (p < .05). Serum IL-10 level and SIRT1 expression in PBMC were significantly increased (p < .05). There were no significant differences in the remaining dependent variables. Conclusions: Ⅰ. Elevated serum TG, TNF-α, and MCP-1 levels and inflammatory signaling pathwaysin PBMCs were associated with abnormal glucose metabolism in older adults. Lower serum IL-10 level and SIRT1 expression were a risk factor of developing diabetes in older adults with PDM. Ⅱ. A 10-week of resistance training was capable of decreasing the levels of TNF-α, MCP-1, and NF-κB signaling pathway in PBMCs. Furthermore, resistance training increases IL-10 level and SIRT-1 in PBMCs. These findings emphasized the ability of resistance exercise in reducing circulating inflammation.