Journal Logo

You can read the full text of this article if you:

Access through Ovid
00019616-200611000-00002ReportThe EndocrinologistThe Endocrinologist© 2006 Lippincott Williams & Wilkins, Inc.16November 2006 p 303-307Soluble Cellular Adhesion Molecules in Patients With Diabetes MellitusRelation to Microvascular ComplicationsCase ReportEschen, Ole MD*; Christensen, Jeppe Hagstrup DMSci†; Schmidt, Erik Berg DMSci*From the *Center for Cardiovascular Research, Department of Cardiology and the †Department of Nephrology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark.Reprints: Ole Eschen, MD, Department of Cardiology, Aalborg Hospital, Aarhus University Hospital, 9100 Aalborg, Denmark. E-mail: [email protected] adhesion molecules (CAMs) may be involved in the development of diabetic complications. The aim of the present study is to investigate the relation of serum CAMs to diabetic microvascular complications in patients with diabetes mellitus (DM). Forty-three patients with type 1 DM and 38 patients with type 2 DM had fasting serum levels of soluble intercellular CAM-1 (ICAM-1), vascular CAM-1 (VCAM-1), and P-selectin determined. The albumin/creatinine ratio was measured and a ratio >2 g/mol was considered indicative of microalbuminuria and nephropathy. The vibration perception threshold was measured to diagnose peripheral neuropathy, whereas diabetic retinopathy was diagnosed by an ophthalmologist. Microalbuminuria (n = 13) was significantly associated with higher mean P-selectin levels compared with patients with normoalbuminuria in all patients with DM (110 ± 36 ng/L vs 83 ± 27 ng/L, P < 0.01). Patients with type 1 DM and microalbuminuria had significantly higher levels of sVCAM-1, whereas patients with type 2 DM had significantly higher levels of sP-selectin. No significant differences were found in soluble CAMs (sCAMs) between patients with or without neuropathy. Patients with type 2 DM and proliferative retinopathy had significantly higher serum levels of sVCAM-1 compared with patients with type 2 DM and a normal eye background or simplex retinopathy (1015 ± 88 vs 747 ± 274, P < 0.05). Patients with at least one microvascular complication (n = 42) had significantly higher sP-selectin (99 ± 31 vs 76 ± 25 ng/L, P < 0.001) and sVCAM-1 (889 ± 291 vs 711 ± 160 ng/L, P < 0.001), but not sICAM-1 (298 ± 71 vs 286 ± 70 ng/L), compared with patients without any microvascular complications (n = 39). These results indicate that sCAMs may be associated with microvascular complications in patients with DM.Cellular adhesion molecules (CAMs) promote adhesion and transendothelial migration of circulating monocytes, which is one of the earliest events in atherogenesis.1 A soluble part of cellular adhesion molecules (sCAMs) is shed into the circulation and can be measured in serum. These CAMs include vascular adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and P-selectin. CAMs have been implicated in the pathogenesis of both diabetic microangiopathy2,3 and macroangiopathy.4Microvascular disease in patients with diabetes mellitus (DM) is a multifactorial disorder resulting in part from accelerated atherosclerosis, increased inflammation, and thrombosis. Diabetic nephropathy is a serious complication of DM and a major cause of end-stage renal failure. Infiltration of macrophages into the glomeruli and interstitium is one of the characteristic features of diabetic nephropathy along with extracellular matrix expansion and interstitial fibrosis. Leukocyte infiltration into atherosclerotic lesions is mediated by sequential engagement of CAMs.5 Animal experiments suggest that sICAM-1,6–8 selectins,9 and VCAM-110 are causally involved in the pathogenesis of diabetic nephropathy. In accordance, most human studies have reported increased selectins and/or ICAM-1 and/or VCAM-1 in patients with DM with microalbuminuria and overt nephropathy.11–14 Furthermore, increased sCAMs have also been reported to be increased in patients with diabetic retinopathy15 and neuropathy.2In the present study, we have investigated the association between sCAMs and microvascular complications among patients with DM in an outpatient setting.MATERIALS AND METHODSPatientsIn a cross-sectional design, 81 patients (43 patients with type 1 DM and 38 patients with type 2 DM) were included consecutively from the outpatient diabetic clinic at Hjørring/Brønderslev Hospital, Hjørring, Denmark. Patients were enrolled primarily to investigate a possible association between n-3 fatty acids and heart rate variability,16 and for this reason, patients were excluded if they had 1) acute myocardial infarction or cardiac surgery or angioplasty within the past 6 months, 2) nonischemic cardiomyopathy, 3) an implanted pacemaker, or 4) permanent tachyarrhythmia.A group of 60 healthy subjects recruited from the medical staff, bank employees, and students free of medication or any known disease also was included.17The study was approved by the Regional Ethics Committee, and all patients gave their informed signed consent.Blood SamplesVenous blood was collected between 8:00 am and 9:30 am after an overnight fast. Blood samples were allowed to clot for 1 hour at room temperature, and serum was collected after centrifugation at 2500 × g for 20 minutes and stored at −80°C until analysis. Determination of serum levels of VCAM-1, ICAM-1, and P-selectin was performed using commercially available kits (Bender MedSystems, Vienna, Austria).Hemoglobin A1C (reference interval 4.5–6%) and plasma lipids and lipoproteins were measured by routine methods.Discrimination Between Type 1 and Type 2 Diabetes MellitusPatients with type 1 DM all had a history of acute-onset DM requiring prompt insulin therapy and were younger than 40 years at onset. Patients with type 2 DM all had a slow onset of DM and were all older than 30 years at onset. At the time of diagnosis, in some patients, analysis of fasting C-peptide was used to help classify the patients.Diabetic ComplicationsThe albumin/creatinine ratio was measured in the first-morning urine and a ratio >2 g/mol was considered indicative of microalbuminuria and diabetic nephropathy.Peripheral neuropathy was examined on the medial malleoli and the first toe on both sides by biotensiometry. The highest value was recorded and patients with age-standardized values above the 90th percentile18 were considered to have peripheral neuropathy.All patients were regularly examined (at least annually) by experienced ophthalmologists, and patients with proliferative retinal changes were diagnosed with diabetic retinopathy.Statistical AnalysisComparisons of differences between 2 groups were tested by nonpaired t test for continuous variables. Differences between the 3 groups were tested by one-way analysis of variance. If significant differences were found, Tukey's test was applied. Pearson's test was used for correlation analyses. Backward stepwise linear regression analysis was conducted to relate sCAMs to microvascular complication independently of confounding variables. A P value <0.05 (2-tailed) was considered statistically significant.RESULTSThe characteristics of the study population are given for the control group and the patients with type 1 DM and type 2 DM in Table 1. Patients with DM had significantly higher sP-selectin than the control group (P < 0.05).JOURNAL/endst/04.03/00019616-200611000-00002/table1-2/v/2021-02-17T201820Z/r/image-tiff The Characteristics of the Study Population (Mean ± Standard Deviation or Exact Numbers)Between patients with type 1 DM and type 2 DM, metabolic control (glycosylated hemoglobin A1C) and sCAMs levels were nearly identical in the 2 groups. Patients with type 1 DM were younger and had longer diabetes duration, lower body mass index, lower systolic blood pressure, less low-density lipoprotein cholesterol and triglyceride levels, and higher high-density lipoprotein cholesterol than patients with type 2 DM.In all patients with DM, sP-selectin was correlated to hemoglobin A1C (r = 0.434, P < 0.01), but no correlation was found between hemoglobin A1C and sVCAM-1 and sICAM-1. sVCAM-1 was correlated to body mass index (r = 0.466, P < 0.01) and s-creatinine (r = 0.348, P < 0.001). Smokers had significantly higher sICAM-1 (309 ± 67 vs 271 ± 69 ng/L, P < 0.05) and sP-selectin (96 ± 32 vs 77 ± 24 ng/L, P < 0.01) than nonsmokers. A positive correlation between sP-selectin and total cholesterol (r = 0.279, P < 0.05) and plasma triglycerides (0.321, P < 0.01) was noted.Patients with diabetes and presence of one or more complications were more often treated with angiotensin converting enzyme inhibitors or angiotensin II antagonists (43%) than patients without any microvascular complications (15%). All patients with microalbuminuria were treated with an angiotensin converting enzyme inhibitor or angiotensin II antagonist.Microvascular Complications and Adhesion MoleculesIn Table 2, the patients with type 1 DM and type 2 DM are divided according to presence or absence of microvascular complications. Similar trends were observed between patients with type 1 and type 2 DM. However, patients with type 1 DM and microalbuminuria had significantly higher levels of sVCAM-1 compared with patients with type 1 DM with normoalbuminuria. Patients with type 2 DM had significantly higher sP-selectin compared with patients with type 2 DM with normoalbuminuria. In all patients with microalbuminuria, only sP-selectin was significantly higher than in patients with normoalbuminuria. In a backward stepwise linear regression analysis taking into account possible confounding variables, the difference remained significant (Table 3).JOURNAL/endst/04.03/00019616-200611000-00002/table2-2/v/2021-02-17T201820Z/r/image-tiff Serum Cellular Adhesion Molecules 81 Patients With Diabetes Divided According to Absence or Presence of Microvascular Complications (Mean ± Standard Deviation)JOURNAL/endst/04.03/00019616-200611000-00002/table3-2/v/2021-02-17T201820Z/r/image-tiff Linear Stepwise Regression Analysis With Serum Cellular Adhesion Molecules as Dependent Factors (all patients with diabetes)The patients were divided according to absence or presence of neuropathy at the medial malleolus (Table 2). No significant differences were observed.The presence of retinopathy was associated with increased sP-selectin and sVCAM-1 but not sICAM-1 (Table 2). Patients with type 2 DM and proliferative retinopathy (n = 6) had significantly higher mean sVCAM-1 in the group with normal eyes or minimal retinopathy (P < 0.05).Patients with one or more microvascular complications (n = 42) had significantly higher sP-selectin (99 ± 31 vs 76 ± 25 ng/L, P < 0.001) and sVCAM-1 (889 ± 291 vs 711 ± 160 ng/L, P < 0.001), but not sICAM-1 (298 ± 71 vs 286 ± 70 ng/L), compared with patients without microvascular complications (n = 39) (Table 2). In a linear stepwise regression analysis, differences remained significant after correction for possible confounding variables (Table 3).Some patients had more than one microvascular complications: 28 had only one, 12 had 2, and only 2 had 3 microvascular complications; only sP-selectin correlated significantly to number of complication (r = 0.270, P = 0.015) (data not shown).DISCUSSIONThe principal findings of this study were that sP-selectin was significantly increased in patients with type 1 or type 2 DM and microalbuminuria compared with patients without. Patients with at least one microvascular complication had significantly higher P-selectin and sVCAM-1, but not sICAM-1, than patients without any complications. However, dividing patients according to type of DM revealed small differences between patients with type 1 DM and patients with type 2 DM. In patients with type 1 DM and microalbuminuria, only sVCAM-1 was significantly higher compared with patients with type 1 DM without microalbuminuria. In patients with type 2 DM, sP-selectin remained significantly associated with microalbuminuria, but also a significantly higher sVCAM-1 was associated with proliferative retinopathy.Recently, a large cross-sectional study of patients (n = 514) with type 1 DM19 has shown a positive association between sVCAM-1 and sE-selectin and retinopathy, microalbuminuria, and cardiovascular disease. Likewise, we report sVCAM-1 associated to one or more microvascular complications in patients with DM. Furthermore, we report sP-selectin is associated with one or more complications.Increased P-selectin in both serum and in the glomeruli and renal interstitium have been shown in kidney tissues from patients with DM compared with kidney tissues from patients with other glomerular diseases.13 In accordance with these reports, we found that sP-selectin was significantly increased in patients with microalbuminuria. Activation of platelets with increased surface P-selectin expression has been reported in patients with DM and nephropathy.14 Although P-selectin is expressed both by platelets and endothelium, the major source of P-selectin is generally believed to be activated platelets.20 Thus, platelet activation may play an important role in the development of diabetic nephropathy. In a well-designed study of patients with type 1 DM, Clausen et al12 showed that microalbuminuria was associated with an increase in sICAM-1 and that macroalbuminuria and overt nephropathy were associated with increasing levels of both sICAM-1 and sVCAM-1 (no selectin was measured). Although only few patients in our study had developed diabetic nephropathy, our patients with type 1 DM and microalbuminuria also had significantly higher levels of sVCAM-1. The presence of microalbuminuria might also depend on comorbidity of the patients. Especially hypertension has been implicated in the pathogenesis of microalbuminuria, and in our study, 46% of patients with microalbuminuria had hypertension. Interestingly, nephroprotective treatments with angiotensin converting enzyme inhibitors or angiotensin II receptor antagonists have been reported11 to decrease both sVCAM-1 and sE-selectin but not sICAM-1. All of our patients with microalbuminuria received either an angiotensin converting enzyme inhibitor or an angiotensin II antagonist, which might have confounded our findings. In conclusion, our study suggests that sCAMs are important in the pathogenesis of diabetic nephropathy in line with most previous studies. Our results also hint at an important role of activated platelets.Diabetic peripheral neuropathy is an important cause of morbidity in patients with DM. The exact pathogenesis is unclear, but metabolic and vascular factors have been implicated.21 Both sP-selectin and sICAM-1 have been shown to be increased in diabetic peripheral neuropathy.2 Also, high levels of sP-selectin are reported to be predictive of development and deterioration of neuropathy.2 The number of activated platelets expressing P-selectin has been shown to be elevated in patients with DM with microvascular complications and also correlated to a poor metabolic control.22 In contrast to these studies, we did not find any association between sCAMs and peripheral neuropathy.Adhesion of leukocytes to retinal vasculature has been implicated in the pathogenesis of diabetic retinopathy. In postmortem studies of human retinas and microvasculature, McLeod et al23 demonstrated that P-selectin and ICAM-1 are localized to the microvasculature, but not to the retina, in tissues from patients with DM compared with patients without DM. A previous study of subjects with diabetic retinopathy15 reported increased sCAMs in patients with retinopathy. We found significantly increased levels of only sVCAM-1 in our patients with type 2 DM and proliferative retinopathy. Thus, increased sCAMs in patients with DM and retinopathy may indicate a pathophysiological role of CAMs in the development of retinopathy, possibly through increased inflammation and endothelial activation.The limitations of this study are the relatively few patients enrolled, therefore increasing the possibility of a type 1 error to occur. Also, only relatively few of our patients had developed diabetic microvascular complications, increasing the possibility of type 2 errors to occur. However, when dividing our patients into 2 groups based on presence or absence of microvascular complication, both sP-selectin and sVCAM-1 were strongly correlated to the presence of complications despite the fact that the patients with microvascular complications more often received medication known to decrease levels of sCAMs. Our control group was far from ideal, consisting of a population of healthy volunteers age-matched with the patients with type 1 DM. Despite this, we found that patients with diabetes had significantly higher sP-selectin than controls, indicative of role of expression of P-selectin in the development of microvascular complications in patients with DM.CONCLUSIONSMicroalbuminuria was associated with higher serum levels of soluble P-selectin in patients with DM. Patients with one or more microvascular complications had significantly higher levels of both sP-selectin and sVCAM-1 compared with patients without any microvascular complications. Also, sP-selectin correlated significantly to the number of microvascular complications. In patients with type 1 DM, sVCAM-1 was significantly associated with microalbuminuria. In patients with type 2 DM, sP-selectin was significantly associated with microalbuminuria, and proliferative retinopathy was associated with significantly higher serum levels of sVCAM-1. The results could hint at a significant role of both endothelial activation and also platelet activation in the pathogenesis of microvascular complications in DM. Although small differences in the association between sCAMs and microvascular complications were observed between patients with type 1 DM and patients with type 2 DM, trends were similar between the 2 groups.REFERENCES1. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med. 1999;340:115–126.[Context Link][Full Text][CrossRef][Medline Link]2. Jude EB, Abbott CA, Young MJ, et al. The potential role of cell adhesion molecules in the pathogenesis of diabetic neuropathy. Diabetologia. 1998;41:330–336.[Context Link][CrossRef][Medline Link]3. Fasching P, Veitl M, Rohac M, et al. Elevated concentrations of circulating adhesion molecules and their association with microvascular complications in insulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1996;81:4313–4317.[Context Link][CrossRef][Medline Link]4. Becker A, van Hinsbergh VW, Jager A, et al. Why is soluble intercellular adhesion molecule-1 related to cardiovascular mortality? Eur J Clin Invest. 2002;32:1–8.[Context Link][Full Text][CrossRef][Medline Link]5. Furuta T, Saito T, Ootaka T, et al. The role of macrophages in diabetic glomerulosclerosis. Am J Kidney Dis. 1993;21:480–485.[Context Link][CrossRef][Medline Link]6. Matsui H, Suzuki M, Tsukuda R, et al. Expression of ICAM-1 on glomeruli is associated with progression of diabetic nephropathy in a genetically obese diabetic rat, Wistar fatty. Diabetes Res Clin Pract. 1996;32:1–9.[Context Link][CrossRef][Medline Link]7. Okada S, Shikata K, Matsuda M, et al. Intercellular adhesion molecule-1-deficient mice are resistant against renal injury after induction of diabetes. Diabetes. 2003;52:2586–2593.[Context Link][Full Text][CrossRef][Medline Link]8. Sugimoto H, Shikata K, Hirata K, et al. Increased expression of intercellular adhesion molecule-1 (ICAM-1) in diabetic rat glomeruli: glomerular hyperfiltration is a potential mechanism of ICAM-1 upregulation. Diabetes. 1997;46:2075–2081.[Context Link][Full Text][CrossRef][Medline Link]9. Narumi S, Onozato ML, Tojo A, et al. Tissue-specific induction of E-selectin in glomeruli is augmented following diabetes mellitus. Nephron. 2001;89:161–171.[Context Link][CrossRef][Medline Link]10. Ina K, Kitamura H, Okeda T, et al. Vascular cell adhesion molecule-1 expression in the renal interstitium of diabetic KKAy mice. Diabetes Res Clin Pract. 1999;44:1–8.[Context Link][CrossRef][Medline Link]11. Andersen S, Schalkwijk CG, Stehouwer CD, et al. Angiotensin II blockade is associated with decreased plasma leukocyte adhesion molecule levels in diabetic nephropathy. Diabetes Care. 2000;23:1031–1032.[Context Link][Full Text][CrossRef][Medline Link]12. Clausen P, Jacobsen P, Rossing K, et al. Plasma concentrations of VCAM-1 and ICAM-1 are elevated in patients with type 1 diabetes mellitus with microalbuminuria and overt nephropathy. Diabet Med. 2000;17:644–649.[Context Link][CrossRef][Medline Link]13. Hirata K, Shikata K, Matsuda M, et al. Increased expression of selectins in kidneys of patients with diabetic nephropathy. Diabetologia. 1998;41:185–192.[Context Link][CrossRef][Medline Link]14. Omoto S, Nomura S, Shouzu A, et al. Significance of platelet-derived microparticles and activated platelets in diabetic nephropathy. Nephron. 1999;81:271–277.[Context Link][CrossRef][Medline Link]15. Matsumoto K, Sera Y, Ueki Y, et al. Comparison of serum concentrations of soluble adhesion molecules in diabetic microangiopathy and macroangiopathy. Diabet Med. 2002;19:822–826.[Context Link][Full Text][CrossRef][Medline Link]16. Christensen JH, Skou HA, Madsen T, et al. Heart rate variability and n-3 polyunsaturated fatty acids in patients with diabetes mellitus. J Intern Med. 2001;249:545–552.[Context Link][Full Text][CrossRef][Medline Link]17. Eschen O, Christensen JH, De Caterina R, et al. Soluble adhesion molecules in healthy subjects: a dose–response study using n-3 fatty acids. Nutr Metab Cardiovasc Dis. 2004;14:180–185.[Context Link][CrossRef][Medline Link]18. Bloom S, Till S, Sonksen P, et al. Use of a biothesiometer to measure individual vibration thresholds and their variation in 519 non-diabetic subjects. BMJ (Clin Res Ed). 1984;288:1793–1795.[Context Link][CrossRef][Medline Link]19. Soedamah-Muthu SS, Chaturvedi N, Schalkwijk CG, et al. Soluble vascular cell adhesion molecule-1 and soluble E-selectin are associated with micro- and macrovascular complications in type 1 diabetic patients. J Diabetes Complications. 2006;20:188–195.[Context Link][CrossRef][Medline Link]20. Blann AD, Lip GY. Hypothesis: is soluble P-selectin a new marker of platelet activation? Atherosclerosis. 1997;128:135–138.[Context Link][CrossRef][Medline Link]21. Cameron NE, Cotter MA. Metabolic and vascular factors in the pathogenesis of diabetic neuropathy. Diabetes. 1997;46(suppl 2):S31–S37.[Context Link][CrossRef][Medline Link]22. Shouzu A, Nomura S, Hayakawa T, et al. Effect of sarpogrelate hydrochloride on platelet-derived microparticles and various soluble adhesion molecules in diabetes mellitus. Clin Appl Thromb Hemost. 2000;6:139–143.[Context Link][CrossRef][Medline Link]23. McLeod DS, Lefer DJ, Merges C, et al. Enhanced expression of intracellular adhesion molecule-1 and P-selectin in the diabetic human retina and choroid. Am J Pathol. 1995;147:642–653.[Context Link][Medline Link]P-selectin; VCAM-1; ICAM-1; diabetes mellitus; microvascular complications00019616-200611000-0000200003218_1999_44_1_ina_interstitium_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e801_citationRF_FLOATING))|11065213||ovftdb|SL00003218199944111065213citation_FROM_JRF_ID_d21e801_citationRF_FLOATING[CrossRef]10.1016%2FS0168-8227%2899%2900011-X00019616-200611000-0000200003218_1999_44_1_ina_interstitium_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e801_citationRF_FLOATING))|11065405||ovftdb|SL00003218199944111065405citation_FROM_JRF_ID_d21e801_citationRF_FLOATING[Medline Link]1041493400019616-200611000-0000200003458_2000_23_1031_andersen_angiotensin_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e839_citationRF_FLOATING))|11065404||ovftdb|SL00003458200023103111065404citation_FROM_JRF_ID_d21e839_citationRF_FLOATING[Full Text]00003458-200007000-0003700019616-200611000-0000200003458_2000_23_1031_andersen_angiotensin_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e839_citationRF_FLOATING))|11065213||ovftdb|SL00003458200023103111065213citation_FROM_JRF_ID_d21e839_citationRF_FLOATING[CrossRef]10.2337%2Fdiacare.23.7.103100019616-200611000-0000200003458_2000_23_1031_andersen_angiotensin_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e839_citationRF_FLOATING))|11065405||ovftdb|SL00003458200023103111065405citation_FROM_JRF_ID_d21e839_citationRF_FLOATING[Medline Link]1089586800019616-200611000-0000200003135_2000_17_644_clausen_microalbuminuria_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e876_citationRF_FLOATING))|11065213||ovftdb|SL0000313520001764411065213citation_FROM_JRF_ID_d21e876_citationRF_FLOATING[CrossRef]10.1046%2Fj.1464-5491.2000.00347.x00019616-200611000-0000200003135_2000_17_644_clausen_microalbuminuria_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e876_citationRF_FLOATING))|11065405||ovftdb|SL0000313520001764411065405citation_FROM_JRF_ID_d21e876_citationRF_FLOATING[Medline Link]1105128300019616-200611000-0000200003441_1998_41_185_hirata_nephropathy_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e913_citationRF_FLOATING))|11065213||ovftdb|SL0000344119984118511065213citation_FROM_JRF_ID_d21e913_citationRF_FLOATING[CrossRef]10.1007%2Fs00125005088800019616-200611000-0000200003441_1998_41_185_hirata_nephropathy_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e913_citationRF_FLOATING))|11065405||ovftdb|SL0000344119984118511065405citation_FROM_JRF_ID_d21e913_citationRF_FLOATING[Medline Link]949865200019616-200611000-0000200006085_1999_81_271_omoto_microparticles_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e950_citationRF_FLOATING))|11065213||ovftdb|SL0000608519998127111065213citation_FROM_JRF_ID_d21e950_citationRF_FLOATING[CrossRef]10.1159%2F00004529200019616-200611000-0000200006085_1999_81_271_omoto_microparticles_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e950_citationRF_FLOATING))|11065405||ovftdb|SL0000608519998127111065405citation_FROM_JRF_ID_d21e950_citationRF_FLOATING[Medline Link]1005008000019616-200611000-0000200003135_2002_19_822_matsumoto_microangiopathy_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e987_citationRF_FLOATING))|11065404||ovftdb|SL0000313520021982211065404citation_FROM_JRF_ID_d21e987_citationRF_FLOATING[Full Text]00003135-200210000-0000500019616-200611000-0000200003135_2002_19_822_matsumoto_microangiopathy_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e987_citationRF_FLOATING))|11065213||ovftdb|SL0000313520021982211065213citation_FROM_JRF_ID_d21e987_citationRF_FLOATING[CrossRef]10.1046%2Fj.1464-5491.2002.00799.x00019616-200611000-0000200003135_2002_19_822_matsumoto_microangiopathy_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e987_citationRF_FLOATING))|11065405||ovftdb|SL0000313520021982211065405citation_FROM_JRF_ID_d21e987_citationRF_FLOATING[Medline Link]1235886800019616-200611000-0000200004777_2001_249_545_christensen_polyunsaturated_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e1024_citationRF_FLOATING))|11065404||ovftdb|SL00004777200124954511065404citation_FROM_JRF_ID_d21e1024_citationRF_FLOATING[Full Text]00004777-200106000-0000800019616-200611000-0000200004777_2001_249_545_christensen_polyunsaturated_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e1024_citationRF_FLOATING))|11065213||ovftdb|SL00004777200124954511065213citation_FROM_JRF_ID_d21e1024_citationRF_FLOATING[CrossRef]10.1046%2Fj.1365-2796.2001.00841.x00019616-200611000-0000200004777_2001_249_545_christensen_polyunsaturated_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e1024_citationRF_FLOATING))|11065405||ovftdb|SL00004777200124954511065405citation_FROM_JRF_ID_d21e1024_citationRF_FLOATING[Medline Link]1142266100019616-200611000-0000200019148_2004_14_180_eschen_molecules_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e1062_citationRF_FLOATING))|11065213||ovftdb|SL0001914820041418011065213citation_FROM_JRF_ID_d21e1062_citationRF_FLOATING[CrossRef]10.1016%2FS0939-4753%2804%2980002-400019616-200611000-0000200019148_2004_14_180_eschen_molecules_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e1062_citationRF_FLOATING))|11065405||ovftdb|SL0001914820041418011065405citation_FROM_JRF_ID_d21e1062_citationRF_FLOATING[Medline Link]1555359400019616-200611000-0000200002419_1984_288_1793_bloom_biothesiometer_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e1099_citationRF_FLOATING))|11065213||ovftdb|SL000024191984288179311065213citation_FROM_JRF_ID_d21e1099_citationRF_FLOATING[CrossRef]10.1136%2Fbmj.288.6433.179300019616-200611000-0000200002419_1984_288_1793_bloom_biothesiometer_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e1099_citationRF_FLOATING))|11065405||ovftdb|SL000024191984288179311065405citation_FROM_JRF_ID_d21e1099_citationRF_FLOATING[Medline Link]642854700019616-200611000-0000200001828_2006_20_188_soedamah_macrovascular_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e1136_citationRF_FLOATING))|11065213||ovftdb|SL0000182820062018811065213citation_FROM_JRF_ID_d21e1136_citationRF_FLOATING[CrossRef]10.1016%2Fj.jdiacomp.2005.06.00500019616-200611000-0000200001828_2006_20_188_soedamah_macrovascular_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e1136_citationRF_FLOATING))|11065405||ovftdb|SL0000182820062018811065405citation_FROM_JRF_ID_d21e1136_citationRF_FLOATING[Medline Link]1663224000019616-200611000-0000200006024_1999_340_115_ross_atherosclerosis_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e479_citationRF_FLOATING))|11065404||ovftdb|SL00006024199934011511065404citation_FROM_JRF_ID_d21e479_citationRF_FLOATING[Full Text]00006024-199901140-0000700019616-200611000-0000200006024_1999_340_115_ross_atherosclerosis_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e479_citationRF_FLOATING))|11065213||ovftdb|SL00006024199934011511065213citation_FROM_JRF_ID_d21e479_citationRF_FLOATING[CrossRef]10.1056%2FNEJM19990114340020700019616-200611000-0000200006024_1999_340_115_ross_atherosclerosis_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e479_citationRF_FLOATING))|11065405||ovftdb|SL00006024199934011511065405citation_FROM_JRF_ID_d21e479_citationRF_FLOATING[Medline Link]988716400019616-200611000-0000200000898_1997_128_135_blann_hypothesis_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e1173_citationRF_FLOATING))|11065213||ovftdb|SL00000898199712813511065213citation_FROM_JRF_ID_d21e1173_citationRF_FLOATING[CrossRef]10.1016%2FS0021-9150%2896%2905980-100019616-200611000-0000200000898_1997_128_135_blann_hypothesis_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e1173_citationRF_FLOATING))|11065405||ovftdb|SL00000898199712813511065405citation_FROM_JRF_ID_d21e1173_citationRF_FLOATING[Medline Link]905076900019616-200611000-0000200003439_1997_46_s31_cameron_pathogenesis_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e1203_citationRF_FLOATING))|11065213||ovftdb|SL00003439199746s3111065213citation_FROM_JRF_ID_d21e1203_citationRF_FLOATING[CrossRef]10.2337%2Fdiab.46.2.S3100019616-200611000-0000200003439_1997_46_s31_cameron_pathogenesis_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e1203_citationRF_FLOATING))|11065405||ovftdb|SL00003439199746s3111065405citation_FROM_JRF_ID_d21e1203_citationRF_FLOATING[Medline Link]928549600019616-200611000-0000200045529_2000_6_139_shouzu_microparticles_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e1235_citationRF_FLOATING))|11065213||ovftdb|SL000455292000613911065213citation_FROM_JRF_ID_d21e1235_citationRF_FLOATING[CrossRef]10.1177%2F10760296000060030400019616-200611000-0000200045529_2000_6_139_shouzu_microparticles_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e1235_citationRF_FLOATING))|11065405||ovftdb|SL000455292000613911065405citation_FROM_JRF_ID_d21e1235_citationRF_FLOATING[Medline Link]1089827300019616-200611000-0000200000457_1995_147_642_mcleod_intracellular_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e1273_citationRF_FLOATING))|11065405||ovftdb|SL00000457199514764211065405citation_FROM_JRF_ID_d21e1273_citationRF_FLOATING[Medline Link]754587300019616-200611000-0000200003441_1998_41_330_jude_pathogenesis_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e504_citationRF_FLOATING))|11065213||ovftdb|SL0000344119984133011065213citation_FROM_JRF_ID_d21e504_citationRF_FLOATING[CrossRef]10.1007%2Fs00125005091100019616-200611000-0000200003441_1998_41_330_jude_pathogenesis_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e504_citationRF_FLOATING))|11065405||ovftdb|SL0000344119984133011065405citation_FROM_JRF_ID_d21e504_citationRF_FLOATING[Medline Link]954117400019616-200611000-0000200004678_1996_81_4313_fasching_concentrations_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e541_citationRF_FLOATING))|11065213||ovftdb|SL00004678199681431311065213citation_FROM_JRF_ID_d21e541_citationRF_FLOATING[CrossRef]10.1210%2Fjc.81.12.431300019616-200611000-0000200004678_1996_81_4313_fasching_concentrations_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e541_citationRF_FLOATING))|11065405||ovftdb|SL00004678199681431311065405citation_FROM_JRF_ID_d21e541_citationRF_FLOATING[Medline Link]895403300019616-200611000-0000200003653_2002_32_1_becker_cardiovascular_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e578_citationRF_FLOATING))|11065404||ovftdb|SL00003653200232111065404citation_FROM_JRF_ID_d21e578_citationRF_FLOATING[Full Text]00003653-200201000-0000100019616-200611000-0000200003653_2002_32_1_becker_cardiovascular_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e578_citationRF_FLOATING))|11065213||ovftdb|SL00003653200232111065213citation_FROM_JRF_ID_d21e578_citationRF_FLOATING[CrossRef]10.1046%2Fj.1365-2362.2002.00919.x00019616-200611000-0000200003653_2002_32_1_becker_cardiovascular_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e578_citationRF_FLOATING))|11065405||ovftdb|SL00003653200232111065405citation_FROM_JRF_ID_d21e578_citationRF_FLOATING[Medline Link]1185172000019616-200611000-0000200000431_1993_21_480_furuta_glomerulosclerosis_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e616_citationRF_FLOATING))|11065213||ovftdb|SL0000043119932148011065213citation_FROM_JRF_ID_d21e616_citationRF_FLOATING[CrossRef]10.1016%2FS0272-6386%2812%2980393-300019616-200611000-0000200000431_1993_21_480_furuta_glomerulosclerosis_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e616_citationRF_FLOATING))|11065405||ovftdb|SL0000043119932148011065405citation_FROM_JRF_ID_d21e616_citationRF_FLOATING[Medline Link]848881500019616-200611000-0000200003218_1996_32_1_matsui_progression_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e653_citationRF_FLOATING))|11065213||ovftdb|SL00003218199632111065213citation_FROM_JRF_ID_d21e653_citationRF_FLOATING[CrossRef]10.1016%2F0168-8227%2896%2901209-000019616-200611000-0000200003218_1996_32_1_matsui_progression_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e653_citationRF_FLOATING))|11065405||ovftdb|SL00003218199632111065405citation_FROM_JRF_ID_d21e653_citationRF_FLOATING[Medline Link]880347600019616-200611000-0000200003439_2003_52_2586_okada_intercellular_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e690_citationRF_FLOATING))|11065404||ovftdb|SL00003439200352258611065404citation_FROM_JRF_ID_d21e690_citationRF_FLOATING[Full Text]00003439-200310000-0001800019616-200611000-0000200003439_2003_52_2586_okada_intercellular_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e690_citationRF_FLOATING))|11065213||ovftdb|SL00003439200352258611065213citation_FROM_JRF_ID_d21e690_citationRF_FLOATING[CrossRef]10.2337%2Fdiabetes.52.10.258600019616-200611000-0000200003439_2003_52_2586_okada_intercellular_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e690_citationRF_FLOATING))|11065405||ovftdb|SL00003439200352258611065405citation_FROM_JRF_ID_d21e690_citationRF_FLOATING[Medline Link]1451464400019616-200611000-0000200003439_1997_46_2075_sugimoto_hyperfiltration_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e727_citationRF_FLOATING))|11065404||ovftdb|SL00003439199746207511065404citation_FROM_JRF_ID_d21e727_citationRF_FLOATING[Full Text]00003439-199712000-0002500019616-200611000-0000200003439_1997_46_2075_sugimoto_hyperfiltration_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e727_citationRF_FLOATING))|11065213||ovftdb|SL00003439199746207511065213citation_FROM_JRF_ID_d21e727_citationRF_FLOATING[CrossRef]10.2337%2Fdiab.46.12.207500019616-200611000-0000200003439_1997_46_2075_sugimoto_hyperfiltration_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e727_citationRF_FLOATING))|11065405||ovftdb|SL00003439199746207511065405citation_FROM_JRF_ID_d21e727_citationRF_FLOATING[Medline Link]939249900019616-200611000-0000200006085_2001_89_161_narumi_induction_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e764_citationRF_FLOATING))|11065213||ovftdb|SL0000608520018916111065213citation_FROM_JRF_ID_d21e764_citationRF_FLOATING[CrossRef]10.1159%2F00004606300019616-200611000-0000200006085_2001_89_161_narumi_induction_|00019616-200611000-00002#xpointer(id(citation_FROM_JRF_ID_d21e764_citationRF_FLOATING))|11065405||ovftdb|SL0000608520018916111065405citation_FROM_JRF_ID_d21e764_citationRF_FLOATING[Medline Link]11549898 The Characteristics of the Study Population (Mean ± Standard Deviation or Exact Numbers) Serum Cellular Adhesion Molecules 81 Patients With Diabetes Divided According to Absence or Presence of Microvascular Complications (Mean ± Standard Deviation) Linear Stepwise Regression Analysis With Serum Cellular Adhesion Molecules as Dependent Factors (all patients with diabetes)Soluble Cellular Adhesion Molecules in Patients With Diabetes Mellitus: Relation to Microvascular ComplicationsEschen Ole MD; Christensen, Jeppe Hagstrup DMSci; Schmidt, Erik Berg DMSciCase ReportCase Report616p 303-307