Future research is clearly needed to clarify the role of complement in the development of cardiovascular disease and mechanisms for its action. The complement system may provide a new area for intervention in the prevention of cardiometabolic disease.

Type 1 diabetes mellitus is a chronic state of insulin deficiency which results from destruction of beta cells by the immune system. The long term microvascular and macrovascular complications can be devastating. Since the discovery of insulin almost 100 years ago new medical therapies have improved the long-term survival for people with type 1 diabetes. Each year we come closer to discovering a cure but much work still needs to be done to eliminate this disease.

Background: Complement promotes inflammatory and immune responses and may affect cardiometabolic risk. This study was designed to investigate the effect of complement components C3 and C4 on cardiometabolic risk in healthy non-Hispanic white adolescents. Methods: Body mass index (BMI), BMI percentile, waist circumference, and percent body fat were assessed in 75 adolescents. Arterial stiffness was assessed using arterial tomography and endothelial function using reactive hyperemia. Fasting lipids, inflammatory markers, and complement levels were measured and oral glucose tolerance test was performed. A single C3 polymorphism and C4 gene copy number variations were assessed. Results: C3 plasma levels increased with measures of obesity. Endothelial function worsened with increased C3 and C4 levels. Triglycerides and LDL increased and HDL and insulin sensitivity decreased with increasing C3 levels but the relationships were lost when body habitus was included in the model. C4 negatively related to HDL and positively to inflammatory markers. Subjects with at least one C3F allele had increased BMI and fat mass index. HDL was significantly related to C4L, C4S, C4A and C4B gene copy number variation. Conclusions: C3 levels increase with increasing body mass and increased C4 levels and copy number are associated with increased cardiometabolic risk in healthy adolescents. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Background Cardiovascular disease has its origins in adolescents. Endothelial dysfunction, arterial stiffness, and decreased endocardial oxygen supply: demand ratios are early functional markers of cardiovascular risk. The goal of this study was to determine the relationships of these markers to physical, inflammatory, and metabolic markers in healthy non‐Hispanic, white adolescents. Methods Thirty‐four of the 75 subjects were female. Mean age was 15.0 ± 1.7 years and mean body mass index (BMI) was 22.0 ± 5.8 kg/m2 (mean ± SD). Reactive hyperemia was measured using venous occlusion plethysmography. Arterial tonometry was used to measure the augmentation index (AIx75) and the Buckberg subendocardial viability ratio. Blood samples were taken to measure inflammatory and lipid markers and oral glucose tolerance test was used to assess insulin sensitivity. Results Reactive hyperemia decreased as body mass and fat mass increased. It also decreased with increasing neutrophil count. The Buckberg index was higher in males and was positively related to insulin sensitivity even when accounting for age, sex, and resting heart rate. AIx75 was not related to any of the other variables. Conclusions These results demonstrate that increased fat mass and decreased insulin sensitivity are related to poorer vascular function and cardiac risk in adolescents before the development of actual cardiovascular disease.

Background: Adipocytes produce complement C3 and respond to activation products of the complement cascade. Increased complement levels in adults predict future cardiometabolic disease such as type 2 diabetes and myocardial infarction. Since these diseases have their origins in childhood we studied the relationships of complement components, C3 and C4, to cardiometabolic risk factors in healthy, nonHispanic white adolescents. Methods: C3 and C4 levels, endothelial function (reactive hyperemia (RH), venous occlusion plethysmography), arterial stiffness (augmentation index (AI), arterial tonometry), lipids, interleukin-6 (IL-6), c-reactive protein, plasminogen activator inhibitor 1 (PAI1) insulin sensitivity and secretion (oral glucose tolerance test) were measured in 59 subjects (29 female, age=15.3±1.7 years, BMI=22.4.1±5.9 kg/m2, mean±SD). BMI percentile, waist circumference and percent body fat (air displacement) were measured to assess adiposity. Results: C3 correlated with multiple cardiometabolic risk factors including reactive hyperemia (r=0.41, p=0.002), LDL (r=0.34 p=0.012), triglycerides (r=0.56, p<0.001), PAI1 (r=0.30, p=0.023) insulin sensitivity (r=-0.31, p=0.024). C3 tended to correlated with AIX (r=0.25, p=0.074) and insulin secretion (r=0.24, p=0.079). C4 levels correlated with RH (r=0.28, p=0.043), AI (r=0.26, p=0.074) and IL-6 (r=0.41, p=0.003). Stepwise regression found that C3 levels predicted LDL independent of measures of adiposity and triglycerides in conjunction with waist circumference while C4 levels in conjunction with BMI%tile predicted AI, and IL-6 in conjunction with waist circumference. Adiposity measures alone predicted RH, HDL, PAI1 and insulin secretion and sensitivity. Conclusions: These results indicate that obesity induced increases in C3 are likely to play a significant role in the development of adverse lipids with increased plasma triglyceride and LDL levels while C4 plays a role in the development of increased arterial stiffness and inflammation. Disclosure R.P. Hoffman: None. M.M. Copenhaver: None. C. Yu: None.

Background: Although not usually manifest until adulthood, evidence indicates that cardiometabolic disease has its origins in pediatrics. If we are truly to decrease cardiometabolic disease we must understand the pathophysiology of cardiometabolic risk in childhood. Individuals with the F polymorphism of the complement C3 gene have increased rates of myocardial infarction and athereosclerosis. Individuals with increased gene copy number of the complement C4 long and A genes have decreased longevity. Methods: C3 F vs. S genotype and C4A, C4B, C4L and C4s gene copy number were measured in 59 non-Hispanic white subjects (29 female, age=15.3±1.7 years, BMI=22.4.1±5.9 kg/m2,, mean±SD). Endothelial function (reactive hyperemia (RH), venous occlusion plethysmography), arterial stiffness (augmentation index (AI), arterial tonometry), lipids, interleukin-6 (IL-6), c-reactive protein, plasminogen activator inhibitor 1 (PAI1) insulin sensitivity and secretion (oral glucose tolerance test) were used to assess cardiometabolic risk. BMI percentile, waist circumference and percent body fat (air displacement) were measured to assess adiposity. Results: Forty percent of subjects had at least one C3F allele. These subjects were found to have increased waist circumference (78±18 vs. 70±11 cm, p=0.029) and higher HDL levels (55±14 vs. 46±11 mg/dl, p=0.024) compared to those with only the S allele. Increased C4L (r=0.34, p=0.017) and C4A (r=0.33, p=0.019) gene copy number were associated with decreased endothelial function. Multiple linear regression including percent body fat and either C4L or C4A showed that both relationships became more significant. Conclusions: In adolescent the C3 F polymorphism gene is associated with increased central obesity but surprisingly increased HDL. Increased C4L and C4A gene copy are associated with decreased endothelial function. This could explain their association with deceased longevity. Disclosure R.P. Hoffman: None. M.M. Copenhaver: None. C. Yu: None.

Objectives In obese adults the shape of the glucose response curve during an oral glucose tolerance test (OGTT) predicts future type 2 diabetes. Patients with an incessant increase or monophasic curves have increased risk compared to those with biphasic curves. Since type 2 diabetes is associated with increased cardiometabolic risk, we studied whether differences in OGTT response curve are associated with differences in cardiometabolic risk factors in healthy adolescents across a wide body mass index (BMI) range. Methods Sixty-nine (33F/36M), white adolescents (age: 15.2 ± 1.7 years; BMI: 21.5 ± 4.7 kg/m2; mean ± SD) were studied. Risk factors measured included percent body fat, blood pressure, lipids, augmentation index, reactive hyperemia, endothelin 1, plasminogen activator 1, inflammatory markers (interleukin 6, c-reactive protein), insulin secretion, insulin sensitivity (Matusda index), and disposition index (DI). Results Thirty-two subjects had biphasic responses; 35 subjects had monophasic responses and two females had incessant increases. Sex did not affect the frequency of responses. Glucose area under the curve during OGTT was greater in those with a mono vs. biphasic curves (p=0.01). Disposition index was markedly lower in subjects with a monophasic curve than in those with a biphasic curve (3.6 [2.3–5.0] vs. 5.8 [3.8–7.6], median [25th, 75th%] p=0.003). Triglyceride to high-density lipoprotein cholesterol (HDL) ratio was higher in subjects with a monophasic curve (p=0.046). Conclusions The decreased disposition index indicates that in healthy adolescents a monophasic response to OGTT is due to decreased insulin secretion relative to the degree of insulin resistance present. This was not associated with differences in most other cardiometabolic risk markers. Trial registration Clinical Trials.gov, NCT02821104.