从胰岛微循环探索“脾气散精”环节对血糖稳态的调节机制
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摘要
减少血糖波动是目前干预糖尿病和预防并发症的重点,也是中医药在糖尿病治疗中的优势所在。越来越多的研究表明,胰岛微循环障碍是胰岛功能下降进而引发血糖波动的关键病理环节,而胰岛微循环局部肾素-血管紧张素系统(renin-angiotensin system,RAS)的过度激活作为胰岛功能失代偿的使动环节,与胰岛内分泌细胞功能密切相关,是研究胰岛功能的关键靶点。中医学认为糖尿病血糖波动与"脾气散精"障碍密切相关,脾不散"精"(血糖),精滞为浊,浊邪壅塞,是血糖稳态失衡的使动环节,亦为糖尿病全病程的关键病机。通过补益"脾"气以促进"胰"中精微物质的布散能够恢复糖调节激素间的平衡,从而减少血糖波动。目前,"脾气散精"对血糖波动的调节机制尚不明确。作者基于以往的临床和科研工作基础,提出"脾气散精"环节通过促进机体胰岛微循环从而发挥其改善胰岛功能、调节血糖稳态的作用,其机制可能与抑制胰岛微循环局部RAS的激活状态相关。RAS系统在胰岛微循环中各信号通路的相互拮抗关系,与中医理论中脾气散精与固精作用的对立制约关系相类似。因此"脾气散精"环节对血糖波动的调节机制有必要从胰岛微循环RAS整体调控的角度进行深入探索,以此揭示中医药调节机体内环境稳态,减少糖尿病患者血糖波动的科学内涵。
Reducing glycemic excursion is of great importance to the successful practice for diabetes intervention and complication prevention. This is also an advantage of traditional Chinese medicine( TCM) in the treatment of diabetes. More and more studies have shown that the dysfunction of islet microcirculation is the key pathological link for glycemic excursion caused by decrease of islet function. The over-activation of local reninangiotensin system( RAS) in islet microcirculation is a key ring to the islet decompensation,intimately related to the functionality of islet endocrine cells,and has gradually become the focus in the study of islet functionality. In TCM,it is believed that glycemic excursion in diabetes mellitus is closely related to the incapability of "spleen Qi to dispersing essence". If spleen fails to disperse essence,the essence will be accumulated in the body and become harmful stuffs. The stuffs further break the blood glucose homeostasis,acting as the key pathogenesis of diabetes.By supplementing the "spleen"Qi and promoting the dispersion of nutrient substance( hormone) in "pancreas",the balance between sugar-regulated hormones can be restored and therefore glycemic excursion can be reduced.However,the regulation mechanism of "spleen Qi to dispersing essence"on glycemic excursion remains unclear at present. Based on the previous clinical and scientific work,the following ideas were proposed by the authors: the effects of "spleen Qi to dispersing essence"on the improvement of islet function and the regulation of glycemic excursion may be achieved by promoting islet microcirculation,and its mechanism may be related to inhibiting the activation status of local RAS in islet microcirculation. It is important to note that the mutual antagonistic relationship between the signal pathways of RAS in islet microcirculation is similar to the antagonistic relationship between "spleen Qi to dispersing essence "and spermatozoa in TCM. Thus,the mechanism of "spleen Qi to dispersing essence"on the regulation mechanism of blood glucose fluctuations needs to be further explored from the perspective of the overall regulation of RAS in islet microcirculation,so as to reveal the scientific connotation of TCM on regulating the body's environmental homeostasis and reducing glycemic excursion in diabetic patients.
Reducing glycemic excursion is of great importance to the successful practice for diabetes intervention and complication prevention. This is also an advantage of traditional Chinese medicine( TCM) in the treatment of diabetes. More and more studies have shown that the dysfunction of islet microcirculation is the key pathological link for glycemic excursion caused by decrease of islet function. The over-activation of local reninangiotensin system( RAS) in islet microcirculation is a key ring to the islet decompensation,intimately related to the functionality of islet endocrine cells,and has gradually become the focus in the study of islet functionality. In TCM,it is believed that glycemic excursion in diabetes mellitus is closely related to the incapability of "spleen Qi to dispersing essence". If spleen fails to disperse essence,the essence will be accumulated in the body and become harmful stuffs. The stuffs further break the blood glucose homeostasis,acting as the key pathogenesis of diabetes.By supplementing the "spleen"Qi and promoting the dispersion of nutrient substance( hormone) in "pancreas",the balance between sugar-regulated hormones can be restored and therefore glycemic excursion can be reduced.However,the regulation mechanism of "spleen Qi to dispersing essence"on glycemic excursion remains unclear at present. Based on the previous clinical and scientific work,the following ideas were proposed by the authors: the effects of "spleen Qi to dispersing essence"on the improvement of islet function and the regulation of glycemic excursion may be achieved by promoting islet microcirculation,and its mechanism may be related to inhibiting the activation status of local RAS in islet microcirculation. It is important to note that the mutual antagonistic relationship between the signal pathways of RAS in islet microcirculation is similar to the antagonistic relationship between "spleen Qi to dispersing essence "and spermatozoa in TCM. Thus,the mechanism of "spleen Qi to dispersing essence"on the regulation mechanism of blood glucose fluctuations needs to be further explored from the perspective of the overall regulation of RAS in islet microcirculation,so as to reveal the scientific connotation of TCM on regulating the body's environmental homeostasis and reducing glycemic excursion in diabetic patients.
引文
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[7] Kumar H K, Kota S, Basile A, et al. Profile of microvascular disease in type 2 diabetes in a tertiary health care hospital in India[J]. Ann Med Health Sci Res,2012,2(2):103-108.
[8] Ceriello A,Kilpatrick E S. Glycemic variability:both sides of the story[J]. Diabetes Care, 2013, 36(Supplement 2):S272-S275.
[9]刘桠,康健,高泓.从“脾胰同源”论血糖波动的中医辨治思路[J].辽宁中医杂志,2015,42(7):1246-1247.
[10]岳仁宋,陈源,王帅,等.试论助脾散精法治疗糖尿病[J].新中医,2011,43(2):155-156.
[11]庞洁,高怀林,王宏涛,等.津力达对糖尿病大鼠血糖调节激素及胰岛细胞功能干预作用研究[J].中国中医基础医学杂志,2014,20(5):605-607,648.
[12]庞洁,梁俊清,王志鑫,等.津力达联合通心络对高糖诱导胰岛微血管内皮细胞损伤干预作用及机制研究[J].中国药理学通报,2015,31(3):430-435.
[13]富晓旭.养阴益气活血法阻断糖尿病GK大鼠“代谢记忆”的分子机制探索[D].成都:成都中医药大学,2016.
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[15] Richards O C,Raines S M,Attie A D. The role of blood vessels,endothelial cells,and vascular pericytes in insulin secretion and peripheral insulin action[J].Endocr Rev,2010,31(3):343-363.
[16] WU L, Olverling A, Fransson L, et al. Early intervention with liraglutide improves glucose tolerance without affecting islet microcirculation in young GotoKakizaki rats[J]. Regul Peptides,2012,177(1/3):92-96.
[17] Iwase M,Nakamura U,Uchizono Y,et al. Nateglinide,a non-sulfonylurea rapid insulin secretagogue,increases pancreatic islet blood flow in rats[J]. Eur J Pharmacol,2005,518(2/3):243-250.
[18] LIU M,ZHANG X,LI A,et al. Insulin treatment restores islet microvascular vasomotion function in diabetic mice[J]. J Diabetes,2016,15(2):117-134.
[19] Leung P S. Mechanisms of protective effects induced by blockade of the rennin-angiotensin system:novel role of the pancreatic islet angiotensin-generating system in Type 2 diabetes[J]. Diabetic Med,2007,24(2):110-116.
[20] Olverling A,HUANG Z,Nystr9m T,et al. Acute regulation of pancreatic islet microcirculation and glycaemia by telmisartan and ramipril:discordant effects between normal and type 2 diabetic rats[J]. Clin Sci,2013,125(9):433-438.
[21] LAN K C,CHIU C Y,KAO C W,et al. Advanced glycation end-products induce apoptosis in pancreatic islet endothelial cells via NF-κB-activated cyclooxygenase-2/prostaglandin E2 up-regulation[J].PLo S One,2015,10(4):e0124418.
[22] Leung P S. Current research of the RAS in diabetes mellitus[M]. The Renin-Angiotensin System:Current Research Progress in The Pancreas. Springer Netherlands,2010:131-153.
[23] LIU Q F,ZHANG L X,GONG L,et al. Glucagon-like peptide 1 protects microvascular endothelial cells by inactivating the PARP-1/i NOS/NO pathway[J]. Mol Cell Endocrinol,2011,339(1):25-33.
[24] YAN F,ZHANG G,FENG M,et al. Glucagon-like peptide 1 protects against hyperglycemic-induced endothelial-to-mesenchymal transition and improves myocardial dysfunction by suppressing poly(ADPribose)polymerase 1 activity[J]. Mol Med,2015,21(1):15-25.
[25] ZHANG Z,YANG L,LEI L,et al. Glucagon-like peptide-1 attenuates advanced oxidation protein productmediated damage in islet microvascular endothelial cells partly through the RAGE pathway[J]. Int J Mol Med,2016,38(4):1161-1169.
[26] SUN L,WANG C,DAI Y,et al. Coumaglutide,a novel long-acting GLP-1 analog,inhibitsβ-cell apoptosis in vitro and invokes sustained glycemic control in vivo[J]. Eur J Pharmacol,2015,767(11):211-219.
[27] Prentki M,Roduit R,Susini S,et al. GLP-1 promotes DNA synthesis,activates PI3-kinase and increases PDX-1 DNA binding activity in beta(INS-1)-cells[J].Diabetologia,1999,42(8):856-864.
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