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Evidence of Increased Inflammation and Microcirculatory Abnormalities in Patients With Type 1 Diabetes and Their Role in Microvascular Complications

¹ Department of Pathology, Laboratory for Atherosclerosis and Metabolic Research, UCDavis Medical Center, Sacramento, California
² Department of Internal Medicine, Laboratory for Atherosclerosis and Metabolic Research, UCDavis Medical Center, Sacramento, California
³ Department of Biostatistics, Laboratory for Atherosclerosis and Metabolic Research, UCDavis Medical Center, Sacramento, California

Address correspondence and reprint requests to S. Devaraj, PhD, Associate Professor of Pathology, UCDavis Medical Center, Sacramento, CA 95817. E-mail: sdevaraj{at}ucdavis.edu

Abbreviations: CAIM, computer-assisted intravital microscopy; CRP, C-reactive protein; hsCRP, high sensitive CRP; IL, interleukin; LPS, lipopolysaccharide; NF, nuclear factor; TNF, tumor necrosis factor; sVCAM, soluble vascular cell adhesion molecule

OBJECTIVE—Type 1 diabetes is associated with increased microvascular complications and inflammation. The monocyte-macrophage is a pivotal cell in atherogenesis. There are scanty data on noninvasive measures of microvascular abnormalities and inflammation in type 1 diabetic subjects with microvascular complications. Thus, we examined systemic and cellular biomarkers of inflammation in type 1 diabetic patients with microvascular complications (T1DM-MV patients) and type 1 diabetic patients without microvascular complications (T1DM patients) compared with matched control subjects and determined the microcirculatory abnormalities in the T1DM and T1DM-MV patients using computer-assisted intravital microscopy (CAIM).

RESEARCH DESIGN AND METHODS—Fasting blood, 24-h urine, and CAIM measurements were obtained from the T1DM and T1DM-MV patients and matched control subjects. C-reactive protein, E-selectin, nitrotyrosine, monocyte superoxide, and cytokines were elevated in the T1DM and T1DM-MV patients compared with control subjects (P < 0.01).

RESULTS—Severity index, as assessed by CAIM, was significantly increased in the T1DM and T1DM-MV patients compared with the control subjects (P < 0.001). There was a significant increase in C-reactive protein, nitrotyrosine, vascular cell adhesion molecule and monocyte superoxide anion release, and interleukin-1 release in T1DM-MV compared with T1DM patients (P < 0.05). T1DM-MV patients had significantly increased CAIM severity index and microalbumin-to-creatinine ratio compared with T1DM patients (P < 0.05). Furthermore, pp38MAPK, pp65, and pERK activity were significantly increased in monocytes from the T1DM and T1DM-MV patients compared with those from the controls subjects, and pp38MAPK and pp65 activity were significantly increased in the T1DM-MV compared with the T1DM patients (P < 0.01).

CONCLUSIONS—T1DM-MV patients have increased inflammation compared with T1DM patients. CAIM provides an effective biomarker of microvascular complications, since it is significantly elevated in T1DM-MV compared with T1DM patients and can be monitored following therapies targeted at improving inflammation and/or microvascular complications of type 1 diabetes.

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