Jaime S. Rosa

Sustained IL‐1α, IL‐4, and IL‐6 elevations following correction of hyperglycemia in children with type 1 diabetes mellitus

Objective:  An imbalance of pro‐/anti‐inflammatory cytokines may accelerate diabetic vascular complications and interfere with proper wound healing. Currently, limited available literature suggests that plasma concentrations of certain pro‐ and anti‐inflammatory cytokines may be altered during hyperglycemia/diabetes mellitus. It is still unclear, however, whether these concepts also apply to children with diabetes, and whether alterations in circulating cytokine levels are a permanent feature of diabetes or an acute effect of fluctuating glucose concentrations.

Increased oxidative stress and altered substrate metabolism in obese children

OBJECTIVE Pediatric obesity, a major risk factor for cardiovascular diseases and diabetes, has steadily increased in the last decades. Although excessive inflammation and oxidation are possible biochemical links between obesity and cardiovascular events in adults, little information is available in children. Furthermore, effects of gender and fitness on the interaction between dyslipidemia and oxidative/inflammatory stress in children are mostly unknown. METHODS Therefore, we measured systemic markers of oxidation (F(2)-isoprostanes [F(2)-IsoP] and antioxidants) and inflammation (interleukin-6 [IL-6] and leukocyte counts) and metabolic variables in 113 peripubertal children (55 obese [Ob] age and gender-adjusted BMI% ≥ 95(th), 25 Females [F]; 15 overweight [OW] BMI% 85(th)-95(th), 8 F; 43 normoweight [NW] 25 F). RESULTS When compared with NW, Ob displayed elevated F(2)-IsoP (99 ± 7 vs. 75 ± 4 pg/mL, p<0.005), IL-6 (2.2 ± 0.2 vs. 1.5 ± 0.3 pg/mL, p<0.005), elevated total leukocytes and neutrophils, altered levels of total cholesterol , low- and high-density-lipoprotein cholesterol, triglycerides, free fatty acids, glucose, and insulin (all p<0.005). This pattern was present in both genders and over a broad range of fitness in Ob. CONCLUSIONS Our data indicate that alterations in metabolic control and a concomitant increase in inflammation and oxidative stress occur early in life in obese children, likely exposing both genders to a similar degree of increased risk of future cardiovascular diseases.

Aspects of Inflammation and Oxidative Stress in Pediatric Obesity and Type 1 Diabetes: An Overview of Ten Years of Studies

Obesity and type 1 diabetes (T1DM) are the two most common conditions of altered metabolism in children and adolescents. In both, similar long-term cardiovascular complications are known to occur, mediated in large part by underlying inflammatory and oxidative processes whose biochemical details remain relatively unclear. Through a series of experiments in these patient populations, over the last decade our laboratory has clarified a number of key issues in this field. Interestingly, while obese and type 1 diabetic children often differed in the specific type and magnitude of molecular alterations, in both groups a clear exaggeration of inflammatory and oxidative activation was detected when compared to healthy, age-matched controls. Our main findings include definition of resting and exercise-induced cytokine patterns and leukocyte profiles, patterns of activation of immune cells in vitro, and correlation of the magnitude of observed alterations with severity of obesity and quality of glycemic control. Further, we have identified a series of alterations in growth factor profiles during exercise that parallel inflammatory changes in obese children. This paper offers a concise overview of the salient results from this decade-long research effort.

Altered inflammatory, oxidative, and metabolic responses to exercise in pediatric obesity and type 1 diabetes

Rosa JS, Oliver SR, Flores RL, Ngo J, Milne GL, Zaldivar FP, Galassetti PR. Altered inflammatory, oxidative, and metabolic responses to exercise in pediatric obesity and type 1 diabetes.

Inflammatory Cytokine Profiles During Exercise in Obese, Diabetic, and Healthy Children

Objective: Modulation of inflammatory status is considered a key component of the overall health effects of exercise. This may be especially relevant in children with obesity (Ob) or type 1 diabetes (T1DM), in which an imbalance between pro- and anti-inflammatory mediators could accelerate onset and progression of cardiovascular complications. To date, exercise-induced alterations in immuno-modulatory mediators in Ob and T1DM children remain largely unknown. Methods: In this study, we monitored the kinetic profiles of 8 pro-and anti-inflammatory cytokines (TNF-a, IL-6, IL-2, IL-8, IL-5, IL-13, IL-10, IL-4) during a standardized exercise challenge (ten 2-min cycling bouts at 80% VO2max, separated by 1-min intervals) in 23 Ob (12 females, 11 males), 23 T1DM (10 females and 13 males) patients and 20 healthy (CL, 10 females and 10 males) children. Blood glucose of T1DM patients was kept in the 4.4-6.1 mM range for at least 90 minute prior to and during exercise. Blood samples were drawn at rest and after every other exercise bout. Results: In Ob, TNF-a and IL-2 were significantly greater (p<0.0167) as compared to T1DM and CL, both at baseline and throughout exercise. All other variables, while not significant, were quantitatively elevated in Ob vs. CL. In T1DM, IL-4 and IL-8 levels were similar to Ob, IL-2 and TNF-a similar to CL, and IL-6, IL-5, IL-13, IL-4 levels were intermediate between the Ob and CL groups. Conclusions: During exercise, therefore, both Ob and T1DM children displayed exaggerated pro-inflammatory responses, although with clearly different magnitude and involved mediators. Our data support the necessity to identify specific exercise formats through which each at-risk pediatric population can draw maximal beneficial health effects. Conflict of interest:None declared.

Resting and exercise-induced IL-6 levels in children with Type 1 diabetes reflect hyperglycemic profiles during the previous 3 days

Poor glycemic control in Type 1 diabetes (T1DM) causes long-term cardiovascular complications, at least in part via chronic, low-grade inflammation associated with recurrent hyperglycemia. While physical activity can reduce both inflammation and cardiovascular risks, the underlying molecular mechanisms remain unclear. This is particularly important for T1DM children, for whom the prevention of long-term cardiovascular complications must include optimization of exercise-related anti-inflammatory strategies. We therefore studied the effect of prior hyperglycemia on resting and exercise-induced inflammatory status (plasma IL-6) in T1DM children. Glycemia was continuously recorded with a continuous glucose monitoring system (CGMS) system for 63 h preceding a 30-min intermittent cycling exercise protocol at approximately 80% peak rate of oxygen uptake (VO2max). Euglycemia (4.4-6.1 mM) was maintained for 90 min before, during, and 30 min after exercise. IL-6 plasma concentration (pg/ml) was measured at baseline, at end exercise, and 30 min postexercise. Subjects were then divided into quartiles based on average glycemia during the CGMS recording. IL-6 levels (pg/ml) were lowest in the quartile with lowest average 3-day glycemia and increased proportionally to greater hyperglycemic exposure; this was observed at baseline (0.86 +/- 0.10, 1.06 +/- 0.16, 1.14 +/- 0.14, 1.20 +/- 0.16), absolute IL-6 change (Delta) at end exercise (0.20 +/- 0.16, 0.32 +/- 0.10, 0.48 +/- 0.09, 0.62 +/- 0.13), and Delta at 30 min postexercise (0.49 +/- 0.13, 0.71 +/- 0.16, 0.89 +/- 0.14, 1.38 +/- 0.33). Therefore, poorly controlled glycemic profile, even in the 63 h preceding an exercise challenge, can alter inflammatory adaptation in T1DM children. Our data underscore the necessity to fully understand all molecular aspects of physical activity to provide the scientific rationale for exercise regimens that will be able to maximize health benefits for T1DM children.

Altered Kinetics of Interleukin-6 and Other Inflammatory Mediators During Exercise in Children With Type 1 Diabetes

Background Leukocyte mobilization and secretions of cytokines, chemokines, and growth factors in children during exercise are necessary biochemical signals for physiological growth and long-term cardiovascular protection. Because of glycemic instability, altered exercise responses, particularly the proinflammatory cytokine interleukin (IL)-6, may occur in type 1 diabetes mellitus (T1DM) that could influence the onset/progression of diabetic vascular complications. Relatively little is known, however, on most molecular aspects of immunomodulatory adaptation to exercise in diabetic children. Methods We therefore studied 21 children (age, 13.4 ± 0.3 years; 13 boys/8 girls) with T1DM and 21 age-matched healthy controls during 30 minutes of intense and intermittent cycling exercise. Euglycemia was maintained during and for greater than 90 minutes before exercise; blood samples for IL-6 and other cytokines/chemokines were drawn before, during (every 6 minutes), and after (every 15 minutes) exercise. Results In T1DM, exercise-induced IL-6 peak occurred earlier and with greater magnitude than that in controls; an exploratory analysis of additional inflammatory mediators displayed a similarly accelerated/exaggerated pattern in T1DM, including the kinetic profiles of tumor necrosis factor α, IL-4, IL-12p70, IL-17, granulocyte-monocyte colony-stimulating factor, monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, and eotaxin (interferon-inducible protein-10 was the only measured variable essentially indistinguishable between groups). Conclusion Therefore, during intense and intermittent exercise, significant alterations in the immunologic pattern of inflammatory regulation occurred in children with T1DM as compared with healthy controls. Our findings underscore how the understanding of all the underlying molecular mechanisms is a necessary prerequisite for achieving effective use of exercise and the full manifestation of its health benefits, particularly in understudied populations such as children with T1DM who are at increased risk for cardiovascular complications.

Dose-dependent relationship between severity of pediatric obesity and blunting of the growth hormone response to exercise.

In children, exercise modulates systemic anabolism, muscle growth, and overall physiological development through the growth hormone (GH)-insulin-like growth factor I (IGF-I) axis. GH secretion, at rest and during exercise, changes with age and maturational status and can be blunted by hyperlipidemia and obesity, with possible negative effects on physiological growth. However, little is known about the effect of progressively more severe pediatric obesity on the GH response to exercise and its relationship to pubertal status. We therefore studied 48 early- or late-pubertal obese children [body mass index (BMI) >95th percentile, separated in tertiles with progressively greater BMI] and 42 matched controls (BMI <85th percentile), who performed ten 2-min cycling bouts at approximately 80% of maximal O2 consumption, separated by 1-min rest intervals. Plasma GH and IGF-I were measured at baseline and end exercise. GH responses were systematically blunted in obese children, with more pronounced blunting paralleling increasing BMI. Although overall the GH response to exercise was greater in late-pubertal than in younger children, this blunting pattern was observed in early- and late-pubertal children. Our results reveal insight into the interaction between pediatric obesity and key modulators of physiological growth and development and underscore the necessity of optimizing physical activity strategies for specific pediatric dysmetabolic conditions.

Ex vivo TCR-induced leukocyte gene expression of inflammatory mediators is increased in type 1 diabetic patients but not in overweight children.

Abnormal systemic concentrations of proinflammatory cytokines/chemokines have been implicated in the development of long‐term cardiovascular complications in type 1 diabetes (T1DM) and obesity. Whether leukocyte white blood cell (WBC) gene expression of these proinflammatory mediators contributes to their increased systemic levels, however, remains unclear, especially in the pediatric patient populations. This study examines mRNA changes of 9 cytokines and chemokines in WBCs following ex vivo immunostimulation from 9 T1DM (13.4 ± 0.5 year, 4F/5 M), 23 overweight (OW, 12.3 ± 0.5 year, 10F/13M, BMI% 97.1 ± 0.5 and > 90.0), and 21 healthy (CL, 13.8 ± 0.7 year, 9F/12 M, BMI% 59.6 ± 4.6 and < 85.0) children.

Kinetic profiles of 18 systemic pro- and anti-inflammatory mediators during and following exercise in children.

While acute changes in systemic pro-/antiinflammatory cytokines occur with exercise, individual kinetics during and following exercise remain unclear; particularly, information is scarce regarding children. This study investigated the exercise-induced kinetic profiles of major pro-/anti-inflammatory mediators in 21 healthy children (13.9 +/- 0.8 yr, 7 M/14 F). Exercise was 30 min of intermittent cycling at approximately 80% VO2max. Multiple blood samples were drawn at baseline, during, and following exercise for cytokines assay. IL-1alpha, IL-6, IL-17, IL-8, IP-10, MIP-1alpha, and MIP-1beta initially decreased (nadir: 14-19 min into exercise) and subsequently exceeded baseline levels (peaks: 20-24 min into exercise). TNF-alpha, IL-12p70, IL-1RA, IL-4, EGF, TGF-alpha, GM-CSF, Eotaxin, and MCP-1 were moderately and persistently decreased throughout. VEGF was unchanged; sCD40L was elevated during exercise and recovery. Our results indicate that key immunomodulators display non-linear, biphasic kinetic profiles in response to exercise, suggesting that detection of exercise-induced changes over baseline may depend on exercise duration and sampling timing.