馮傳林 郁 彪 方彥雯 方志財 張 欣,3

磁場影響血糖和糖尿病并發(fā)癥研究進展

馮傳林1,2郁 彪2,3方彥雯4方志財4張 欣1,2,3

（1. 安徽大學(xué)物質(zhì)科學(xué)與信息技術(shù)研究院 合肥 230601 2. 中國科學(xué)院合肥物質(zhì)科學(xué)研究院強磁場科學(xué)中心 合肥 230031 3. 中國科學(xué)技術(shù)大學(xué)科學(xué)島研究生分院 合肥 230026 4. 和也健康科技有限公司 湖州 313300）

多項研究表明，磁場會對機體血糖水平和糖尿病并發(fā)癥產(chǎn)生一定影響。該文系統(tǒng)地比較并分析多種參數(shù)的磁場對多種生物系統(tǒng)的血糖、胰島素水平以及糖尿病并發(fā)癥的影響。研究結(jié)果顯示，盡管磁場對血糖和胰島素水平的影響會因為磁場參數(shù)和檢測樣品的多樣化而導(dǎo)致其結(jié)果不同，但磁場對糖尿病傷口愈合以及骨關(guān)節(jié)病有著比較一致的正面效應(yīng)，顯示了良好的應(yīng)用前景。雖然目前對磁場影響血糖的相關(guān)機制探索還不夠系統(tǒng)深入，但已有證據(jù)表明，磁場可能通過影響細胞膜、膜蛋白以及Ca2+濃度等來影響胰島素分泌。這不僅有助于人們深入了解磁場對血糖調(diào)節(jié)和糖尿病的影響，而且為未來進行更系統(tǒng)深入的研究，開發(fā)磁場在糖尿病及其并發(fā)癥臨床治療中的潛在應(yīng)用奠定基礎(chǔ)。

磁場 血糖 胰島素 糖尿病 糖尿病并發(fā)癥

0 引言

磁場可以根據(jù)其強度和方向是否隨時間變化而分為穩(wěn)態(tài)磁場（Static Magnetic Fields, SMF）和動態(tài)磁場（Dynamic Magnetic Fields, DMF）。而根據(jù)其強度可進一步分為弱磁場（小于1mT）、中等磁場（1mT～1T）、強磁場（1～20T）和超強磁場（20T及以上）[1-3]。目前已有大量證據(jù)表明，磁場可以對多種生物體產(chǎn)生影響。例如，特定參數(shù)的脈沖磁場已被成功應(yīng)用于經(jīng)顱磁刺激，被全世界多個國家批準(zhǔn)應(yīng)用于臨床，在治療抑郁和癲癇等多方面發(fā)揮了獨特的作用[4-7]。

糖尿病是一種以胰島素分泌缺陷、作用缺陷或兩者兼有而導(dǎo)致的以高血糖為特征的代謝性疾 病[8]。近年來，由于人口增長、老齡化、城市化、肥胖和缺乏體育鍛煉等因素，糖尿病患者數(shù)量逐漸增加，嚴(yán)重危及人類健康并增加了社會醫(yī)療負擔(dān)。而目前已有一些初步研究結(jié)果顯示，一定條件下的磁場處理可能會對血糖調(diào)節(jié)產(chǎn)生影響，但由于實驗條件不統(tǒng)一和數(shù)據(jù)不充分等，導(dǎo)致目前并無統(tǒng)一定論。本文旨在對相關(guān)研究進行總結(jié)和梳理，分析磁場對血糖和胰島素等的影響，分析其機制，從而為進一步系統(tǒng)深入的研究奠定基礎(chǔ)。

1 糖尿病簡介

圖1 糖尿病相關(guān)并發(fā)癥

2 磁場對血糖的影響

2012年，Y. Touitou等[10]在正常的地磁場條件下，對15名長期暴露在50Hz、大于3×10-7T的工頻磁場下的成年男性與對照組人群進行對比，發(fā)現(xiàn)某些血液參數(shù)發(fā)生了具有統(tǒng)計學(xué)意義的變化，其中包括了血糖水平。除此之外，大多數(shù)磁場對血糖影響的研究都是在動物水平上，磁場對動物血糖的影響見表1。在13項相關(guān)研究中，有7項研究顯示了磁場會升高機體的血糖水平（其中6項來自于Y. Tunisia的關(guān)于128mT的穩(wěn)態(tài)磁場），3項研究顯示降低血糖水平，3項顯示無影響。

表1 磁場對動物血糖的影響

Tab.1 Effect of magnetic field on blood glucose in animals

注：本文排除了少數(shù)幾項具有明顯缺陷的文獻。

3 磁場對胰島素的影響

不同參數(shù)的磁場對胰島素水平的變化呈現(xiàn)出不同的作用效果見表2，在15項研究中，8項顯示胰島素釋放減少，6項顯示增高。但有趣的是，A. Hayek等[24]在研究穩(wěn)態(tài)磁場對Sprague-Dawley大鼠離體胰島功能的影響時發(fā)現(xiàn)，在0.1～1mT的磁感應(yīng)強度下，比較低濃度（5.4mmol/L）葡萄糖條件下，磁場能夠升高胰島素水平，并且磁感應(yīng)強度越高，效果越明顯；但是在較高濃度（16.7mmol/L）葡萄糖條件下，效果并不明顯。這說明磁場對胰島素的影響與機體初始葡萄糖水平以及所用磁感應(yīng)強度都直接相關(guān)。

4 磁場對糖尿病并發(fā)癥的影響

4.1 磁場對糖尿病神經(jīng)病變的生物學(xué)效應(yīng)

糖尿病神經(jīng)病變（Diabetic Neuropathy, DN）是糖尿病患者排除其他原因后出現(xiàn)外周神經(jīng)功能損害的一種病癥[32]，是糖尿病所有長期并發(fā)癥中最常見的一種。大約50%的糖尿病患者會出現(xiàn)疼痛性糖尿病神經(jīng)病變，癥狀包括超敏、自發(fā)性疼痛、麻木和痛覺過敏[33-34]。高血糖會引起中樞或外周神經(jīng)系統(tǒng)結(jié)構(gòu)損傷或功能異常[35]，是糖尿病神經(jīng)病變最重要的致病因素。目前關(guān)于磁場對糖尿病神經(jīng)病變的影響見表3。例如，對于糖尿病患者的人體實驗共有四項相關(guān)研究，發(fā)現(xiàn)其中兩項可以對其神經(jīng)病變產(chǎn)生緩解效果[36-37]，而另外兩項則無效果[38-39]。相比之下，三項中等強度低頻脈沖磁場的動物研究都顯示出了正面效果[40-42]。

表2 磁場對胰島素的影響研究

Tab.2 Effect of magnetic field on insulin

表3 磁場對糖尿病神經(jīng)病變的影響研究

Tab.3 Effect of magnetic field on diabetic neuropathy

4.2 磁場對糖尿病小鼠傷口愈合的影響

糖尿病性皮膚潰瘍所造成的傷口往往難以愈合，是糖尿病患者入院、截肢和死亡的主要原因，給患者帶來了極大的痛苦[43]。而動物實驗研究表明，多種參數(shù)的磁場都有可能作為一種無創(chuàng)的物理方法，來加快糖尿病小鼠的傷口愈合，見表4。例如，就穩(wěn)態(tài)磁場而言，2013年，聶志勇等[48]使用直徑為3cm、磁感應(yīng)強度為300mT的釹鐵硼永磁片粘附在糖尿病大鼠創(chuàng)面的紗布上，發(fā)現(xiàn)可以促進其傷口愈合速度，并且傷口組織的抗張強度亦顯著提升。就脈沖磁場而言，2015年，M. C. Choi等[54]發(fā)現(xiàn)磁感應(yīng)強度為5mT、頻率為25Hz的脈沖電磁場（Pulsed Electromagnetic Fields, PEMF）可以加速傷口早期的愈合、增加膠原沉積以及增強傷口閉合處瘢痕組織的抗拉伸強度，從而對糖尿病創(chuàng)面早期愈合過程產(chǎn)生有益作用，但對傷口中后期愈合過程沒有明顯影響。就交變磁場而言，2020年，郭毅敏等[23]探究了輸出波形為50Hz、峰值磁感應(yīng)強度為2mT的正弦波交變電磁場對Ⅱ型糖尿病db/db小鼠創(chuàng)面愈合修復(fù)影響，發(fā)現(xiàn)低強度的正弦波交變電磁場可以顯著加快小鼠創(chuàng)傷修復(fù)并提高創(chuàng)傷組織的抗張強度。

表4 磁場對糖尿病傷口愈合的影響研究

Tab.4 Effect of magnetic field on diabetic wound healing

4.3 磁場對糖尿病骨關(guān)節(jié)病的影響

由于糖尿病可顯著損害骨的形成，削弱骨的機械強度，加速骨骼結(jié)構(gòu)的退化[56-57]，因此糖尿病患者較容易發(fā)生骨折[58]、骨折后難以愈合[59]和骨質(zhì)疏松[60]等。并且由于糖尿病患者的組織再生能力較差，因而由骨折導(dǎo)致的死亡率明顯高于非糖尿病人群[61]。因此開發(fā)一種針對糖尿病骨關(guān)節(jié)病更安全、更有效的防治方法具有重要的臨床意義。目前已有多項研究表明，多種類型的磁場可以對糖尿病骨關(guān)節(jié)?。―iabetic Osteoarthropathy, DOAP）產(chǎn)生有益的影響，見表5。例如，就穩(wěn)態(tài)磁場而言，2018年，Zhang Hao等[63]研究發(fā)現(xiàn)，Ⅰ型糖尿病大鼠全身暴露于4mT的穩(wěn)態(tài)磁場中16周后可抑制小鼠骨小梁和皮質(zhì)骨的結(jié)構(gòu)退化和機械強度的降低，并且可以使小鼠血清骨鈣素、骨小梁骨礦物質(zhì)沉積率和成骨細胞數(shù)增加，同時成骨細胞骨鈣素、骨形成蛋白-2（Bone Morphogenetic Protein 2, BMP2）和Runx2的基因表達也有所增強，提示適度的穩(wěn)態(tài)磁場通過抑制Ⅰ型糖尿病小鼠骨損失來防止骨結(jié)構(gòu)的退化和強度的降低。就脈沖磁場而言，2018年，Cai Jing等[66]報道了頻率為15Hz、強度峰值為2mT的PEMF對Ⅰ型糖尿病兔骨的影響，研究也發(fā)現(xiàn)了PEMF刺激下糖尿病兔骨髓腔變窄、增加皮質(zhì)骨厚度以及松質(zhì)骨數(shù)量，緩解了松質(zhì)骨和皮質(zhì)骨結(jié)構(gòu)及組織水平機械強度的退化，PEMF使骨形成標(biāo)志物血清骨鈣素（Osteocalcin, OCN）和血清Ⅰ型前膠原肽（Propeptide of type1 Procollagen, P1NP）濃度顯著升高，促進了骨的整合和生長，此外，PEMF還上調(diào)了股骨OCN、BMP2和Runx2 mRNA的表達，激活T1DM骨骼中與成骨相關(guān)的Wnt/b-catenin信號，并顯著減輕Ⅰ型糖尿病引起的骨形成的減少。

表5 磁場對糖尿病骨關(guān)節(jié)病的影響研究

Tab.5 Effect of magnetic field on diabetic osteoarthritis

5 磁場影響糖尿病的可能機制

目前對于磁場對糖尿病的影響的機制已有一些初步探索，如圖2所示。但是由于不同研究所用磁場參數(shù)和研究對象大多不同，所以對磁場影響糖尿病的機制目前尚無定論。例如，胰島b細胞是調(diào)節(jié)血糖平衡的重要細胞，它可以釋放胰島素從而促進血液循環(huán)中葡萄糖合成糖原使血糖降低，促進脂肪及蛋白質(zhì)的合成，因此胰島b細胞釋放胰島素是血糖調(diào)節(jié)的關(guān)鍵步驟。目前有多項研究表明，磁場可以影響胰島b細胞的細胞膜及離子通道[25-26, 67]。但除胰島細胞外，人們還發(fā)現(xiàn)了其他一些關(guān)于磁場調(diào)節(jié)血糖或胰島素的機制。例如，通過胰高血糖素、皮質(zhì)醇、甲狀腺激素和生長激素[11]、兒茶酚胺、葡萄糖轉(zhuǎn)運蛋白[68-69]以及白細胞介素-1b（Interleukin-1b, IL-1b）受體[70]，如圖2所示。圖中，途徑1，脈沖磁場（Pulsed Magnetic Field, PMF）產(chǎn)生的電場梯度使細胞膜上鈣離子結(jié)合位點發(fā)生改變，胰島b細胞內(nèi)游離Ca2+的含量降低，胰島素釋放減少[25]。 途徑2，極低頻磁場（Extremely Low Frequency Magnetic Field, ELFMF）使腺嘌呤核苷三磷酸（Adenosine Triphosphate, ATP）與腺嘌呤核苷二磷酸（Adenosine Diphosphate, ADP）之間的比值降低，ATP依賴性鉀離子通道關(guān)閉，阻止膜去極化，引起電壓依賴性鈣離子通道的關(guān)閉，胞漿游離Ca2+濃度降低，胰島素?zé)o法分泌[26]。途徑3，可溶性N-乙基馬來酰亞胺敏感因子附著蛋白受體（Soluble N- ethylmaleimide-sensitive fusion protein Attachment protein Receptor, SNARE）蛋白復(fù)合物可以幫助胰島素轉(zhuǎn)運出細胞，而ELFMF會降低SNARE蛋白復(fù)合物組成部分突觸小體相關(guān)蛋白25（Synaptosomal- Associated Protein 25, SNAP 25）和突觸結(jié)合蛋白1（Synaptotagmin 1, Syt 1）的mRNA表達水平，使胰島素?zé)o法釋放[71]。途徑4，SMF的刺激通過調(diào)節(jié)一些SNARE囊泡蛋白的表達來調(diào)節(jié)胰島素的分泌[31]。途徑5，SMF下誘導(dǎo)多種轉(zhuǎn)錄因子的表達，轉(zhuǎn)錄因子與胰島素基因的啟動子區(qū)域結(jié)合，并促進胰島素基因的表達[30]。途徑6，穩(wěn)態(tài)磁場促使去甲腎上腺素水平升高，而去甲腎上腺素會干擾胰島素的釋放[72]。途徑7，氧化應(yīng)激會破壞胰島素生成，SMF處理后可以降低氧化應(yīng)激，促進胰島素生成[70]。途徑8，SMF處理后類似于白細胞介素-1b受體（Interleukin-1 Receptor, IL-1R）拮抗劑的效果，降低IL-1b影響，減少先天免疫細胞的募集，協(xié)助胰島素釋放，從而降低血糖[70]。途徑9，穩(wěn)態(tài)磁場可能破壞胰島b細胞中的葡萄糖轉(zhuǎn)運蛋白2（Glucose Transporters 2, GLUT2），胰島b細胞無法感知外界葡萄糖濃度，胰島素?zé)o法順利釋放[68]。

在目前的為數(shù)不多的機制研究中，關(guān)于穩(wěn)態(tài)磁場的研究都集中在生物學(xué)機制的探索上。而在動態(tài)磁場方面，發(fā)現(xiàn)動態(tài)磁場引起的膜電位和電壓依賴性離子通道可能通過降低鈣離子來影響胰島素分泌[25-26]（見圖2）。此外，有研究發(fā)現(xiàn)，波形為矩形的脈沖磁場通常會導(dǎo)致生物膜的結(jié)構(gòu)特性和滲透性發(fā)生更加顯著的變化[73-74]，A. Laitl-Kobierska等[18]認為這種效應(yīng)很可能是造成磁場下胰島素分泌過程更加劇烈的原因。未來本領(lǐng)域亟需在生物物理和生物電磁的角度對磁場影響糖尿病的機制進行系統(tǒng)深入的研究，從而找出導(dǎo)致其生物學(xué)效應(yīng)的根源。

圖2 磁場對糖尿病影響的可能機制

6 磁場影響糖尿病效果不統(tǒng)一原因分析

目前磁場與血糖或胰島素的實驗結(jié)果多種多樣（見表1和表2）可能與不同研究中所采用的曝磁裝置（見圖3）產(chǎn)生的磁場參數(shù)（強度、梯度、方向、波形）、處理方式（曝磁時間、時間間隔、總時長）、所研究對象以及聯(lián)合治療的方法等多因素有關(guān)。例如，磁場梯度與磁感應(yīng)強度的乘積對生物效應(yīng)起著關(guān)鍵的作用[71]，可以影響細胞成分和培養(yǎng)基中溶解氧等的分布等[75-76]。相關(guān)研究所用的不同磁場裝置如圖3所示。圖3a為Lake Shore電磁鐵裝置產(chǎn)生穩(wěn)態(tài)磁場，磁感應(yīng)強度為128mT[13]；圖3b為交變磁場系統(tǒng)，磁感應(yīng)強度為1.4mT，頻率為50Hz[20]；圖3c為由一塊釹鐵硼磁鐵提供的非均勻穩(wěn)態(tài)磁場，表面磁感應(yīng)強度為0.6T[49]；圖3d為脈沖磁場裝置，磁感應(yīng)強度為2mT，頻率為15Hz[65]；圖3e為由兩塊組合磁板（內(nèi)含多個1cm直徑和1cm高的圓柱形釹鐵硼小磁鐵）提供的非均勻穩(wěn)態(tài)磁場，磁感應(yīng)強度在2.8～476.7mT范圍內(nèi)[70]。

圖3 相關(guān)研究所用的不同磁場裝置

2009年，T. Sakurai等[29]研究發(fā)現(xiàn)，在磁感應(yīng)強度為6T時可以顯著提高胰島素分泌水平，并通過檢測和計算磁場梯度與磁感應(yīng)強度的乘積發(fā)現(xiàn)，在其研究系統(tǒng)中，6T時的磁場梯度與磁感應(yīng)強度乘積最高。又如，動態(tài)磁場參數(shù)中的波形也會影響胰島素釋放，以及生物體初始血糖水平和磁感應(yīng)強 度[24]，磁場空間分布和磁場處理時間等都可能會直接影響磁場效果。此外，最近C. S. Carter等發(fā)現(xiàn)，3mT穩(wěn)態(tài)磁場和7kV/m穩(wěn)態(tài)電場聯(lián)合作用于多種Ⅱ型糖尿病鼠可以顯著改善其血糖水平和胰島素抵抗；但當(dāng)僅用3mT磁場處理這些糖尿病鼠模型時會惡化其血糖水平和葡萄糖耐受[77]。而本課題組發(fā)現(xiàn)，穩(wěn)態(tài)磁感應(yīng)強度、方向和分布可以直接導(dǎo)致對糖尿病小鼠血糖調(diào)節(jié)的不同作用（未發(fā)表數(shù)據(jù)）。因此對于推進磁場與糖尿病相關(guān)標(biāo)準(zhǔn)化研究，建議研究者按照所要研究糖尿病類型構(gòu)建相應(yīng)的糖尿病動物模型，再經(jīng)一定參數(shù)的磁場處理（準(zhǔn)確標(biāo)明實驗動物所處磁場環(huán)境，包括磁感應(yīng)強度、方向、分布、頻率、波形等多種磁場參數(shù)，以及磁場處理方式和時間），然后根據(jù)所要研究的糖尿病并發(fā)癥的特點來決定具體檢測的實驗參數(shù)。建議檢測的基本參數(shù)包括糖尿病小鼠體重、飲食和血糖變化曲線。其他可根據(jù)并發(fā)癥類型和實驗條件，如對胰島素水平、骨密度、血管生成相關(guān)指標(biāo)（例如腎小球毛細血管和血管生成標(biāo)志物）等進行檢測。其中，磁場參數(shù)是最為關(guān)鍵的因素，此外，所用實驗動物的性別、年齡、品種等多種關(guān)鍵因素也需明確記錄。

7 結(jié)論

總體而言，雖然由于磁場本身參數(shù)以及生物樣品的不同導(dǎo)致了目前有關(guān)磁場調(diào)節(jié)血糖和糖尿病癥狀的作用大多無確鑿定論。但從目前的數(shù)據(jù)看來,磁場在改善糖尿病的特定并發(fā)癥，尤其在減少傷口愈合時間和改善糖尿病骨病等方面有著非常正面的效果。然而與此同時，也存在一些磁場條件會升高血糖和減少胰島素釋放。因此，需要從多方面研究不同磁場條件（包括磁場類型、強度、方向和處理時間等）對各種生物樣品（如細胞類型、形態(tài)和動物種類，以及不同血糖濃度起始狀態(tài)等）造成不同影響的原因，深入探索其分子機制，優(yōu)化磁場條件，從而推動未來磁場在調(diào)節(jié)血糖和緩解糖尿病并發(fā)癥等方面的臨床應(yīng)用。

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Research Progress of the Effects of Magnetic Field on Blood Glucose and Diabetic Complications

1,22,3441,2,3

（1. Institutes of Physical Science and Information Technology Anhui University Hefei 230601 China 2. High Magnetic Field Laboratory Hefei Institutes of Physical Science Chinese Academy of Sciences Hefei 230031 China 3. Science Island Branch of Graduate School University of Science and Technology of China Hefei 230026 China 4. Heye Health Technology Co. Ltd Huzhou 313300 China）

Several studies have shown that magnetic fields have various effects on the blood glucose level and diabetic complications. This paper systematically compares and analyzes the effects of magnetic fields with different parameters on blood glucose, insulin levels, as well as diabetes complications in different biological systems. The results show that although the effects of magnetic fields on blood glucose and insulin levels are variable due to the diversity of magnetic parameters and biological samples examined, the magnetic fields usually have positive effects on diabetic wound healing and osteoarthropathy, indicating their promising clinical application potential. Although the mechanism of magnetic field affecting blood glucose has not been systematically explored, there are evidences showing that magnetic field may affect insulin levels by affecting cell membrane, membrane proteins and Ca2+concentrations. This will not only help people to understand the effect of magnetic field on blood glucose regulation and diabetes, but also lay a foundation for the systematic investigations and potential application of magnetic field in the treatment of diabetes and its complications in the future.

Magnetic field, blood glucose, insulin, diabetes mellitus, diabetic complications

Q689

10.19595/j.cnki.1000-6753.tces.201257

中科院合肥物質(zhì)科學(xué)研究院院長基金資助項目（YZJJ201704）。

2020-09-20

2020-09-27

馮傳林 男，1997年生，碩士研究生，研究方向為穩(wěn)態(tài)磁場對糖尿病小鼠的影響及機制。E-mail: fengcl@yeah.net

張 欣 女，1979年生，研究員，博士生導(dǎo)師，研究方向為不同參數(shù)穩(wěn)態(tài)和低頻磁場的生物學(xué)效應(yīng)、機制及其生物醫(yī)學(xué)應(yīng)用。E-mail: xinzhang@hmfl.ac.cn （通信作者）

（編輯 崔文靜）