Diabetologia：哈尔滨医科大学孙长颢发现补充组氨酸可改善胰岛素抵抗

炎症反应和氧化应激的增加与胰岛素抵抗（IR）和代谢紊乱有关。在肥胖女性，血清组氨酸水平降低，并与炎症反应和氧化应激成负相关。为了评估在伴有代谢综合征（Mets）的肥胖女性，组氨酸补充治疗对IR、炎症反应、氧化应激和代谢紊乱的功效，来自哈尔滨医科大学公共卫生学院的孙长颢教授及其团队进行了一项研究（Histidinesupplementation improves insulin resistance through suppressed inflammation in obese women with the metabolic syndrome: a randomised controlled trial），该研究发现在伴有代谢综合征的肥胖女性，组氨酸补充治疗可以改善IR，降低体重指数（BMI）、脂肪含量和非酯化脂肪酸（NEFA），以及抑制炎症反应和氧化应激；组氨酸可能通过脂肪细胞的NF–κB通路，抑制促炎性细胞因子表达，改善胰岛素抵抗。该研究结果发表在2013年5月的《糖尿病学》（Diabetologia）杂志上。

该研究是一项随机、双盲、安慰剂对照试验，共有100例年龄33–51岁的、BMI≥28kg/m²、并被诊断为代谢综合征的肥胖女性入选，并在社区医院进行健康体检。参与者被研究者使用顺序编码的密封信封分配到不同干预治疗中，接受组氨酸4g/天（50例）或者相同剂量的安慰剂（50例）治疗12周。然后参与者每2周参加同一诊所的预定谈话，并数剩余药片的数量。在基线和第12周测量血清组氨酸、HOMA－IR，BMI，腰围，脂肪含量，血清NEFA，以及炎症反应和氧化应激相关变量。参与者、体检医师和评估结局的研究者对分组方案一无所知。此外，同时探讨脂肪细胞中组氨酸的炎症机制。

该研究结果表明，在第12周，共有92例参与者完成这项研究。与安慰剂组（47例）相比，组氨酸补充治疗显著降低HOMA–IR（-1.09[95%CI -1.49，-0.68]）,BMI(-0.86 kg/m²[95%CI -1.55,-0.17]),腰围（-2.86cm[95%CI -3.86，-1.86]）,脂肪含量（-2.71kg[95%CI -3.69，-1.73]）,血清NEFA（-173.26umol/l[95%CI -208.57，-137.94]）,血清炎性细胞因子（TNF–α，-3.96pg/ml[95%CI -5.29，-2.62]）；IL–6，-2.15pg/ml[95%CI -2.52，-1.78]），氧化应激（超氧化物歧化酶，17.84U/ml[95%CI 15.03，20.65]；谷胱甘肽过氧化物酶，13.71nmol/ml[95%CI 9.65，17.78]），并在组氨酸补充治疗组（45例），血清组氨酸和脂联素分别增加18.23umol/l[95%CI 11.74，24.71]和2.02ng/ml[95%CI 0.60，3.44]。血清组氨酸改变与IR及其危险因素的改变之间显著相关。在干预期间没有观察到任何不良反应。体外研究显示组氨酸抑制IL6和TNF的mRNA表达，并且在棕榈酸诱导脂肪细胞中，组氨酸抑制核因子kappa–B(NF–κB)蛋白产生呈剂量依赖方式，且这些改变可被NF–κB抑制剂消弱。

该研究发现，在伴有代谢综合征的肥胖女性，组氨酸补充治疗可以改善IR，降低体重指数（BMI）、脂肪含量和非酯化脂肪酸（NEFA），以及抑制炎症反应和氧化应激；组氨酸可能通过脂肪细胞的NF–κB通路，抑制促炎性细胞因子表达，改善胰岛素抵抗。

Histidine supplementation improves insulin resistance through suppressed inflammation in obese women with the metabolic syndrome: a randomised controlled trial.
AIMS/HYPOTHESIS
Increased inflammation and oxidative stress are associated with insulin resistance (IR) and metabolic disorders. Serum histidine levels are lower and are negatively associated with inflammation and oxidative stress in obese women. The objective of this study was to evaluate the efficacy of histidine supplementation on IR, inflammation, oxidative stress and metabolic disorders in obese women with the metabolic syndrome (MetS).
METHODS
A total of 100 obese women aged 33-51 years with BMI ≥ 28 kg/m(2) and diagnosed with MetS were included following a health examination in the community hospital in this randomised, double-blinded, placebo-controlled trial. Participants were allocated to interventions by an investigator using sequentially numbered sealed envelopes and received 4 g/day histidine (n = 50) or identical placebo (n = 50) for 12 weeks. Participants then attended the same clinic every 2 weeks for scheduled interviews and to count tablets returned. Serum histidine, HOMA-IR, BMI, waist circumference, fat mass, serum NEFA, and variables connected to inflammation and oxidative stress were measured at baseline and 12 weeks. Participants, examining physicians and investigators assessing the outcomes were blinded to group assignment. In addition, the inflammatory mechanisms of histidine were also explored in adipocytes.
RESULTS
At 12 weeks, a total of 92 participants completed this trail. Compared with the placebo group (n = 47), histidine supplementation significantly decreased HOMA-IR (-1.09 [95% CI -1.49, -0.68]), BMI (-0.86 kg/m(2) [95% CI -1.55, -0.17]), waist circumference (-2.86 cm [95% CI -3.86, -1.86]), fat mass (-2.71 kg [95% CI -3.69, -1.73]), serum NEFA (-173.26 μmol/l [95% CI -208.57, -137.94]), serum inflammatory cytokines (TNF-α, -3.96 pg/ml [95% CI -5.29, -2.62]; IL-6, -2.15 pg/ml [95% CI -2.52, -1.78]), oxidative stress (superoxide dismutase, 17.84 U/ml [95% CI 15.03, 20.65]; glutathione peroxidase, 13.71 nmol/ml [95% CI 9.65, 17.78]) and increased serum histidine and adiponectin by 18.23 μmol/l [95% CI 11.74, 24.71] and 2.02 ng/ml [95% CI 0.60, 3.44] in histidine supplementation group (n = 45), respectively. There were significant correlations between changes in serum histidine and changes of IR and its risk factors. No side effects were observed during the intervention. In vitro study indicated that histidine suppresses IL6 and TNF mRNA expression and nuclear factor kappa-B (NF-κB) protein production in palmitic acid-induced adipocytes in a dose-dependent manner, and these changes were diminished by an inhibitor of NF-κB.
CONCLUSIONS/INTERPRETATION
Histidine supplementation could improve IR, reduce BMI, fat mass and NEFA and suppress inflammation and oxidative stress in obese women with MetS; histidine could improve IR through suppressed pro-inflammatory cytokine expression, possibly by the NF-κB pathway, in adipocytes.