臺灣博碩士論文加值系統

敗血症(sepsis)在發生早期即可觀察到葡萄糖代謝異常的現象，其原因為體內受到壓力所引起的激素分泌改變，促進體內分解作用而使得葡萄糖釋出血中並造成主要作用器官－骨骼肌的胰島素訊號受阻，無法活化下游葡萄糖轉運蛋白4 (GLUT4)，降低葡萄糖攝取；另一方面，骨骼肌中的肝醣分解增加，加劇了高血糖(hyperglycemia)的情形。研究指出，敗血症併發高血糖程度越嚴重會造成病情惡化與死亡率的提升。雌激素(estrogen)在許多疾病上皆扮演著保護的作用，且能降低胰島素阻抗並參與維持體內葡萄糖的恆定，而敗血症中亦可發現女性存活率高於男性。我們以盲腸結紮與穿刺術(cecal ligation and puncture，CLP)誘發大鼠敗血症，導致體內高血糖和骨骼肌胰島素阻抗現象，探討敗血症早期所引發的高血糖程度是否有性別差異？並探討此差異性的可能原因。另一方面，雌激素又會透過何種調控機制，穩定敗血症早期所導致的葡萄糖代謝異常？由實驗結果顯示，不同性別的大鼠在敗血症誘發後約3小時均有高血糖現象發生，其中雄鼠血糖又顯著高於雌鼠血糖，且雌激素可以有效降低敗血症早期的高血糖現象。進而觀察CLP後3小時體內腎上腺素(epinephrine)和腎上腺皮質醇(cortisol)在血中的濃度，發現在敗血症雄鼠與雌鼠的這些反向調控激素(counter-regulatory hormone)在體內分泌量大幅增加，且增加程度相似，而雌激素對其分泌量並無顯著影響。另外以[3H]-2-deoxyglucose檢測胰島素刺激後骨骼肌對血中葡萄糖攝取的情形，發現雄鼠骨骼肌的胰島素敏感度(insulin sensitivity)明顯低於雌鼠，而雌激素可有效降低敗血症早期所引起的胰島素阻抗，並能夠顯著增加雄鼠CLP後骨骼肌中的肝醣含量。這些實驗結果顯示，在敗血症早期雄鼠體內產生的胰島素阻抗現象較雌鼠嚴重，導致骨骼肌無法正常攝取循環血中的葡萄糖，同時骨骼肌中的肝醣消耗量也較雌鼠為高，故使得雄鼠體內的高血糖現象較雌鼠嚴重，而此結果也可能與死亡率上的性別差異雄鼠高過雌鼠相關；給予補充雌激素治療可增加骨骼肌對胰島素的敏感度，並提高肝醣含量，降低敗血症早期的高血糖程度。

The initial abnormality of glucose metabolic response during sepsis can be affected by the counter-regulatory hormones (i.e., catecholamines and cortisol) increase. Hyperglycemia and insulin resistance in skeletal muscle occurred. Studies have shown that sepsis-induced stress hyperglycemia is an important risk marker of morbidity and mortality. Estradiol (E2) plays a protective role in sepsis and it regulates insulin actions and maintains glucose homeostasis. We had also found that the survival rate of females is better than males during sepsis. Sepsis was induced in Sprague-Dawley rats of both genders by cecal ligation and puncture (CLP). We found that CLP-induced hyperglycemia in all animals at 3 hours later and it was severer in males than females. E2 administration (10mg/kg, i.p.) reduced the level of blood glucose. In order to investigate the mechanisms of hyperglycemia and potential effects of E2, we than explored the gender difference and E2 effect on glucose uptake and glycogen storage in skeletal muscle during early-phase sepsis. We measured the blood concentrations of epinephrine and cortisol, and found that the two counter- regulatory hormones were sharply increased by CLP but E2 did not reverse it. We next assessed insulin-stimulated glucose uptake in skeletal muscle during early sepsis, and the results showed that insulin sensitivity (EC50) of [3H]-2-deoxyglucose (2-DG) uptake was reduced in both extensor digitorum longus (EDL) muscle and soleus (SOL) muscle from male rats and was significantly worse than female rats. Glycogen content was diminished in skeletal muscle of male rats only at 3 hour post-CLP. E2 administration to male rats could improve these CLP-induced defects except epinephrine and cortisol. In view of these findings, we infer that early sepsis-induced insulin resistance in male rats is more serious than female rats, and result in aberrant glucose uptake in skeletal muscle, expediting muscle glycogen break down. Taken together, these changes caused higher blood glucose level in males than females, and similar pattern was also observed for mortality. E2 treatment also appeared to ameliorate the disturbance of glucose metabolism and to reduce the mortality of sepsis.

目錄

指導教授推薦書
口試委員會審定書
授權書...................................................iii
誌謝......................................................iv
中文摘要...................................................vi
英文摘要.................................................viii
第一章．緒論
1.1敗血症(sepsis) .........................................1
1.2敗血症對葡萄糖代謝的影響...................................2
1.3敗血症造成骨骼肌對胰島素的阻抗性(insulin resistance)........3
1.4敗血症之性別差異(gender difference).......................5
1.5雌激素對體內葡萄糖代謝的恆定作用(homeostasis)...............6
1.6雌激素受體(estrogen receptor，ER)對葡萄糖代謝的調節作用.....8
第二章．研究目的與假說......................................10
第三章．研究材料與方法
3.1 實驗材料
3.1.1 實驗動物.............................................11
3.1.2 實驗藥品與試劑.......................................11
3.1.3 實驗儀器.............................................12
3.2 實驗方法
3.2.1 實驗動物模式.........................................13
3.2.2 實驗動物分組.........................................14
3.2.3 母鼠動情週期(estrus cycle)的觀察......................15
3.2.4 生化值檢測...........................................15
3.2.5 骨骼肌中肝醣(glycogen)含量之分析......................18
3.2.6 血漿中胰島素(insulin)濃度之分析.......................18
3.2.7 血漿中雌二醇(estradiol)濃度之分析.....................19
3.2.8 血漿中腎上腺素(epinephrine)濃度之分析..................19
3.2.9 血漿中腎上腺皮質醇(cortisol)濃度之分析.................20
3.2.10 骨骼肌對胰島素刺激後葡萄糖攝取能力之分析................21
3.2.11 統計分析............................................22
第四章．實驗結果
4.1比較雄鼠與雌鼠在各時間點的存活率(Survival rate)............23
4.2 CLP對雄鼠與雌鼠生化參數之影響及雌激素的調控作用
4.2.1 肝功能損傷情形.......................................23
4.2.2 腎功能損傷情形.......................................23
4.3 CLP對雄鼠與雌鼠體內代謝之影響及雌激素的調控作用
4.3.1 脂質代謝情形.........................................24
4.3.2 葡萄糖代謝情形.......................................24
4.4 CLP對公鼠與母鼠血中雌二醇(estradiol，E2)濃度之影響........26
4.5 CLP對公鼠與母鼠血漿中反向調控激素(counter-regulatory hormone)濃度之影響及雌激素的調控作用.........................26
4.6 CLP影響雄鼠與雌鼠骨骼肌對胰島素刺激所引發的葡萄糖攝取反應及雌激素的調控作用
4.6.1CLP影響比目魚肌(SOL)對胰島素的敏感性及雌激素的調控作用....27
4.6.2CLP影響伸趾長肌(EDL)對胰島素的敏感性及雌激素的調控作用....29
第五章．討論
5.1 敗血症早期高血糖對大鼠死亡率的影響及雌激素的調控作用........31
5.2敗血症早期對大鼠體內反向調控激素的影響及雌激素的調控作用......33
5.3 敗血症早期對骨骼肌胰島素阻抗的影響及雌激素的調控作用........35
5.4 敗血症早期對骨骼肌中肝醣含量的影響及雌激素的調控作用........37
5.5 敗血症早期對雌激素濃度的影響.............................40
第六章．結論................... ...........................42
參考文獻...................................................62


圖表目錄

表一．雄鼠與雌鼠手術後SHAM組與CLP組在各個時間點(3、6、9、15小時)的存活率....................................................44
圖一．CLP早期對雄鼠與雌鼠血漿中天門冬胺酸轉胺酶(AST)濃度之影響..45
圖二．CLP早期與晚期對雄鼠與雌鼠血漿中丙胺酸轉胺酶(ALT)濃度之影響........................................................46
圖三．CLP早期對雄鼠與雌鼠血漿中尿素濃度之影響..................47
圖四．CLP早期對雄鼠與雌鼠血漿中肌酸酐濃度之影響................48
圖五．CLP早期對雄鼠與雌鼠血漿中膽固醇濃度之影響................49
圖六．CLP早期對雄鼠與雌鼠血漿中三酸甘油脂濃度之影響.............50
圖七．雌激素對CLP早期雄鼠與雌鼠血漿中葡萄糖濃度之影響...........51
圖八．雌激素對CLP早期雄鼠與雌鼠血漿中乳酸濃度之影響.............52
圖九．雌激素對CLP早期雄鼠與雌鼠骨骼肌中肝醣含量之影響...........53
圖十．CLP早期對雄鼠與雌鼠血漿中胰島素濃度之影響................54
圖十一．CLP早期對雄鼠與雌鼠血漿中雌二醇濃度之影響..............55
圖十二．雌激素對CLP早期雄鼠與雌鼠血漿中腎上腺素(epinephrine)濃度之影響......................................................56
圖十三．雌激素對CLP早期雄鼠與雌鼠血漿中腎上腺皮質醇(cortisol)濃度之影響....................................................57
圖十四．雌激素對CLP早期雄鼠與雌鼠比目魚肌(SOL)在不同濃度胰島素刺激所引起的葡萄糖攝取反應之影響.................................58
表二．CLP早期雄鼠與雌鼠比目魚肌(SOL)在給予不同濃度胰島素刺激後，引起50%葡萄糖最大攝取反應所需之胰島素濃度(EC50) 、最大的反應速率(Vmax)，以及雌激素對二者之影響...............................59
圖十五．雌激素對CLP早期雄鼠與雌鼠伸趾長肌(EDL)在不同濃度胰島素刺激所引起的葡萄糖攝取反應之影響.................................60
表三．CLP早期雄鼠與雌鼠伸趾長肌(EDL)在給予不同濃度胰島素刺激後，引起50%葡萄糖最大攝取反應所需之胰島素濃度(EC50) 、最大的反應速率(Vmax)，以及雌激素對二者之影響...............................61

【1】 Martin GS, Mannino DM, Eaton S, Moss M. (2003) The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 17;348(16):1546-1554.
【2】 Hunter P. (2006) Sepsis under siege: a new understanding of sepsis might lead to the development of therapies to treat septic shock. EMBO Rep. 7(7):667-669.
【3】 Cohen J. (2002) The immunopathogenesis of sepsis. Nature 420(6917):885-891.
【4】 Rangel-Frausto MS. (2005) Sepsis: still going strong. Arch Med Res. 36(6):672-681.
【5】 Cunneen J, Cartwright M. (2004) The puzzle of sepsis: fitting the pieces of the inflammatory response with treatment. AACN Clin Issues. 15(1):18-44.
【6】 Chambrier C, Laville M, Rhzioual Berrada K, Odeon M, Boulétreau P, Beylot M. (2000) Insulin sensitivity of glucose and fat metabolism in severe sepsis. Clin Sci (Lond). 99(4):321-328.
【7】 Maitra SR, Wojnar MM, Lang CH. (2000) Alterations in tissue glucose uptake during the hyperglycemic and hypoglycemic phases of sepsis. Shock 13(5):379-385.
【8】 Leonidou L, Mouzaki A, Michalaki M, DeLastic AL, Kyriazopoulou V, Bassaris HP, Gogos CA. (2007) Cytokine production and hospital mortality in patients with sepsis-induced stress hyperglycemia. J Infect. 55(4):340-346.
【9】 Falciglia M. (2007) Causes and consequences of hyperglycemia in critical illness. Curr Opin Clin Nutr Metab Care. 10(4):498-503.
【10】 Andersen SK, Gjedsted J, Christiansen C, Tønnesen E. (2004) The roles of insulin and hyperglycemia in sepsis pathogenesis. J Leukoc Biol. 75(3):413-421.
【11】 Van Den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. (2001) Intensive insulin therapy in the critically ill patients. N Engl J Med. 345(19):1359-1367.
【12】 Träger K, DeBacker D, Radermacher P. (2003) Metabolic alterations in sepsis and vasoactive drug-related metabolic effects. Curr Opin Crit Care. 9(4):271-278.
【13】 van den Berghe G. (2000) Novel insights into the neuroendocrinology of critical illness. Eur J Endocrinol. 143(1):1-13.
【14】 Angerås U, Hall-Angerås M, Wagner KR, James H, Hasselgren PO, Fischer JE. (1991) Tissue metabolite levels in different types of skeletal muscle during sepsis. Metabolism. 40(11):1147-1151.
【15】 Lang CH, Dobrescu C, Meszaros K. (1990) Insulin-mediated glucose uptake by individual tissues during sepsis Metabolism. 39(10):1096-1107.
【16】 Hsieh YC, Frink M, Choudhry MA, Bland KI, Chaudry IH. (2007) Metabolic modulators following trauma sepsis: sex hormones. Crit Care Med. 35(9 Suppl):S621-629.
【17】 Lange MP, Dahn MS, Jacobs LA. (1985) The significance of hyperglycemia after injury. Heart Lung. 14(5):470-472.
【18】 Watson RT, Pessin JE. (2007) GLUT4 translocation: the last 200 nanometers. Cell Signal. 19(11):2209-2217.
【19】 Huang S, Czech MP. (2007) The GLUT4 glucose transporter. Cell Metab. 5(4):237-252.
【20】 Dugani CB, Klip A. (2005) Glucose transporter 4: cycling, compartments and controversies. EMBO Rep. 6(12):1137-1142.
【21】 Saltiel AR, Kahn CR. (2001) Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414(6865):799-806.
【22】 Barreiro GC, Prattali RR, Caliseo CT, Fugiwara FY, Ueno M, Prada PO, Velloso LA, Saad MJ, Carvalheira JB. (2004) Aspirin inhibits serine phosphorylation of IRS-1 in muscle and adipose tissue of septic rats. Biochem Biophys Res Commun. 320(3):992-997.
【23】 del Aguila LF, Claffey KP, Kirwan JP. (1999) TNF-alpha impairs insulin signaling and insulin stimulation of glucose uptake in C2C12 muscle cells. Am J Physiol. 276(5 Pt 1):E849-855.
【24】 Oberholzer A, Keel M, Zellweger R, Steckholzer U, Trentz O, Ertel W. (2000) Incidence of septic complications and multiple organ failure in severely injured patients is sex specific. J Trauma. 48(5):932-937.
【25】 Offner PJ, Moore EE, Biffl WL. (1999) Male gender is a risk factor for major infections after surgery. Arch Surg. 134(9):935-938.
【26】 Gannon CJ, Pasquale M, Tracy JK, McCarter RJ, Napolitano LM. (2004) Male gender is associated with increased risk for postinjury pneumonia. Shock 21(5):410-414.
【27】 Schröder J, Kahlke V, Staubach KH, Zabel P, Stüber F. (1998) Gender differences in human sepsis. Arch Surg. 133(11):1200-1205.
【28】 Zellweger R, Wichmann MW, Ayala A, Stein S, DeMaso CM, Chaudry IH. (1997) Females in proestrus state maintain splenic immune functions and tolerate sepsis better than males. Crit Care Med. 25(1):106-110.
【29】 Altura BM. (1976) Sex and estrogens in protection against circulatory stress reactions. Am J Physiol. 231(3):842-847.
【30】 Choudhry MA, Bland KI, Chaudry IH. (2007) Trauma and immune response--effect of gender differences. Injury. 38(12):1382-1391.
【31】 Kuebler JF, Jarrar D, Toth B, Bland KI, Rue L 3rd, Wang P, Chaudry IH. (2002) Estradiol administration improves splanchnic perfusion following trauma-hemorrhage and sepsis. Arch Surg. 137(1):74-79.
【32】 Mostafa G, Huynh T, Sing RF, Miles WS, Norton HJ, Thomason MH. (2002) Gender-related outcomes in trauma. J Trauma. 53(3):430-434.
【33】 Wohltmann CD, Franklin GA, Boaz PW, Luchette FA, Kearney PA, Richardson JD, Spain DA. (2001) A multicenter evaluation of whether gender dimorphism affects survival after trauma. Am J Surg. 181(4):297-300.
【34】 Merkel SM, Alexander S, Zufall E, Oliver JD, Huet-Hudson YM. (2001) Essential role for estrogen in protection against Vibrio vulnificus-induced endotoxic shock. Infect Immun. 69(10):6119-6122.
【35】 Wismann J, Willoughby D. (2006) Gender differences in carbohydrate metabolism and carbohydrate loading. J Int Soc Sports Nutr. 5(3):28-34.
【36】 Blaak E. (2001) Gender differences in fat metabolism. Curr Opin Clin Nutr Metab Care. 4(6):499-502.
【37】 May AK, Dossett LA, Norris PR, Hansen EN, Dorsett RC, Popovsky KA, Sawyer RG. (2008) Estradiol is associated with mortality in critically ill trauma and surgical patients. Crit Care Med. 36(1):62-68.
【38】 Chisari AN, Gaillard RC, Giovambattista A, Voirol M-J, Piermaria J, Spinedi E. (2000) Sexual dimorphism in the hypothalamo-pituitary-adrenal (HPA) axis and TNFalpha responses to phospholipase A2-related neurotoxin (from crotalus durissus terrifcus) challenge. J Endocrinol Invest. 23(7):440-448.
【39】 Moreno M, Ordoñez P, Alonso A, Díaz F, Tolivia J, González C. (2009) Chronic 17beta-estradiol treatment improves skeletal muscle insulin signaling pathway components in insulin resistance associated with aging. Age Dordr. (in press)
【40】 Campbell SE, Febbraio MA. (2002) Effect of the ovarian hormones on GLUT4 expression and contraction-stimulated glucose uptake. Am J Physiol Endocrinol Metab. 282(5):E1139-1146.
【41】 Simpson ER, Mahendroo MS, Means GD, Kilgore MW, Hinshelwood MM, Graham-Lorence S, Amarneh B, Ito Y, Fisher CR, Michael MD, et al. (1994) Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocr Rev. 15(3):342-355.
【42】 Takeda K, Toda K, Saibara T, Nakagawa M, Saika K, Onishi T, Sugiura T, Shizuta Y. (2003) Progressive development of insulin resistance phenotype in male mice with complete aromatase (CYP19) deficiency. J Endocrinol. 176(2):237-246.
【43】 Gonzalez CG, Garcia FD, Fernandez SF, Patterson AM. (1997) Role of 17-beta-estradiol and progesterone on glucose homeostasis: effects of food restriction (50%) in pregnant and non pregnant rats. J Endocrinol Invest. 20(7):397-403
【44】 Hsieh YC, Choudhry MA, Yu HP, Shimizu T, Yang S, Suzuki T, Chen J, Bland KI, Chaudry IH. (2006) Inhibition of cardiac PGC-1alpha expression abolishes ERbeta agonist-mediated cardioprotection following trauma-hemorrhage. FASEB J. 20(8):1109-1117.
【45】 Hsieh YC, Yu HP, Suzuki T, Choudhry MA, Schwacha MG, Bland KI, Chaudry IH. (2006) Upregulation of mitochondrial respiratory complex IV by estrogen receptor-beta is critical for inhibiting mitochondrial apoptotic signaling and restoring cardiac functions following trauma-hemorrhage. J Mol Cell Cardiol. 41(3):511-521.
【46】 Jarrar D, Wang P, Knoferl MW, Kuebler JF, Cioffi WG, Bland KI, Chaudry IH. (2000) Insight into the mechanism by which estradiol improves organ functions after trauma-hemorrhage. Surgery 128(2):246-252.
【47】 Kuiper GG, Carlsson B, Grandien K, Enmark E, Häggblad J, Nilsson S, Gustafsson JA. (1997) Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 138(3):863-870.
【48】 Barros RP, Machado UF, Warner M, Gustafsson JA. (2006) Muscle GLUT4 regulation by estrogen receptors ERbeta and ERalpha. Proc Natl Acad Sci U S A. 103(5):1605-1608.
【49】 Barros RP, Machado UF, Gustafsson JA. (2006) Estrogen receptors: new players in diabetes mellitus. Trends Mol Med. 12(9):425-431.
【50】 Bryzgalova G, Gao H, Ahren B, Zierath JR, Galuska D, Steiler TL, Dahlman-Wright K, Nilsson S, Gustafsson JA, Efendic S, Khan A. (2006) Evidence that oestrogen receptor-alpha plays an important role in the regulation of glucose homeostasis in mice: insulin sensitivity in the liver. Diabetologia 49(3):588-597.
【51】 Umpierrez GE, Isaacs SD, Bazargan N, You X, Thaler LM, Kitabchi AE. (2002) Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab. 87(3):978-982.
【52】 Henderson WR, Chittock DR, Dhingra VK, Ronco JJ. (2006) Hyperglycemia in acutely ill emergency patients--cause or effect? CJEM. 8(5):339-343.
【53】 McMahon CD, Elsasser TH, Gunter DR, Sanders LG, Steele BP, Sartin JL. (1998) Estradiol/progesterone implants increase food intake, reduce hyperglycemia and increase insulin resistance in endotoxic steers. J Endocrinol. 159(3):469-478.
【54】 Tracey KJ, Cerami A. (1990) Metabolic responses to cachectin/TNF. A brief review. Ann N Y Acad Sci.587:325-331.
【55】 Levy B. (2006) Lactate and shock state: the metabolic view. Curr Opin Crit Care. 12(4):315-321.
【56】 Buczkowska EO. (2002) Alterations of blood glucose homeostasis during septic or injury stress—hyperglycemia. Wiad Lek. 55(11-12):731-744.
【57】 Pyle A, Ibbett IM, Gordon C, Keers SM, Walker M, Chinnery PF, Baudouin SV. (2009) A common UCP2 polymorphism predisposes to stress hyperglycaemia in severe sepsis. J Med Genet. (in press)
【58】 Leonidou L, Michalaki M, Leonardou A, Polyzogopoulou E, Fouka K, Gerolymos M, Leonardos P, Psirogiannis A, Kyriazopoulou V, Gogos CA. (2008) Stress-induced hyperglycemia in patients with severe sepsis: a compromising factor for survival. Am J Med Sci. 336(6):467-471.
【59】 Heuer JG, Sharma GR, Zhang T, Ding C, Bailey DL, Stephens EJ, Holmes KC, Grubbs RL, Fynboe KA, Chen YF, Jakubowski JA. (2006) Effects of hyperglycemia and insulin therapy on outcome in a hyperglycemic septic model of critical illness. J Trauma. 60(4):865-872.
【60】 Croner RS, Hoerer E, Kulu Y, Hackert T, Gebhard MM, Herfarth C, Klar E. (2006) Hepatic platelet and leukocyte adherence during endotoxemia. Crit Care. 10(1):R15.
【61】 Van den Berghe G. (2000) Novel insights into the neuroendocrinology of critical illness. Eur J Endocrinol. 143(1):1-13.
【62】 Bessey PQ, Watters JM, Aoki TT, Wilmore DW. (1984) Combined hormonal infusion simulates the metabolic response to injury. Ann Surg. 200(3):264-281.
【63】 Norbury WB, Jeschke MG, Herndon DN. (2007) Metabolism modulators in sepsis: propranolol. Crit Care Med. 35(9 Suppl):S616-620.
【64】 Steven G. Ball. Metabolic and Endocrine Changes in Sepsis and the Catabolic State. Competency-Based Critical Care. (in press)
【65】 Angstwurm MW, Gaertner R, Schopohl J. (2005) Outcome in elderly patients with severe infection is influenced by sex hormones but not gender. Crit Care Med. 33(12):2786-2793.
【66】 Stump CS, Henriksen EJ, Wei Y, Sowers JR. (2006) The metabolic syndrome: role of skeletal muscle metabolism. Ann Med. 38(6):389-402.
【67】 Baron AD, Laakso M, Brechtel G, Edelman SV. (1991) Reduced capacity and affinity of skeletal muscle for insulin-mediated glucose uptake in noninsulin-dependent diabetic subjects. Effects of insulin therapy. J Clin Invest. 87(4):1186-1194.
【68】 Baron AD, Brechtel G, Wallace P, Edelman SV. (1988) Rates and tissue sites of non-insulin- and insulin-mediated glucose uptake in humans. Am J Physiol. 255(6 Pt 1):E769-774.
【69】 Mizock BA. (1995) Alterations in carbohydrate metabolism during stress: a review of the literature. Am J Med. 98(1):75-84.
【70】 T. J. Horton, E. C. Gayles, P. A. Prach, T. A. Koppenhafer and M. J. Pagliassotti. (1997) Female rats do not develop sucrose-induced insulin resistance. Am J Physiol Regul Integr Comp Physiol. 272: R1571-R1576.
【71】 Riant E, Waget A, Cogo H, Arnal JF, Burcelin R, Gourdy P. (2009) Estrogens protect against high-fat diet-induced insulin resistance and glucose intolerance in mice. Endocrinology. 150(5):2109-2117.
【72】 Cristina Pacheco M, Miles L, Bove KE. (2007) False negative histochemical reaction for myophosphorylase activity in fulminant sepsis due to methicillin resistant Staphylococcus aureus. Neuromuscul Disord. 17(11-12):983-985.
【73】 Virkamaki A, Yki-Jarvinen H. (1994) Mechanisms of insulin resistance during acute endotoxemia Endocrinology. 134(5):2072-2078.
【74】 Bellomo R, Ronco C. (1999) The pathogenesis of lactic acidosis in sepsis. Curr Opin Crit Care. 5:452–457.
【75】 Mizock BA, Falk JL. (1992) Lactic acidosis in critical illness. Crit Care Med. 20(1):80-93.
【76】 Hsu JT, Kan WH, Hsieh CH, Choudhry MA, Bland KI, Chaudry IH. (2009) Role of extracellular signal-regulated protein kinase (ERK) in 17beta-estradiol-mediated attenuation of lung injury after trauma-hemorrhage. Surgery. 145(2):226-234.
【77】 De Backer D. (2003) Lactic acidosis. Minerva Anestesiol. 69(4):281-284.
【78】 Bakker J, Gris P, Coffernils M, Kahn RJ, Vincent JL. (1996) Serial blood lactate levels can predict the development of multiple organ failure following septic shock. Am J Surg. 171(2):221-226.
【79】 Hubacek JA, Stuber F, Frohlich D, Book M, Wetegrove S, Ritter M, Rothe G, Schmitz G. (2001) Gene variants of the bactericidal/permeability increasing protein and lipopolysaccharide binding protein in sepsis patients: gender-specific genetic predisposition to sepsis. Crit Care Med. 29(3):557-561.
【80】 Zellweger R, Wichmann MW, Ayala A, Stein S, DeMaso CM, Chaudry IH. (1997) Females in proestrus state maintain splenic immune functions and tolerate sepsis better than males. Crit Care Med. 25(1):106-110.
【81】 Fourrier F, Jallot A, Leclerc L, Jourdain M, Racadot A, Chagnon JL, Rime A, Chopin C. (1994) Sex steroid hormones in circulatory shock, sepsis syndrome, and septic shock. Circ Shock. 43(4):171-178.
【82】 Christeff N, Benassayag C, Carli-Vielle C, Carli A, Nunez EA. (1988) Elevated oestrogen and reduced testosterone levels in the serum of male septic shock patients. J Steroid Biochem. 29(4):435-440.
【83】 Gonzalez CG, Garcia FD, Fernandez SF, Patterson AM. (1997) Role of 17-beta-estradiol and progesterone on glucose homeostasis: effects of food restriction (50%) in pregnant and non pregnant rats. J Endocrinol Invest. 20(7):397-403.
【84】 Chisari AN, Gaillard RC, Giovambattista A, Voirol M-J, Piermaria J, Spinedi E. (2000) Sexual dimorphism in the hypothalamo-pituitary-adrenal (HPA) axis and TNFalpha responses to phospholipase A2-related neurotoxin (from crotalus durissus terrifcus) challenge. J Endocrinol Invest. 23(7):440-448.
【85】 Speyer CL, Rancilio NJ, McClintock SD, Crawford JD, Gao H, Sarma JV, Ward PA. (2005) Regulatory effects of estrogen on acute lung inflammation in mice. Am J Physiol Cell Physiol. 288(4):C881-890.
【86】 Hsieh YC, Frink M, Thobe BM, Hsu JT, Choudhry MA, Schwacha MG, Bland KI, Chaudry IH. (2007) 17Beta-estradiol downregulates Kupffer cell TLR4-dependent p38 MAPK pathway and normalizes inflammatory cytokine production following trauma-hemorrhage. Mol Immunol. 44(9):2165-2172.