指南速递 | 2019 意大利内分泌学会（SIE）共识声明：极低热量生酮饮食（VLCKD）在代谢疾病中的管理（中）

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接上文：2019 意大利内分泌学会（SIE）共识声明：极低热量生酮饮食（VLCKD）在代谢疾病中的管理（上）

译者：刘睿  佛山市妇幼保健院

审校：贾彤 江苏省太仓市妇幼保健计划生育服务中心

极低热量生酮饮食（VLCKD）与骨骼肌和骨骼健康

推荐建议

•本共识确定在VLCKD治疗少肌性肥胖（sarcopenic obesity）时，去脂体质量（lean body mass）并不会下降（1ØØØO）。

•本共识认为VLCKD在治疗在重度肥胖时，不会损害骨骼健康（2ØØØO）。

证据

众所周知，如果没有结合阻力训练（resistance training），仅用能量限制通常会导致去脂体重下降。实际上，蛋白质摄入可以将氨基酸用于糖异生，使去脂体重不受影响，从而维持肌肉质量（muscle mass）[30]。损失，特别是在生酮饮食的第一阶段里。在实施VLCKD接下来的几周，可用的葡萄糖减少，但其需求也减少，这是由于可替代葡萄糖的能量燃料增加，如脂肪酸（FFA）和酮体，并且通过蛋白质供应来提高糖异生的需求也减少了。

生酮饮食对身体组分的长期影响，只有少数数据可用。一项小型病例系列的研究结果表明，转运蛋白-1（GLUT-1）缺乏综合症（glucose transporter-1 deficiency syndrome）的患者保持生酮饮食超过5年不会对其身体组分和骨密度产生任何重大的负面影响[79]。一项为期3周，指导25名受试者使用VLCKD的初步研究表明，VLCKD在减轻体重方面非常有效，并且不会引起去脂体重减轻，从而预防肌肉减少症的发生风险[18]。一项小型研究观察了6名癌症患者接受放射治疗的同时使用生酮饮食，发现生酮饮食引起的体重减轻主要是由于脂肪质量损失（fat mass loss），并且维持了肌肉质量[80]。一项为期21天的RCT比较了不同蛋白质来源的VLCKD方案，研究发现VLCKD并未对包括肌肉减少症在内的营养状况产生任何不利影响[81]。最近的一项研究确认了VLCKD可引起的脂肪量大幅度减少，而静息代谢率（resting metabolic rate，RMR）没有像预期的那样下降。有趣的是，RMR的减少并不是由于交感神经的作用，而是可能与去脂体重的维持有关[82]。这也能说明为什么VLCKD后短期内不会发生体重反弹。

值得注意的是，大多数关于生酮饮食的研究是基于持续的热量缺乏，并没有给予运动干预，而在减肥期间，运动干预可能对保持肌肉质量有益。在生酮饮食模式中加入结构化阻力训练，这可能有利于进一步改善身体组分[83,84]。

虽然现今并没有关于VLCKD对骨骼代谢影响的研究，但众所周知，慢性代谢性酸中毒增加钙在尿液中排出而不增加其在肠内的吸收，这将导致在物理化学溶解的作用下发生急性骨钙丢失，也可引起骨吸收增加，导致慢性骨钙丢失[85,86]。该作用与代谢性酸中毒的本身无关。因此，导致代谢性酸中毒的生酮饮食可能对骨矿物质含量（bone mineral conetent，BMC）产生不利影响[87]。然而，VLCKD不会导致代谢性酸中毒，但目前也没有评估其对骨骼健康的影响。关于VLCKD对磷代谢影响的数据非常有限，使用这些饮食期间维生素D代谢也尚未被纳入研究。

研究表明，难治性癫痫患儿长期使用生酮饮食可诱发进行性骨矿物质含量减少，导致骨骼健康状况不佳[88,89]。此外，一些动物实验也表明，低热量饮食（low-calories diet，LCDs）可导致骨质量差，这可能与钙在胃肠道中吸收不良[90]。

然而，在VLCKD相关不良代谢影响方面，多数研究的调查时间都在3个月以下。一些调查的关键终点，例如用于体重控制的总体膳食替代品（total diet replacements）对钙丢失和骨骼健康的影响，也没有超过8周。现有证据未能说明这些饮食方案实施达到8周时能够损害成人骨骼健康，并且，当这些饮食方案延期使用或短时间内重复使用时，关于钙损失增加影响骨骼健康的数据也非常罕见[87]。

Carter等发表的一项研究显示使用LCD的患者体重明显减轻，但骨转换标记物并未发生改变（例如尿N端肽，uNTx；骨特异性碱性磷酸酶，BSAP）[90]。一项为期21天的RCT比较了不同蛋白质来源的VLCKD方案发现它们对营养状态都没有负面影响，包括BMC、脂质谱以及肝肾功能[81]。

评述

由于缺乏关于长期使用VLCKD对骨骼健康影响的数据，需要进一步研究以充分揭示VLCKD可能对骨骼产生的任一副作用。

极低热量生酮饮食（VLCKD）对肠道菌群的影响

推荐建议

•本共识建议可以将VLCKD用于肥胖症治疗，将其作为把肠道微生物群调整为瘦表型（lean phenotype）的重要工具（2ØØØO）。

•在实施VLCKD时，本共识推荐使用乳清蛋白和植物蛋白，因为在调节肠道菌群健康方面，它们比动物蛋白更有效（1ØØOO）。

证据

目前有证据表明微生物群在人类健康和疾病中有重要作用，比如消化，能量和葡萄糖代谢，以及免疫调节和脑功能[91]。另一方面，多种因素（例如宿主遗传、饮食、环境、抗生素使用和年龄）对人类肠道微生物群的生长和组成有极大影响。尤其是几份研究数据均表明饮食和主要常量营养素摄入量的变化可以迅速和反复地改变人类肠道微生物群。已经在肥胖患者中证实了其体内拟杆菌的相对丰度降低，厚壁菌增加，以及细菌多样性降低[92]。有趣的是，已知乳清和豌豆蛋白能够增加肠道共生菌，即双歧杆菌和乳酸杆菌，而豌豆蛋白还可以增加肠内短链脂肪酸的水平，这有助于维持粘膜屏障[93,94]。

已有研究表明，非生酮极低碳水化合物饮食（non-ketogenic VLCD）有助于改善肥胖症患者体内肠道微生物菌群的多样性和代谢，并且能够调节肠黏膜通透性，从而降低炎症标志物的含量。根据最近的研究，这些活动似乎与急性和显著的热量限制和营养成分有关，而不是与体重减少有关[95]。

近期，有研究证明生酮饮食对于肠道微生物菌群也有一定作用。研究急性电诱导性癫痫发作的小鼠实验初步表明，生酮饮食能够改变肠道微生物菌群，诱导嗜黏蛋白阿克曼氏菌（Akkeransia Muciniphila）和肠道共生菌狄氏副拟杆菌（Parabacteroides）的增加，这是避免癫痫发作的必需条件。事实上，小鼠在使用抗生素干预或无菌处理后，对生酮饮食介导的避免癫痫发作作用具有抵抗性。在后续治疗中，因生酮饮食使嗜黏蛋白阿卡曼氏菌和肠道共生菌狄氏副拟杆菌增加，此作用又得到了恢复。这些研究结果更进一步证实了生酮饮食诱导了肠道微生物菌群重新恢复平衡，这些菌群组份本身在生酮饮食发挥作用上即具有关键作用[96]。

评述

极低热量生酮饮食（VLCKD）是限制肥胖患者热量摄入的重要方法。然而，目前相关研究仍然很有限。因此，进行VLCKDs调节肠道细菌能力的评估性研究是很有必要的。

极低热量生酮饮食（VLCKD），胰岛素抵抗和2型糖尿病

推荐建议

•VLCKD可达到控制血糖的早期效果，特别是在病程较短的肥胖患者中（1ØØØO）。

•VLCKD可减少降糖药物的使用，包括胰岛素（1ØØØO）。

证据

在肥胖的非糖尿病患者中，VLCKD降低血浆胰岛素的效果十分突出; 因此，分别代表胰岛素抵抗和β细胞功能标志物的HOMA-IR和HOMA-β在这种类型的饮食干预后有显著地改善[97,98]。相应的，VLCKD可改善年青肥胖患者的胰岛素抵抗，这一重要益处是显而易见的[99-102]。

患有2型糖尿病的肥胖患者在使用VLCKD 1周后可以显著改善β细胞的功能，这一现象不能完全用达到目标体重来解释。碳水化合物摄入量的减少与肝脏三酰基甘油含量的早期显著降低有关。因此，由于肝脏胰岛素敏感性的改善，肝内葡萄糖生成可以得到更有效地抑制。肝脏胰岛素敏感性升高也与空腹血糖和血浆胰岛素水平降低相关。然而，外周胰岛素敏感性的变化仅部分解释了VLCKD的短期作用[103]。另一方面，延长VLCKD应用时间后随访监测，才能发现仅在体重明显减轻后可出现大幅度骨骼肌葡萄糖摄取增加。短期使用VLCKD后也可以观察到胰岛素对精氨酸反应增加（可反应β细胞功能的指数）[104]。具体地讲，在实施VLCKD1周后，肥胖伴2型糖尿病的患者血糖得到良好控制，通过葡萄糖评估可发现快速胰岛素反应得到了恢复，在胰岛素分泌的第2时相也同样[105]。在延期治疗结束后（8周），包括其他临床表现各不相同的2型糖尿病患者，VLCKD[103]可使40％观察对象的胰岛素分泌的第1时相得到恢复。此外，处置指数也有所升高（译注：原词为depostion index，在引文中指反应β细胞能够调节当前胰岛素抵抗及胰岛素清除的指标）[106]。有趣的是，在短期内提高2型糖尿病患者的胰岛素敏感性和改善β细胞功能方面[104]，VLCKD与Roux-en-Y胃旁路术同样有效[107]。

除了现下已知的短期效果之外，评估VLCKD对胰岛素抵抗和β细胞功能的远期效果以及VLCKD与其他标准饮食的比较仍然缺乏报道。

VLCKD对2型糖尿病患者的代谢控制迅速有效。与标准的低碳饮食（LCD）相比，3个月的VLCKD可使糖化血红蛋白（HbA1c）下降得更多[108,109]。也可以观察到在VLCKD的第1天，空腹血浆葡萄糖、快速胰岛素反应、空腹血浆胰岛素、血浆胰岛素和C肽水平即有显著改善[103,104,110]。这些早期效应与β细胞功能的改善有关，而随后内脏脂肪大量减少，体重减轻，又加强了以上效应[103]（图2）。值得注意的是，肥胖伴2型糖尿病的患者使用VLCKD与不伴2型糖尿病的患者相比较，体重减轻程度并不相同，前者脂肪组织减少的程度要低于后者，这是因为糖尿病患者更多地是消耗了体内水分[111]。

图2 VLCD对2型糖尿病或非2型糖尿病肥胖患者葡萄糖稳态和代谢参数的影响

VLCKD对β细胞功能的影响可能是缓解2型糖尿病患者病情的主要原因。有相应比例早期诊断本病的患者在使用VLCKD 3个月可缓解病情[103,109]。长期观察发现，尽管随后体重有所反弹，但有近半数患者的病情是可以得到持续改善的[103,106]，空腹血糖较低、年龄较小和病程较短的患者尤其如此。即使糖尿病治疗未能持续下去，但在VLCKD干预期间血糖控制仍可以得到改善[106,112]。连续[107,108,110]或间歇使用[111]VLCKD可显著降低胰岛素，也可以大量减少口服降糖药物的使用。

评述

尽管在18个月的VLCKD干预后观察到空腹血糖和HbA1c持续下降[112]，但目前大多数研究显示的均是VLCKD短期随访的情况，研究者应充分观察VLCKD对长期维持代谢记忆（metabolic memory）的潜在影响。VLCKD改善代谢状态并不仅限于减肥，因此，这一方法应该纳入肥胖和2型糖尿病患者的生活方式干预当中。

极低热量生酮饮食（VLCKD）和血脂异常 

推荐建议

•本共识推荐VLCKD可用来降低肥胖伴高甘油三酯血症患者的血清甘油三酯（1ØØØO）。

证据

VLCKD调节肥胖患者血浆脂蛋白的研究由来已久：最初，有一些短期的、小规模的、非随机研究提示了VLCKD可以降低肥胖患者血浆甘油三酯，增加低密度脂蛋白（LDL）胆固醇，而对高密度脂蛋白（HDL）胆固醇无用。之后，有一项关于VLCKD随机试验研究，基于初始每日消耗<20克/天的碳水化合物饮食方案证实其有益于甘油三酯的调节[113-117]。体重下降的数量是甘油三酯水平改善的独立预测因子[114]。

不同研究报告的总胆固醇，低密度脂蛋白胆固醇和高密度脂蛋白胆固醇改善情况不同，这可能是由于饮食结构（脂肪摄入量占总热量每日摄入量的40％-50％），遗传背景和研究组的体育活动的差异导致的。有的研究报道在给予6个月的极低碳水化合物饮食后，总胆固醇，低密度脂蛋白胆固醇和高密度脂蛋白胆固醇并没有变化，而在其它随机试验中[113,114,117]，直至12个月时高密度脂蛋白胆固醇得到了改善[115,116]。

在科威特（Kuwaiti）肥胖患者进行的一项研究中发现，无论是血脂正常，还是伴有高胆固醇血症的肥胖患者在使用了VLCKD后，总胆固醇、低密度脂蛋白胆固醇和甘油三酯下降，高密度脂蛋白胆固醇增加[118]，这一现象与性别无关，在BMI降至正常的8周前，胆固醇和甘油三酯水平已经达标，并恢复正常[118]。

评述

在肥胖患者中进行的随机试验表明，与传统饮食方法相比，基于VLCKD的减肥方案通常能更好地使甘油三酯下降，遗憾的是，这一方法应用于肥胖或体重正常但伴有代谢综合征的研究对象后，并没有更长时间的研究（>1年），在肥胖患者当中也没有。

极低热量生酮饮食（VLCKD）和非酒精性脂肪肝

推荐建议

•在患有非酒精性脂肪性肝病（NAFLD）的超重或肥胖患者中，大多数生活方式干预的目标是体重下降7%-10％。因此，本共识推荐对于这种情况应限制能量以及去除促进NAFLD的因素（1ØØØO）。

•本共识建议使用VLCKD治疗肥胖伴NAFLD患者，以便快速缩小肝脏体积和降低肝内甘油三酯含量（2ØØØO）。

非酒精性脂肪肝（NAFLD）是西方可工业化国家中最常见的肝脏疾病，其中肥胖和2型糖尿病是该疾病发生的主要危险因素，这一疾病证据进展为非酒精性脂肪性肝炎（NASH）和肝硬化或肝细胞癌。非酒精性脂肪肝的特征在于，在组织学中存在> 5％的肝细胞脂肪变性，或者当没有其他原因导致继发性肝脏脂肪蓄积时，通过磁共振质子波谱法可检测到肝内甘油三酯水平> 5.6％。

鉴于NAFLD的发生与肥胖紧密相关，即使体重没有大幅度减轻，肝脏脂肪也会显著减少，同时改善肝脏胰岛素抵抗[119,120]。经过饮食干预使体重减轻，这可以促进NASH消退和NAFLD活动评分（NAS）下降，其效果与体重减轻平行。此外，减重7％可改善肝脏组织学[121]。同样，在一项历时12个月的大规模非对照队列研究中，经生活方式改变使体重有大幅度下降（> 10％）可以改善脂肪性肝炎和纤维化。现今并没有NAFLD长期自然发展史的相关数据[122]。地中海饮食是改善NAFLD患者肝功能和组织学特征最合适的方法，但这一说法是基于一些横断面和纵向研究。目前美国肝病研究协会在临床实践中推荐通过低热量和低脂肪饮食，有计划地适度减轻体重[121]。

目前，没有RCT得出任何有关VLCKD应用于非酒精性脂肪肝/非酒精性脂肪性肝炎的临床结果，其减少或改善主要疾病结局的有效性也未得到证实[123]，也缺乏有说服力的具有统计学意义的长期研究[124]。

在人类实验中，2周的VLCKD干预可使非酒精性脂肪肝患者肝脏内甘油三酯下降。重要的是，VLCKD的下降效果明显高于一般的热量限制饮食法。一项类似的研究表明，短期（6天）应用 VLCKD可使肝脏总体积迅速下降[125]，这可能与糖原耗竭有关，并且这种下降程度要高于一般（7个月）低热量饮食[126]。

尽管一些观察性实验研究均检测了低碳水化合物饮食对NAFLD的影响，但各研究之间存在相当大的不一致性。最近一项荟萃分析发现，NAFLD患者使用低碳水化合物饮食可以显著降低肝内脂质组分，但对肝酶水平无作用[127]。

肝内甘油三酯（intrahepatic triglyceride，IHTG）水平高度依赖短期饮食中蛋白质的摄入[128-130]。最近，有一项为历时2年的研究报道，提高饮食中蛋白质量可能会降低NAFLD患者的肝内脂肪组分，降低其发生2型糖尿病的发生风险。值得说明的是，这项研究中既往诊断为NAFLD的研究对象，超过半数不再进展为脂肪肝[131]。

一项为期12周的干预性研究表明，高蛋白-低碳水化合物饮食比低蛋白-高碳水化合物饮食后更能降低IHGT[132]。这表明在健康人群中应用高蛋白低碳水化合物饮食可能会限制IHTG。高蛋白质摄入可刺激肝脏脂质氧化，这是由于能量需求升高，促进了氨基酸分解代谢和酮体生成[133]。蛋白质诱导的胰高血糖素分泌抑制脂肪再生成，却刺激肝内酮体生成[134]。碳水化合物摄入可增加的极低密度脂蛋白（VLDL）胆固醇和甘油三酯浓度[135]，进而增加肝内甘油三酯，提高IHTG组分，而高蛋白摄入可能会减弱这一作用[136]。

评述

正如国际指南所定义的，本病的诊断和随访都缺乏RCT，证据质量也较差，这是因为肝脏发病结局的研究粗糙，也限制了VLCKD在NAFLD应用与验证。

极低热量生酮饮食（VLCKD）和心血管危险因素和疾病

推荐建议

•本共识推荐肥胖患者，在对一般饮食方案无反应时，可使用VLCKD快速降低其心血管疾病相关危险因素（1ØØØO）。

•本共识推荐肥胖伴高血压的患者，对一般饮食方案无反应时，可使用VLCKD（1ØØØO）。

•本共识建议VLCKD可作为使体重快速下降的一种方法，也可作为肥胖伴心衰患者（NYHA I-II）出现心脏超负荷时的一种治疗选择。（2ØOOO）。

证据

现可以明确肥胖能够缩短寿命，并显著增加心血管疾病的发病率和死亡率[137]。值得注意的是，与正常BMI相比较，处于超重状态的人尽管两者寿命相仿，但其在年青时患心血管疾病（CVD）的风险显著增加[138]。众所周知，脂肪过多会使大多数CVD相关危险因素恶化，例如血脂异常，高血压，胰岛素抵抗和全身性炎症[139]。VLCKD可快速减少内脏脂肪，有益于纠正CVD的关键风险因素[30]。因此，VLCKD可纳入至肥胖患者心血管康复的多学科策略当中。Blackburn的开创性研究表明，VLCKD在减轻体重，降低收缩压、舒张压、空腹血糖和甘油三酯水平方面具有明显的多效性[24]。其他研究者也得出了类似的研究数据，并且已经进行了探讨[30]。值得注意的是，与低碳饮食联合奥利司他的联合干预相比，VLCKD降低血压的效果更好[140]，可能与酮体经尿排泄使钠作用增增加有关。

肥胖与左心室每搏输出量和心输出量增加有关。这些变化导致心室肥大和肿大，容易诱发心力衰竭[137]。值得注意的是，长期限制肥胖患者的热量摄入可明显改善舒张期心脏功能，同时可以降低心肌甘油三酯含量，并使BMI的显著下降[141]。一项类似研究显示，通过14个月的随访，T2D伴肥胖的患者，无论体重反弹如何[142]，使用VLCD（450千卡/天，50-60克碳水化合物）后可改善心脏舒张功能。需要说明的是，处于功能衰竭的心脏将酮体作为了生成ATP的主要能量来源[143]。使用肾钠/葡萄糖协同转运蛋白2（SGLT2）进行药物抵制是一种通过增加糖尿和尿钠排泄以降低血糖的疗法，此方法可增加酮体[144]，并可确切使心血管疾病死亡率降低38％，这一现象就不能仅用改善心血管危险因素来解释了[145]。在正常葡萄糖耐受患者使用SGLT2抑制疗法期间，由于尿糖排出的平均值约为70g /天[146]，酮体增加可能是SGLT2抑制剂有保护心脏作用的机制之一[144]。需要指出β羟基丁酸可以通过抑制由G蛋白偶联受体41（GPR41）倡导的短链脂肪酸信息通路，进而抑制交感神经系统，降低心率和总能量消耗[147]。此外，VLCKD的抗炎作用也可以起到重要的心脏保护作用。据报道，长达12周的VLCKD可显著降低促炎性细胞因子的水平【肿瘤坏死因子(TNF-α），白细胞介素6（IL-6），白细胞介素8（IL-8），单核细胞趋化蛋白1（MCP-1）， E-选择蛋白，细胞间粘附分子1（ICAM-1），纤溶酶原激活物抑制因子1（PAI-1）】[148]。因此，动物研究表明β-羟基丁酸可阻断NLRP3炎性小体（含有NOD-，LRR-和热蛋白结构域的蛋白质3）[149]，这一结果支持VLCKD不仅有改善代谢的作用，也有直接抗炎的作用[150]。

评述

VLCKD可降低心血管疾病相关危险因素，其中的机制复杂多样。然而，使用该方案治疗心血管所带来的主要结果，对其远期研究还很少，所以常规推荐VLCKD用于预防和治疗与肥胖相关的CVD这一作法仍是不明确的。

专家简介

贾彤

贾彤（网名大狐之舞），硕士研究生，副主任中医师。现就职于江苏省太仓市妇幼保健计划生育服务中心。聘任中国医药教育协会生殖内分泌专业委员会委员、苏州中西医结合生殖委员会委员。

与明玥（太原市妇幼保健院李艳主任）在2015年组建明玥妇科内分泌团队，主持中国妇产科网专栏《妇科内分泌频道》的日常工作，并在妇产科网13个微信及QQ平台进行实时答疑，制作讲课视频约300个，编写病例问答共约500多个，浏览次数高达200万。2015-2018年编著并已出版妇科内分泌系列书籍《妇科内分泌知识轻松学》5本；为全国40000余名专业妇科内分泌医生提供了学习资源和专业指导。

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