維生素D與2型糖尿病關(guān)系的研究進(jìn)展

周曉春，陳 曉

維生素D(VitD)是一種脂溶性維生素，在鈣磷代謝調(diào)節(jié)方面起著重要作用。近年來，其在癌癥、免疫及代謝性疾病方面的作用也逐漸被人們認(rèn)識(shí)[1]。在糖尿病領(lǐng)域，關(guān)于VitD的研究日益深入。本文就VitD與2型糖尿病(T2DM)的關(guān)系做一綜述。

1 VitD的概述

VitD除了少部分從食物中攝取之外，大部分是通過紫外線對(duì)皮膚的照射由7-脫氫膽固醇合成，然后在肝臟通過25羥化酶轉(zhuǎn)化成25-羥維生素D3〔25-(OH)D3〕，再經(jīng)過腎臟1α羥化酶的作用，形成具有生物活性的1,25-二羥維生素D3〔1,25-(OH)2D3〕。1,25-(OH)2D3在細(xì)胞中與VitD受體(VDR)結(jié)合，參與細(xì)胞增殖、分化與凋亡的調(diào)控。

2 VitD缺乏與T2DM的關(guān)系

美國(guó)醫(yī)學(xué)研究所在2011年時(shí)提出，當(dāng)血清25-(OH)D3低于50 nmol/L時(shí)認(rèn)為VitD缺乏[2]，而VitD缺乏在美國(guó)非常普遍[3]。胰島β細(xì)胞上存在VDR，VitD參與了體內(nèi)葡萄糖代謝，其缺乏可增加糖調(diào)節(jié)異常和T2DM的患病風(fēng)險(xiǎn)[4-5]。在一項(xiàng)對(duì)澳大利亞人關(guān)于糖尿病、肥胖、生活方式進(jìn)行的為期5年的研究中發(fā)現(xiàn)，VitD的缺乏增加了糖尿病及代謝綜合征的患病率[6]。同樣，Pittas等[7]學(xué)者也發(fā)現(xiàn)，VitD缺乏是T2DM發(fā)生發(fā)展的重要誘因。然而，也有部分研究得出，VitD缺乏與T2DM無相關(guān)性[8]。針對(duì)這樣的結(jié)論，Lu等[9]給出的解釋是，肥胖是導(dǎo)致T2DM的重要危險(xiǎn)因素，在肥胖人群中，更加容易出現(xiàn)VitD缺乏，VitD與體質(zhì)指數(shù)呈負(fù)相關(guān)。由于VitD是脂溶性維生素，脂肪可以儲(chǔ)存大量的VitD[10]。因此，體質(zhì)量容易影響對(duì)VitD缺乏與T2DM關(guān)系判斷的準(zhǔn)確性[11]。為了更加明確VitD缺乏與T2DM的關(guān)系，Song等[12]進(jìn)行了一項(xiàng)25-(OH)D3與T2DM關(guān)系的Meta分析，該分析涉及21項(xiàng)前瞻性研究，總共納入4 996例T2DM患者和76 220例非糖尿病患者，分析得出25-(OH)D3缺乏患T2DM的相對(duì)風(fēng)險(xiǎn)為0.62〔95%CI為(0.54，0.70)〕；并且經(jīng)回歸分析顯示，25-(OH)D3水平與患T2DM的風(fēng)險(xiǎn)呈負(fù)相關(guān)，25-(OH)D3水平每升高10 nmol/L，患T2DM的風(fēng)險(xiǎn)即降低4%。因此，目前有更多的觀點(diǎn)趨向于VitD缺乏與T2DM的發(fā)生發(fā)展密切相關(guān)。

3 VitD缺乏對(duì)T2DM胰島素分泌的影響

流行病學(xué)研究提示， VitD參與了胰島素分泌的過程[13]。VitD缺乏可以導(dǎo)致胰島β細(xì)胞分泌胰島素功能受損[14]，其可能的機(jī)制包括直接作用和間接作用。直接作用是指：胰島β細(xì)胞上存在VDR，其與1,25-(OH)2D3結(jié)合后，激活胰島素轉(zhuǎn)錄基因，從而促進(jìn)胰島素分泌[15]；間接作用則是指：通過調(diào)節(jié)胰島β細(xì)胞膜鈣離子通道，進(jìn)而影響胰島素的分泌[16]。VitD的缺乏是胰島β細(xì)胞分泌功能不足的原因之一。

4 VitD缺乏對(duì)T2DM胰島素抵抗的影響

第3次全美營(yíng)養(yǎng)調(diào)查研究發(fā)現(xiàn)，VitD水平與胰島素抵抗呈負(fù)相關(guān)[17]。炎癥是胰島素抵抗的促進(jìn)因素，VitD能夠通過激活巨噬細(xì)胞而降低炎性因子，從而提高胰島素的敏感性[18]。另外，動(dòng)物實(shí)驗(yàn)顯示，VitD缺乏增加了腎素-血管緊張素-醛固酮系統(tǒng)(renin-angiotensin-aldosterone system，RAAS)的活性[19]。而RAAS活性升高容易引起和加重外周組織對(duì)胰島素的抵抗，補(bǔ)充VitD可抑制RAAS的活性，增加胰島素敏感性[20]。眾所周知，胰島素抵抗在肥胖的T2DM患者中更為明顯，低VitD水平是肥胖人群的一個(gè)顯著特征[9]。Muscogiuri等[21]將肥胖人群根據(jù)胰島素抵抗程度不同分為兩組，一組為高胰島素抵抗組，另一組為低胰島素抵抗組，結(jié)果顯示，兩組的體質(zhì)指數(shù)、年齡、性別間無明顯差異，同樣兩組VitD水平間無明顯差異。提示VitD缺乏與肥胖的關(guān)系可能要比與胰島素抵抗的關(guān)系更為密切。

VitD缺乏可以引起甲狀旁腺激素(PTH)的分泌代償性增加，最終刺激腎臟對(duì)鈣的重吸收。升高的PTH可抑制胰島素的合成與分泌，從而導(dǎo)致胰島素抵抗[22]。故有學(xué)者認(rèn)為VitD缺乏可引起繼發(fā)性甲狀旁腺功能亢進(jìn)，從而加重胰島素抵抗。而Soares等[23]認(rèn)為，伴隨著體質(zhì)量和PTH的下降，VitD水平卻沒有明顯變化，肥胖患者PTH與胰島素抵抗的關(guān)系并不依賴于VitD。

5 VitD缺乏對(duì)T2DM并發(fā)癥的影響

5.1 VitD缺乏與T2DM大血管病變的關(guān)系 對(duì)于單純心血管疾病來說，VitD缺乏是其重要危險(xiǎn)因素。一項(xiàng)涉及了6 123例心血管疾病患者的Meta分析提示，當(dāng)血清25-(OH)D3水平低于60 nmol/L時(shí)，發(fā)生心血管事件的風(fēng)險(xiǎn)明顯增加[24]。在T2DM患者中，Cigolini等[25]研究發(fā)現(xiàn)，合并VitD缺乏者心血管疾病的發(fā)病率要明顯高于無VitD缺乏者。心血管系統(tǒng)廣泛存在VDR和1α羥化酶的表達(dá)[26-27]。VitD能夠改善動(dòng)脈粥樣硬化和內(nèi)皮功能紊亂[28]，其機(jī)制可能包括：(1)抑制巨噬細(xì)胞攝取膽固醇和形成泡沫細(xì)胞；(2)下調(diào)血管平滑肌細(xì)胞的增殖和遷移；(3)抑制炎癥觸發(fā)的內(nèi)皮激活和內(nèi)皮黏附分子的表達(dá)；(4)抑制脂質(zhì)過氧化反應(yīng)[28-32]。VitD缺乏與T2DM心血管并發(fā)癥的發(fā)生密切相關(guān)。那么，VitD水平能否預(yù)測(cè)T2DM心血管疾病的發(fā)生風(fēng)險(xiǎn)呢？為了回答這個(gè)問題，Alele等[33]對(duì)退伍軍人試驗(yàn)(VADT)所涉及的936例T2DM患者〔(59.7±8.4)歲，96.9%為男性〕進(jìn)行了分析，結(jié)果顯示，對(duì)心血管疾病發(fā)生風(fēng)險(xiǎn)高危的T2DM患者，VitD水平并不能預(yù)測(cè)心血管疾病的發(fā)生率。

5.2 VitD缺乏與T2DM微血管病變的關(guān)系 目前VitD與糖尿病微血管病變的研究主要集中在糖尿病腎病(DN)領(lǐng)域。Diaz等[34]對(duì)DN的研究發(fā)現(xiàn)，48.9%的患者存在VitD缺乏，36.6%的患者存在VitD不足。提示VitD缺乏在DN患者中普遍存在。DN患者腎臟內(nèi)腎素、血管緊張素處于很高的水平，RAAS被激活，血管緊張素Ⅱ的上升導(dǎo)致腎小球內(nèi)囊壓力升高、腎小球灌注及濾過增加，導(dǎo)致腎小球硬化，同時(shí)，血管緊張素Ⅱ的增加可以引起轉(zhuǎn)化生長(zhǎng)因子β(TGF-β)、單核細(xì)胞趨化蛋白1(MCP-1)的高表達(dá)，而TGF-β、MCP-1是加重DN腎小球硬化的重要因素[35]。VitD與其VDR結(jié)合后，激活核因子κB通路，從而抑制血管緊張素的表達(dá)[36]。VitD在抑制血管緊張素Ⅱ的同時(shí)抑制了TGF-β、MCP-1的表達(dá)，從而抑制了DN腎小球的硬化[35]。除此以外，VitD影響DN的分子靶點(diǎn)可能還包括：肝細(xì)胞生長(zhǎng)因子、血小板反應(yīng)素-1[37]、纖溶酶原激活物抑制劑[38]、nephrin[39]和β-catenin[40]，但對(duì)此還有待于進(jìn)一步研究。糖尿病視網(wǎng)膜病變也是T2DM常見的微血管并發(fā)癥之一。伴有糖尿病視網(wǎng)膜病變的患者，其VitD水平處于更低的水平[41]。然而，對(duì)于VitD缺乏對(duì)糖尿病視網(wǎng)膜病變途徑的影響，目前仍然缺乏足夠的研究來闡明。

6 VitD在T2DM中的干預(yù)研究

Nagpal等[42]在隨機(jī)雙盲安慰劑對(duì)照研究中得出，對(duì)于VitD缺乏的T2DM肥胖男性患者，補(bǔ)充VitD可提高胰島素敏感性。隨后von Hurst等[43]在對(duì)居住于新西蘭的南亞婦女研究中發(fā)現(xiàn)，補(bǔ)充VitD能改善胰島素抵抗。在另外一項(xiàng)研究中，研究者給予T2DM患者口服骨化三醇2片/d，治療12周后，發(fā)現(xiàn)口服VitD能增加胰島素的分泌，但對(duì)胰島素抵抗卻沒有明顯影響[44]。由于VitD的劑量及劑型不同和目前尚缺乏足夠的大樣本隨機(jī)雙盲對(duì)照研究等原因，故尚不能得出對(duì)T2DM患者補(bǔ)充VitD后可改善胰島β細(xì)胞分泌胰島素和胰島素抵抗的最終結(jié)論[45]。

另外，有研究者認(rèn)為，鈣對(duì)VitD有積極影響，建議補(bǔ)充VitD的同時(shí)補(bǔ)充鈣。在一項(xiàng)護(hù)士健康研究中，與每天補(bǔ)充小于600 mg鈣和400 U VitD相比，每天補(bǔ)充大于1 200 mg鈣和大于800 U VitD的患者能減少33%的T2DM患病風(fēng)險(xiǎn)[46]。然而， de Boer等[47]在一項(xiàng)為期7年的研究中發(fā)現(xiàn)，給予1 000 mg/d的鈣加上400 U/d的VitD，卻沒能降低糖尿病的患病風(fēng)險(xiǎn)。

對(duì)于T2DM并發(fā)癥，目前尚缺乏大型的隨機(jī)對(duì)照研究來闡明補(bǔ)充VitD能否降低心血管事件的發(fā)生。有研究顯示，每天給予1 000 U的VitD，預(yù)防心血管事件的效果并不令人滿意[48]。de Zeeuw等[49]的研究是一項(xiàng)將VitD用于干預(yù)DN的隨機(jī)雙盲對(duì)照研究，研究納入281例正在服用血管緊張素轉(zhuǎn)化酶抑制劑或血管緊張素受體阻滯劑的T2DM患者，將患者分為3組(安慰劑組，1 μg帕立骨化醇組，2 μg帕立骨化醇組)，分別每天給予安慰劑、1 μg帕立骨化醇和2 μg帕立骨化醇，持續(xù)治療4個(gè)月，結(jié)果顯示2 μg帕立骨化醇組與安慰劑組相比，24 h尿清蛋白量明顯下降。

7 小結(jié)

VitD缺乏在T2DM患者中普遍存在，由于脂溶性這一特征，VitD缺乏可能在肥胖的T2DM人群中尤為突出。VitD通過不同的機(jī)制影響T2DM患者胰島素的分泌和胰島素抵抗，增加了糖尿病的患病風(fēng)險(xiǎn)。正因?yàn)轶w內(nèi)廣泛存在VDR，VitD與T2DM血管病的發(fā)生也密切相關(guān)。臨床對(duì)于T2DM患者補(bǔ)充VitD，由于缺乏更多的大型隨機(jī)對(duì)照研究，故尚不能最終明確補(bǔ)充VitD能否改善胰島β細(xì)胞分泌胰島素功能和胰島素抵抗，也不能明確在降低T2DM并發(fā)癥方面能否獲益，因此今后還需要更多的大型隨機(jī)對(duì)照研究來進(jìn)一步闡明。

1 Holick MF.Vitamin D deficiency[J].N Engl J Med,2007,357(3):266-281.

2 Ross AC,Manson JE,Abrams SA,et al.The 2011 report on dietary reference intakes for calcium and vitamin D from the institute of Medicine:what clinicians need to know[J].J Clin Endocrinol Metab,2011,96(1):53-58.

3 Binkley N,Ramamurthy R,Krueger D.Low vitamin D status:definition,prevalence,consequences,and correction[J].Endocrinol Metab Clin North Am,2010,39(2):287-301.

4 Cavalier E,Delanaye P,Souberbielle JC,et al.Vitamin D and type 2 diabetes mellitus:where do we stand ?[J].Diabetes Metab,2011,37(4):265-272.

5 Muscogiuri G,Sorice GP,Ajjan R,et al.Can vitamin D deficiency cause diabetes and cardiovascular diseases ? Present evidence and future perspectives[J].Nutr Metab Cardiovasc Dis,2012,22(2):81-87.

6 Gagnon C,Lu ZX,Magliano DJ,et al.Low serum 25-hydroxyvitamin D is associated with increased risk of the development of the metabolic syndrome at five years:results from a national,population-based prospective study(The Australian Diabetes,Obesity and Lifestyle Study:AusDiab)[J].J Clin Endocrinol Metab,2012,97(6):1953-1961.

7 Pittas AG,Sun Q,Manson JE,et al.Plasma 25-hydroxyvitamin D concentration and risk of incident type 2 diabetes in women[J].Diabetes Care,2010,33(9):2021-2023.

8 Grimnes G,Emaus N,Joakimsen RM,et al.Baseline serum 25-hydroxyvitamin D concentrations in the Troms? Study 1994—1995 and risk of developing type 2 diabetes mellitus during 11 years of follow-up[J].Diabet Med,2010,27(10):1107-1115.

9 Lu L,Yu Z,Pan A,et al.Plasma 25-hydroxyvitamin D concentration and metabolic syndrome among middle-aged and elderly Chinese individuals[J].Diabetes Care,2009,32(7):1278-1283.

10 Blum M,Dolnikowski G,Seyoum E,et al.Vitamin D(3) in fat tissue[J].Endocrine,2008,33(1):90-94.

11 Vimaleswaran KS,Berry DJ,Lu C,et al.Causal relationship between obesity and vitamin D status:bi-directional Mendelian randomization analysis of multiple cohorts[J].PLoS Med,2013,10(2):e1001383.

12 Song Y,Wang L,Pittas AG,et al.Blood 25-hydroxy vitamin D levels and incident type 2 diabetes:a meta-analysis of prospective studies[J].Diabetes Care,2013,36(5):1422-1428.

13 Hypp?nen E,Power C.Vitamin D status and glucose homeostasis in the 1958 British birth cohort ：the role of obesity[J].Diabetes Care， 2006， 29(10):2244-2246.

14 Khaleeli AA,Johnson JN,Taylor WH.Prevalence of glucose intolerance in primary hyperparathyroidism and the benefit of parathyroidectomy[J].Diabetes Metab Res Rev,2007,23(1):43-48.

15 Maestro B,Dávila N,Carranza MC,et al.Identification of a Vitamin D response element in the human insulin receptor gene promoter[J].J Steroid Biochem Mol Biol,2003,84(2 / 3):223-230.

16 Beaulieu C,Kestekian R,Havrankova J,et al.Calcium is essential in normalizing intolerance to glucose that accompanies vitamin D depletion in vivo[J].Diabetes,1993,42(1):35-43.

17 Scragg R,Sowers M,Bell C，et al.Serum 25-hydroxyvitamin D,diabetes,and ethnicity in the Third National Health and Nutrition Examination Survey[J].Diabetes Care,2004,27(12):2813-2818.

18 Baeke F,Gysemans C,Korf H,et al.Vitamin D insufficiency:implications for the immune system[J].Pediatr Nephrol,2010,25(9):1597-1606.

19 Cheng Q,Boucher BJ,Leung PS.Modulation of hypovitaminosis D-induced islet dysfunction and insulin resistance through direct suppression of the pancreatic islet rennin-angiotensin system in mice[J].Diabetologia,2013,56(3):553-562.

20 Cheng Q,Li YC,Boucher BJ,et al.A novel role for vitamin D:modulation of expression and function of the local rennin-angiotensin system in mouse pancreatic islets[J].Diabetologia,2011,54(8):2077-2081.

21 Muscogiuri G,Sorice GP,Prioletta A,et al.25-Hydroxyvitamin D concentration correlates with insulin-sensitivity and BMI in obesity[J].Obesity(Silver Spring),2010,18(10):1906-1910.

22 Khaleeli AA,Johnson JN,Taylor WH.Prevalence of glucose intolerance in primary hyperparathyroidism and the benefit of parathyroidectomy[J].Diabetes Metab Res Rev,2007,23(1):43-48.

23 Soares MJ， Ping-Delfos WC,Sherriff JL,et al.Vitamin D and parathyroid hormone in insulin resistance of abdominal obesity:cause or effect ?[J].Eur J Clin Nutr,2011,65(12):1348-1352.

24 Wang L,Song Y,Manson JE,et al.Circulating 25-hydroxyl-vitamin D and risk of cardiovascular disease ：a meta-analysis of prospective studies[J].Circ Cardiovasc Qual Outcomes， 2012， 5(6):819-829.

25 Cigolini M,Iagulli MP,Miconi V,et al.Serum 25-hydroxyvitamin D3concentrations and prevalence of cardiovascular disease among type 2 diabetic patients[J].Diabetes Care,2006,29(3) ：722-724.

26 Chen S， Glenn DJ,Ni W,et al.Expression of the vitamin D receptor is increased in the hypertrophic heart[J].Hypertension,2008,52(6) ：1106-1112.

27 Somjen D,Weisman Y,Kohen F,et al.25-hydroxyvitamin D3-1alpha-hydroxylase is expressed in human vascular smooth muscle cells and is upregulated by parathyroid hormone and estrogenic compounds[J].Circulation,2005,111(13)：1666-1671.

28 Brewer LC,Michos ED,Reis JP.Vitamin D in atherosclerosis,vascular disease,and endothelial function[J].Curr Drug Targets,2011,12(1)：54-60.

29 Oh J,Weng S,Felton SK,et al.1,25(OH)2vitamin d inhibits foam cell formation and suppresses macrophage cholesterol uptake in patients with type 2 diabetes mellitus[J].Circulation,2009,120(8):687-698.

30 Chen S， Law CS,Grigsby CL,et al.A role for the cell cycle phosphatase Cdc25a in vitamin D-dependent inhibition of adult rat vascular smooth muscle cell proliferation[J].J Steroid Biochem Mol Biol,2010,122(5):326-332.

31 Martinesi M,Bruni S,Stio M,et al.1,25-Dihydroxyvitamin D3inhibits tumor necrosis factor-alpha-induced adhesion molecule expression in endothelial cells[J].Cell Biol Int,2006,30(4):365-375.

32 Husain K， Ferder L,Mizobuchi M,et al.Combination therapy with paricalcitol and enalapril ameliorates cardiac oxidative injury in uremic rats[J].Am J Nephrol,2009,29(5)：465-472.

33 Alele JD,Luttrell LM,Hollis BW,et al.Relationship between vitamin D status and incidence of vascular events in the Veterans Affairs Diabetes Trial[J].Atherosclerosis,2013,228(2):502-507.

34 Diaz VA,Mainous AG 3rd,Carek PJ,et al.The association of vitamin D deficiency and insufficiency with diabetic nephropathy:implications for health disparities[J].J Am Board Fam Med,2009,22(5):521-527.

35 Thomas MC,Cooper ME.Into the light ? Diabetic nephropathy and vitamin D[J].Lancet,2010,376(9752):1521-1522.

36 Zhang Z,Yuan W,Sun L,et al.1,25-Dihydroxyvitamin D3targeting of NF-kappaB suppresses high glucose-induced MCP-1 expression in mesangial cells[J].Kidney Int,2007,72(2):193-201.

37 Li Y,Spataro BC,Yang J,et al.1,25-Dihydroxyvitamin D inhibits renal interstitial myofibroblast activation by inducing hepatocyte growth factor expression[J].Kidney Int,2005,68(4):1500-1510.

38 Wu-Wong JR,Nakane M,Ma J.Vitamin D analogs modulate the expression of plasminogen activator inhibitor-1,thrombospondin-1 and thrombomodulin in human aortic smooth muscle cells[J].J Vasc Res,2007,44(1):11-18.

39 Zhang Z,Zhang Y,Ning G,et al.Combination therapy with AT1 blocker and vitamin D analog markedly ameliorates diabetic nephropathy:blockade of compensatory renin increase[J].Proc Natl Acad Sci USA,2008,105(41):15896-15901.

40 Dai C,Stolz DB,Kiss LP,et al.Wnt / beta-catenin signaling promotes podocyte dysfunction and albuminuria[J].J Am Soc Nephrol,2009,20(9):1997-2008.

41 Payne JF,Ray R,Watson DG,et al.Vitamin D insufficiency in diabetic retinopathy[J].Endocr Pract,2012,18(2):185-193.

42 Nagpal J,Pande JN,Bhartia A.A double-blind,randomized,placebo-controlled trial of the short-term effect of vitamin D3supplementation on insulin sensitivity in apparently healthy,middle-aged,centrally obese men[J].Diabet Med,2009,26(1)：19-27.

43 von Hurst PR,Stonehouse W,Coad J.Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D deficient-a randomised,placebo-controlled trial[J].Br J Nutr,2010,103(4):549-555.

44 Eftekhari MH,Akbarzadeh M,Dabbaghmanesh MH,et al.Impact of treatment with oral calcitriol on glucose indices in type 2 diabetes mellitus patients[J].Asia Pac J Clin Nutr,2011,20(4):521-526.

45 Khan H,Kunutsor S,Franco OH,et al.Vitamin D,type 2 diabetes and other metabolic outcomes:a systematic review and meta-analysis of prospective studies[J].Proc Nutr Soc,2013,72(1):89-97.

46 Liu S,Song Y,Ford ES,et al.Dietary calcium,vitamin D,and the prevalence of metabolic syndrome in middle-aged and older U.S.women[J].Diabetes Care,2005,28(12):2926-2932.

47 de Boer IH,Tinker LF,Connelly S,et al.Calcium plus vitamin D supplementation and the risk of incident diabetes in the Women′s Health Initiative[J].Diabetes Care,2008,31(4):701-707.

48 Wang L,Manson JE,Song Y,et al.Systematic review:Vitamin D and calcium supplementation in prevention of cardiovascular events[J].Ann Intern Med,2010,152(5)：315-323.

49 de Zeeuw D,Agarwal R,Amdahl M,et al.Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes(VITAL study):a randomised controlled trial[J].Lancet,2010,376(9752):1543-1551.