Search

The health effects of exercise depend on a complex equilibrium of often opposing mechanisms that may become altered in pathological states. In type 1 diabetes (T1DM), leukocyte activity dysregulation strongly correlates with diabetic vascular complications; it may therefore be important to identify alterations in exercise-induced leukocyte responses (total/fractional WBC counts, changes in leukocyte gene expression of immuno-modulatory factors). Little is known, however, about these responses, particularly in children. This study therefore investigated exercise-induced changes in leukocyte counts and mRNA expression of IL-6, IL- 10, VEGF, COX2, CD11a and HSP70 in control (n = 24, 14.1 ± 0.7 yrs, 8M/16F) and T1DM (n = 13, 13.3 ± 0.5 yrs, 8M/5F) children. Exercise consisted of 10 bouts of 2-min cycling at 80% VO2max separated by 1-min rest. For at least 90 min prior to and during exercise, euglycemia (80-110 mg/dL) was maintained for T1DM. Blood was drawn at baseline, end-exercise and 30-min post. mRNA expression was calculated as ratios of individual mRNAs and mRNA of the housekeeping protein β-actin to normalize for leukocytosis. The exercise-induced increase in WBC concentrations, observed in controls, was well preserved in T1DM. By 30-min post exercise, neutrophil and monocyte counts returned to baseline in both groups, while lymphocytes dipped below baseline. At end-exercise, WBC VEGF mRNA expression was significantly greater in T1DM than controls (p=0.041), while no difference was measured for other tested genes. Our data show that while the overall leukocytic response to exercise is well preserved in T1DM children, a significant alteration was present in the WBC mRNA expression of at least one major immune-modulator, VEGF, implicated in the pathological thickening of extracellular matrix causing reduced arterial perfusion. Our observations underscore the need for a deeper understanding of all aspects of exercise adaptation in populations at increased risk of long-term cardiovascular complications, including T1DM children. [ABSTRACT FROM AUTHOR]

Understanding the kinetic profiles of immunomodulatory factors during physical activity may help optimize the health benefits of exercise. This may be especially relevant for children with Type 1 Diabetes (T1DM), in which an imbalance of pro-/anti-inflammatory mediators that accelerates diabetic vascular complications may occur during/following exercise due to prior glycemic fluctuations. To date, exercise-induced alterations in immunomoduatory mediators in T1DM children remain largely unknown. This study examines 21 healthy (CNTRL, 13.9 ± 0.8 yrs, 8M/13F) and 21 diabetic (T1DM, 13.4 ± 0.3 yrs, 13M/8F) children. Blood glucose of T1DM was kept in the 80-110 mg/dL range for at least 90 min prior to and during exercise (ten 2-min cycling bouts at 80% VO2max, separated by 1-min intervals). Blood samples were drawn every second exercise bout, and at 15 and 30 min post exercise. In CNTRL, most tested mediators decreased during the first 15 min of exercise; some then increased slightly, remaining at or below baseline by end-exercise (the pro-inflammatory TNF-α, IL-12p70, GM-CSF, Eotaxin, MCP-1, and the anti-inflammatory IL-4); others clearly increased above baseline (IL-1α, IL-6, IL-8 IL-17, and MIP-1α, all pro-inflammatory/chemo-attractants). Conversely, in T1DM, the initial decrease was not observed, and most variables increased above baseline more markedly and more rapidly, resulting in significant differences in kinetic profiles vs CNTRL for TNF-α GM-CSF, Eotaxin, MCP-1, MIP-1α (10<0.05 - 0.001, AUC), and a significantly earlier time to peak values for IL-6, IL-17, and MIP-1α (p<0.05). The profile of the pro-inflammatory chemokine, IP-10, was similar between the 2 groups. During intense, intermittent exercise, the initial anti-inflammatory adaptation observed in age-matched healthy controls was absent in T1DM children. Further, the exercise-associated pro-inflammatory surge was greater in T1DM as compared to CNTRL. Our data suggest that optimization of exercise conditions may be crucial to maximize the health benefits of exercise in children with diabetes. [ABSTRACT FROM AUTHOR]

Altered leukocyte (WBC) activity, such as hypersecretion of pro-inflammatory cytokine/chemokines in type 1 diabetes (T1DM) has been implicated, in addition to early-stage accelerated damage to residual β cells, in the later onset and progression of vascular complications. Relatively little, however, is known about the regulation of WBC genes expressing pro-inflammatory molecules in response to immune stimuli in T1DM, particularly in children. Our study examines humoral and cell-mediated stimulation WBC cytokine/chemokine mRNA expression in T1DM and non-diabetic (nDM) children using a novel ex-vivo technique. Peripheral blood was drawn after at least 2 h of stable euglycemia in 14 T1DMs (13.2 ± 0.4 yrs, 8M/4F, +2 repeat subjects) and 26 nDMs (14.0 ± 0.6 yrs, 13M/13F). Blood was then incubated for 4 h with heat aggregated IgG (HAG) or anti-TCR antibody at body temperature to stimulate humoral and cell-mediated immune responses, respectively, with appropriate PBS and control IgG as comparisons, mRNA expression was then quantified, following WBC lysis, using a novel RT-PCR methodology developed by our group. Following TCR stimulation, most TNF super-family cytokines (TNFSFs) and CCL/CXCL chemokines displayed significantly increased WBC mRNA expression in T1DMs vs nDMs. Conversely, following HAG stimulation, no difference between groups was observed in for TNFSFs, various interleukins, or chemokines. Our data suggests that in T1DM children, WBC display an exaggerated proinflammatory response to immunologic stimuli that is limited to cell-mediated processes, while inflammatory responses to humoral stimulation appear intact. WBC cytokine expression may therefore contribute, at least in part, to the previously reported increased circulatory levels of pro-inflammatory cytokines in T1DM. While further investigations are needed to test the impact of this cell-mediated hyperactivity on the onset/progression of diabetic vascular complications, our findings may help identify new targets for specific, preventive anti-inflammatory strategies. [ABSTRACT FROM AUTHOR]