足部的病變是糖尿病患者常見的併發症之一，伴隨產生足部的潰瘍、感染以至於截肢是造成患者嚴重失能，甚至死亡的重要因素；也使得社會及醫療成本付出龐大的支出。糖尿病合併周邊神經病變及血流的異常使得患者足部容易受到機械性刺激的傷害，而後足部產生潰瘍對於將來引起足以威脅生命的肢體併發症扮演重要的角色。本篇的研究目的是要來評估具有不同交感神經病變嚴重度的初期糖尿病患足部是否有血流檢測異常的現象；另一方面結合神經生理的診斷技術，來評估這些不同診斷方法之間的關聯性。藉以探討這些血流改變的現象是否和神經生理檢查的結果以及病患的物理檢查特性存在有相關，以及研究這些變化背後所代表的生理意義。本研究使用雷射都卜勒儀檢查足部微血管的灌流量，將血流生理訊號數位化再作頻譜分析；並比對具有不同程度足部病變的糖尿病人血流訊號頻率的特異性，預計選擇68位糖尿病患者及25位年齡符合的對照組。糖尿病患者包括18人足部有經常復發性的破皮或有潰瘍的病史，再經交感神經反應檢查，依據反應的有或無，將其餘病患再分為兩組。23人沒有反應，27人保有四肢的交感皮膚反應。我們主要針對0.0095 to 0.145 Hz 這個頻率區間的訊號在時域及頻域下進行訊號的強度分析，探討周邊血液循環的調控機制。訊號的振幅越大相對於振幅越小者表示微血管血流的灌流壓力越強。再將整個頻率帶經由小波轉換後劃分為三個區間：0.0095 to 0.021 Hz 頻譜強度反應了血管內皮的活性； 0.021-0.052 Hz頻率帶強度反應了神經末稍纖維的活性；0.052-0.145 Hz頻率帶強度反應了血管壁平滑肌纖維的活性。就0.0095 to 0.145 Hz整個頻率帶各組之間平均強度的比較，基本上是隨著神經病變的嚴重程度而逐漸降低，表示造成相對灌流壓力減弱的現象。但是只有在有足部病史的at-risk組出現統計學上顯著的差異，而由傳統的物理檢查及神經傳導檢查都顯示在at-risk的這一組有較嚴重的體神經受到影響。但是如果就三個區間頻率帶分別來比較各組之間平均強度的差異；神經末稍纖維的活性在有神經病變的病人SSR-組別會有早期降低的現象；而血管內皮的活性也是只有在at-risk的這一組會出現強度的減弱。而血管壁平滑肌纖維的活性，在本實驗的受試者組間比較並沒有顯著的降低，而第二組有神經病變(SSR-)的病人相較於沒有神經病變(SSR+)之第三組其平滑肌纖維的相對活性平均強度反而出現顯著的增加的現象，在這裡推論平滑肌纖維的活性強度增加，某種程度代償了在有神經病變的病人組別神經末稍纖維的活性降低的現象，所以最終發現有神經病變(SSR-)的病人組別整個頻率帶平均強度並沒有顯著的減少。藉由比對具有不同程度足部病變的糖尿病人血流訊號頻率的特異性，來分析包括血管壁平滑肌、神經末稍纖維以及血管內皮活性三種微循環調控機制在有初期交感神經病變的糖尿病病人會有早期變化的現象，期能更定量化的分析糖尿病患初期微血管病變的病理生理機轉，而有助於是否可在早期以生理或藥理方式介入足部初期病變的治療進而改變修補這些微循環的調控機制。另一方面驗證目前臨床常用神經生理的診斷技術和微循環的調控之間的臨床相關性，藉以研究這些微血管的灌流量改變的現象和神經生理檢查的結果以及病患的物理檢查特性存在有相關，以及探討這些現象背後所代表的生理意義，作為將來預防治療糖尿病患發展成更嚴重足部問題及將來可以作進一步研究的參考。

Foot problems have been recognized as frequent complications of diabetes mellitus. The subsequent foot ulcers and amputations result in increased morbidity, medical costs and disability for people with diabetes. Impaired cutaneous blood flow and sweating dysfunction might be among the earliest manifestations of
diabetic autonomic neuropathy. This study assessed the pathophysiological basis underlying skin vasomotion changes and their relation with progressive sudomotor dysfunction and other autonomic and somatic measures in subclinical diabetic feet. Laser Doppler skin perfusion was assessed on 68 diabetic and 25 control subjects. The low-frequency vasomotion was transformed into three frequency intervals 0.0095–0.021, 0.021–0.052 and 0.052–0.145 Hz, respectively, for the investigation of endothelial, neurogenic and myogenic effects on microcirculatory alterations. The diabetic patients were categorized into three groups by increasing severity of sudomotor dysfunction: SSR+ (sympathetic skin response present; 27 patients), SSR− (SSR absent; 23 patients) and at-risk (SSR absent and of preulcerative cracked skin; 18 patients). All diabetic patients underwent nerve conduction and cardiovascular autonomic studies. The total spectral and endothelial activity was significantly decreased only in the at-risk group. The SSR− group had lower neurogenic vasomotion than the SSR+ group (pb0.05). Although no statistical difference was noted between any group in absolute myogenic spectrum, the SSR−group had higher normalized myogenic activity than the SSR+ group (pb0.01). The larger drop in orthostatic pressure was paralleled by a reduction in the myogenic amplitude (r=−0.33, pb0.01).
These results suggested that early impairment of low-frequency flow motion correlated closely with the presence of sudomotor dysfunction of subclinical feet mainly in neurogenic and endothelial components. Impaired systemic vascular tone as manifested by orthostatic hypotension was proportional to the degree of myogenic dysregulation in diabetic patients.

中文摘要 i
Abstract iv
目錄 vi
表目錄 vii
圖目錄 viii
第一章 前言 ……………………………………………………………1
1.1 研究背景及動機 …………………………………………………1
1.2 文獻回顧 …………………………………………………………3
1.3 研究目的 ………………………………………………………17
第二章 材料及方法 …………………………………………………18
第三章 結果 …………………………………………………………25
第四章 討論 …………………………………………………………33
第五章 結論 …………………………………………………………40
參考文獻 ………………………………………………………………42

1. 國民健康局九十九年年度報告。
2. 健保局年度報告，民國九十九年。
3. Lin T, Chou P, Tsai ST, Lee YC, Tai TY. Predicting factors associated with costs of diabetic patients in Taiwan. Diabetes Res Clin Pract 2004; 63: 119-125.
4. Sumpio BE. Foot ulcers. N Engl J Med. 2000; 343:787-793.
5. Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. JAMA 2005; 293: 217-228.
6. Wang CL, Wang M, Lin MC, Chien KL, Huang YC, Lee YT. Foot complications in people with diabetes: a community-based study in Taiwan. J Formos Med Assoc 2000; 99: 5-10.
7. Boulton A. Foot problems in patients with diabetes mellitus. In: Richard GH, Clive SC, eds. Textbook of diabetes, Oxford UK: Blackwell Science, 2010: 44.1-44.20.
8. Sun PC, Lin HD, Jao SH, Chan RC, Kao MJ, Cheng CK. Thermoregulatory sudomotor dysfunction and diabetic neuropathy develop in parallel in at-risk feet. Diabet Med 2008; 25: 413-418.
9. Pecoraro RE, Reiber GE, Burgess EM. Pathways to diabetic limb. Diabetes Care 2001; 24: 1273-1285
10. Uccioli L, Monticone G, Durola L, Russo F, Mormile F, Mennuni G, Menzinger G. Lower limb arterio-venous shunts, autonomic neuropathy and diabetic foot. Diabetes Res Clin Pract 1992; 16: 123-130.
11. 嘉義長庚醫院 整型外科主辦的的糖尿病足照顧研討會2010/11/27
12. Watkins PJ. The diabetic foot. BMJ. 2003; 326: 977-979.
13. Vinik Al, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diabetes Care 2003; 26:1553-1579.
14. Stefan Z, Frauke D, Marianne E, Martin P, Helmut S. Early detection of microcirculatory impairment in diabetic patients with foot at risk. Diabetes care 2001; 24: 1810-1814.
15. Brown MJ and Asbury AK. Diabetic Neuropathy. Ann Neurol 1984; 15: 2-12.
16. Spencer PS, Schanmburg HM. Classification of neurotoxic disease: A morphological approach. In spencer OS & Schaumburg HH eds. Experimental and Clinical Neurotoxicology. Baltimore, W & W, 92-99, 1980.
17. Greene DA, Latimer SA, Sima AF. Pathogenesis and prevention of diabetic neuropathy. Diabetes/Metab Rev. 1988; 4: 201-7.
18. Quattrini C, Harris ND, Malik RA, Tesfaye S. Impaired skin microvascular reactivity in painful diabetic neuropathy. Diabetes Care. 2007; 30: 655-9.
19. 財團法人糖尿病關懷基金會2005 年「糖尿病家族」
20. Greene DA, Latimer SA, Sima AAF. Sorbitol phosphoinositides and sodium potassium ATPase in the pathogenesis of diabetic complications. N Engl J Med 1987; 316: 599-607.
21. Sun PC, Jao SH, Lin HD, Chan RC, Chou CL, Wei SH. Improving preventive foot care for diabetic patients participating in group education. J Am Podiatr Med Assoc 2009; 99: 295-300.
22. Sun PC, Jao SH, Cheng CK. Assessing foot temperature using infrared thermography. Foot Ankle Int 2005; 26: 847-853.
23. Sun PC, Lin HD, Jao SH, Ku YC, Chan RC, Cheng CK. Relationship of skin temperature to sympathetic dysfunction in diabetic at-risk feet. Diabetes Res Clin Pract 2006; 73: 41-46.
24. Chen HS, Hwu CM, Kuo BI, Chiang SC, Kwok CF, Lee SH. Abnormal cardiovascular reflex tests are predictors of mortality in type 2 diabetes mellitus. Diabet Med 2001; 18: 268-273.
25. Bassirat M, Khalil Z. Short- and long-term modulation of microvascular responses in streptozotocin-induced diabetic rats by glycosylated products. J Diabetes Complications. 2010; 24: 64-72.
26. Jones TW. Discovery that veins of the bat’s wing are endowed with rhythmical contractility and that the onward flow of blood is accelerated by each contraction. Philos Trans R Soc (London) 1852; 142: 131-136.
27. Green AQ, Krishnan ST, Rayman G. C-fiber function assessed by the laser Doppler imager flare technique and acetylcholine iontophoresis. Muscle Nerve 2009; 40: 985-991.
28. Colantuoni A, Bertuglia S, Intaglietta M: Microvascular vasomotion : origin of laser Doppler flux motion. Int J Microcirc Clin Exp 1994; 14: 151-158.
29. Hilz MJ, Heeht MJ, Berghoff M, Singer W, Neundoerfer B: Abnormal vasoreaction to arousal stimuli — An early sign of diabetic sympathetic neuropathy demonstrated by laser Doppler flowmetry. J Clin Neurophysiol 2000; 17: 419-425.
30. Stansberry KB, Shapiro SA, Hill MA, McNitt PM, Meyer MD, Vinik AI. Impaired peripheral vasomotion in diabetes. Diabetes Care 1996; 19: 715 -721.
31. Tooke JE. Microvasculature in diabetes. Cardiovasc Res. 1996; 32: 764-771.
32. Meyer MF, Rose CJ, Hulsmann JO, Schatz H, Pfohl M. Impaired 0.1-Hz vasomotion assessed by laser Doppler anemometry as an early index of peripheral sympathetic neuropathy in diabetes. Microvasc Res 2003; 65: 88-95.
33. Bernardi L, Rossi M, Leuzzi S. Reduction of 0.1 Hz microcirculatory fluctuations as evidence of sympathetic dysfunction in insulin-dependent diabetes. Cardiovasc Res 1997; 34: 185-191.
34. Bernardi L, Rossi M. Fratino P, Finardi G, Mevio E, Orlandi C: Relationship between phasic changes in human skin blood flow and autonomic tone. Microvasc Res 1989; 37:16-27.
35. Benbow SJ, Pryce DW, Noblelt K, MacFarlane IA, Fnedmann PS, Williams CI. Flow motion in peripheral diabetic neuropathy. Clin Sci 1995; 88: 191-196.
36. Lefrandt JD, Bosma E. Oomen PH. Sympathetic mediated vasomotion and skin capillary permeability in diabetic patients with peripheral neuropathy. Diabetologia 2003; 46: 40-44.
37. Bracic M, Stefanovska A. Wavelet-based analysis of human blood flow dynamics. Bull Math Biol 1998; 60: 919-935.
38. Stefanovska A, Bracic M, Kvernmo HD. Wavelet analysis of oscillations in the peripheral blood circulation measured by laser Doppler technique. IEEE Trans Biomed Eng 1999; 46: 1230-9.
39. Ralevic V, Belai A, Burnstock G. Effects of streptozotocin-diabetes on sympathetic nerve, endothelial and smooth muscle function in the rat mesenteric arterial bed. Eur J Pharmacol 1995; 286: 193-199.
40. Litzelman, D.K., Marriott, D.J., Vinicor, F., 1997. Independent physiological predictors of foot lesions in patients with NIDDM. Diabetes Care 1997; 20: 1273-1278.
41. Soderstrom, T., Stefanovska, A., Veber, M., Svensson, H. Involvement of sympathetic nerve activity in skin blood flow oscillations in humans. Am. J. Physiol. Heart Circ. Physiol. 2003; 284: H1638-H1646.
42. Tentolouris N, Marinou K, Kokotis P, Karanti A, Diakoumopoulou E, Katsilambros N. Sudomotor dysfunction is associated with foot ulceration in diabetes. Diabet Med 2009; 26: 302-305.
43. Kimura J. Principles and variations of nerve conduction studies. In: Kimura J ed. Electrodiagnosis in Diseases of Nerve and Muscle: Principles and Practice, 3rd edn. New York: Oxford University Press, 2001: 91–129.
44. Feldman EL, et al. A practical two steps quantitative clinical electrophysiological assessment for the diagnosis and staging diabetic neuropathy. Diabetes care. 1994; 11: 1281-1289.
45. Stansberry, K.B., Peppard, H.R., Babvak, 1.M., Popp, G., McNitt, P.M., Vinik, A.l.. Primary nociecptive afferents mediate the blood flow dysfunction in non-glabrous skin of type 2 diabetes: A new model for the pathogenesis of microvascular dysfunction. Diabetes Care 1999; 26: 302-305.
46. Kilo, S., Berghoff, M., Hilz, M., Freeman, R., 2000. Neural and endothelial control of the microcirculation in diabetic peripheral neuropathy. Neurology 2000; 54: 1246-1252.
47. Durand, S., Zhang, R., Cui, J., Wilson, T.E. and Crandall, C.G., 2004. Evidence of a myogenic response in vasomotor control of forearm and palm cutaneous microcirculations. J. Appl. Physiol. 2004; 97: 535-539.