Pediatrics

Association of leptin and insulin with childhood obesity and retinal vessel diameters

Abstract

Objective:

Childhood obesity is associated with an impaired retinal microcirculation. The aim of the study was to investigate the association between specific obesity-related biomarkers, physical fitness and retinal vessel diameters in school children.

Design and Subjects:

We studied 381 children aged 10–11 years (body mass index (BMI): 19.3±3.7 kg m−2) in a school-based setting.

Measurements:

Anthropometric measurements and blood sampling were conducted using standard protocols for children. The serum biomarkers leptin, adiponectin, insulin as well as interleukin-6 (IL-6) were analyzed. Physical fitness was determined by a six-item-test battery and physical activity by use of a questionnaire. Central retinal arteriolar equivalent (CRAE), central retinal venular equivalent (CRVE) and the arteriolar-to-venular diameter ratio (AVR) were assessed with a non-mydriatic vessel analyzer (SVA-T) using a computer-based program.

Results:

Compared with normal weight children (n=254), obese children (n=39) showed higher leptin (P<0.001), higher insulin (P<0.001), higher IL-6 (P<0.001) and lower adiponectin levels (P=0.013). Obese children demonstrated wider CRVE (P=0.041) and lower AVR (P<0.001). Higher leptin levels were associated with wider CRVE (P=0.032) and lower AVR (P=0.010), that was BMI dependent. Insulin levels were associated with arteriolar (P=0.045) and venular dilatation (P=0.034) after adjustment for BMI. No significant associations between adiponectin levels, IL-6 levels, physical fitness or physical activity and retinal vessel diameter were observed. Lower leptin levels were independently correlated with higher physical fitness (r=−0.33; P<0.001).

Conclusion:

Leptin and insulin levels are associated with changes of the retinal microcirculation. Especially insulin seems to be a good target marker for the cardiometabolic risk assessment in children since elevated insulin levels are independently associated with microvascular end-organ alterations at an early stage. Lifestyle intervention studies are warranted to examine whether improvement of physical fitness or weight reduction can affect cardiometabolic risk markers and reverse alterations of the retinal microcirculation.

Introduction

During the last decades, the prevalence of overweight and obesity has been rising significantly in most parts of the world.1 It is known, that obesity can often be tracked from childhood to adulthood2 and childhood obesity has been associated with early signs of atherosclerosis3 and adult coronary heart disease.4 In recent years, the analysis of retinal vessel diameter has been established to detect subclinical signs of atherosclerosis even in childhood.5 The retinal vasculature is noninvasively accessible with the use of a fundus camera and it offers a unique opportunity to analyze the effects of obesity on small brain vessels.5 Thereby, obesity-related microvascular alterations can be diagnosed before manifestation of vascular disease, which has strong implications for the treatment and prevention of obesity early in life. Retinal vessel diameters are sensitive tissue biomarkers that measure the cumulative influence of cardiovascular risk factors on the microvascular bed.

Retinal arteriolar narrowing and wider retinal venules have been associated with hypertension and cerebral infarction in older population.6 Obesity, inflammation and physical inactivity have all been linked to venular dilatation in large population-based studies in adults.5 In middle-aged and older persons with type 2 diabetes, wider venular diameters have been described with controversial findings for arteriolar diameters.5, 7 The atherosclerosis risk in communities study revealed an independent association of retinal arteriolar narrowing with the risk of diabetes7 whereas the multi-ethnic study of atherosclerosis study related larger retinal arteriolar calibers to diabetes.8

In children, retinal vessel diameters have so far only been linked to obesity and hypertension. Childhood obesity is associated with retinal venular dilatation and a lower arteriolar-to-venular ratio (AVR).9 Similar changes were associated with carbohydrate nutrition as greater consumption of carbohydrates and soft drinks were associated with retinal arteriolar narrowing and venular widening in 2353 12-year-old children, even after multivariable adjustment.10 Also higher childhood blood pressure has been linked to retinal arteriolar narrowing.11 In a previous publication of our parent study, we could demonstrate an association between body mass index (BMI), blood pressure and retinal vessel diameter in school children. The classical cardiovascular risk factors such as high-density lipoprotein, triglycerides and fasting glucose were not associated with retinal vessel diameters after adjusting for BMI. Higher high-sensitive C-reactive protein levels were independently associated with wider venular diameter.12 Nevertheless, high-sensitive C-reactive protein is a nonspecific inflammatory marker, which is also elevated in acute infection and to date no cut off values are established in children to discriminate between acute illness and systemic inflammation.13, 14

The association between more specific metabolic peptides, for example, leptin, insulin or adiponectin and retinal vessel diameters, has not been investigated to date, although leptin, insulin and adiponectin have been linked with overnutrition, obesity, chronic low-grade inflammation and endothelial dysfunction.15

Leptin, an adipocyte-derived hormone and cytokine, is involved in the regulation of food intake, insulin signaling, and fat and lipid metabolism.16 Several studies suggest that elevated leptin concentration, as found in obesity, impairs endothelial function and promotes atherogenesis by inducing oxidative stress.17 Also, raised blood pressure in obesity, is at least partly, mediated by increased leptin levels via activation of the sympathetic nervous system.18 In contrast, leptin decreases after weight loss and exercise interventions.19

Overfeeding and obesity are often associated with insulin resistance and hyperinsulinemia and responsible for an increased sympathetic nervous activity20 as well as the premature development of cardiovascular disease and hypertension,21 which are accompanied by the formation of atherosclerotic plaques even in childhood.22 Physical activity has been shown to lower the risk of developing insulin resistance during adolescence.23

On the contrary, adiponectin, a hormone that is also produced by adipose tissue, has anti-atherogenic properties24 and seems to be protective against insulin resistance and type 2 diabetes.25 Adiponectin levels are lower in children with metabolic syndrome,26 whereas the association between exercise and adiponectin levels is less clear.27 Regular exercise, however, seems to be protective against early changes in retinal microvasculature in obese adults28 and in healthy children.29

Inflammation, oxidative stress, hyperleptinemia and nitric oxide dysregulation have all been implicated as potential pathways in the link between larger retinal venules and obesity development. To date, the association between leptin, insulin, obesity and retinal vessel diameter has not been investigated.5 This study analyzed the association between metabolic peptides leptin, insulin, adiponectin and interleukin-6 (IL-6) with early changes in retinal vessel diameters. This approach helps to determine which circulating risk factors affect vascular structure and function in childhood obesity. In addition, physical fitness and physical activity have been shown to influence adipokine levels, therefore the association between physical fitness, physical activity and retinal vessel diameters were analyzed.

Materials and methods

Presented data are cross-sectional and part of a comprehensive randomized controlled school- and family-based lifestyle intervention trial in secondary schools that aims to analyze and improve cardiometabolic risk factors and vascular function in large and small vessels of children aged 10–11 years over a period of 4 years by increasing physical activity, physical fitness, psychological well-being and the motivation to exercise.12

The study was conducted in 15 secondary schools in southern Germany. Both children and parents were informed (in German and Turkish) about the study and only data from children with written consent were included in the anonymous data analysis. The study protocol was approved by the ethics committee of the University Hospital, Klinikum rechts der Isar, Technische Universität München. The study design follows the fundamental principles of the Declaration of Helsinki. The clinical trial registration number is NCT00988754.30

Anthropometrics

All clinical examinations were conducted by trained medical staff according to standardized procedures during classroom lessons in three separate rooms inside the schools. Body height and body weight were measured with minimal clothing without shoes. Body weight was measured to the nearest 0.1 kg using a calibrated balance scale. Body height was measured to the nearest 0.1 cm by a rigid stadiometer. BMI was calculated as weight in kilograms divided by the square of height in meters. Children with a BMI lower than the 10th percentile were classified as underweight, between the tenth and 90th percentile as normal, between the 90th and 97th percentile as overweight, and above the 97th percentile as obese. Reference data from German children were used.31 The BMI-SDS (BMI-s.d. score) was determined using the LMS method32 using national reference data.31 In addition, overweight and obesity were defined using the international obesity task force age- and sex-specific cut off points.33

Blood pressure was measured manually at the brachial artery in the cubital fossa after 5 min of rest in a supine position according to a standardized protocol. General recommendations were followed for the selection of appropriate cuff size.34

Blood sampling and analysis

Fasting blood samples were taken between 0800 and 1000 at the school by venipuncture of an antecubital vein in either sitting or lying position, using vacuum tubes. Blood samples were collected by qualified medical staff and immediately transported to the laboratory for analysis.

Adiponectin and leptin concentrations were both determined using commercially available quantitative sandwich enzyme-linked immunosorbent assays (R&D Systems, Minneapolis, MN, USA). Serum insulin and IL-6 concentrations were measured using an automated immunoanalyzer system (cobas 411, Roche Diagnostics, Mannheim, Germany). Both tests are sandwich immunoassays using the principle of electrochemiluminescence for signal generation.

Retinal vascular caliber

Retinal microvascular diameters and the AVR were assessed with a non-mydriatic static retinal vessel analyzer (SVA-T, Imedos Systems UG, Jena, Germany), which has been described in detail elsewhere.12 Briefly, the diameters of retinal arterioles and venules were measured using a fundus camera and a semi-automated software package (Visualis 2.80, Imedos Systems UG). The system allows noninvasive online measurement of the diameters of retinal vessels without mydriasis. All retinal arterioles and venules were differentiated by a single experienced examiner in the outer ring zone and measured by the automated software. Diameters were calculated to central retinal arteriolar and venular equivalents (CRAE and CRVE), using the Parr-Hubbard formula.35 The CRAE and CRVE were used to calculate the AVR.

Two valid retinal photographs were taken from the right eye and were gradable for each child. In six children, only one retinal photograph was gradable. Reproducibility of measurements was assessed by repeated analysis of 20 randomly selected retinal photographs. The correlation between the measurements was r=0.92 (CRAE), r=0.97 (CRVE) and r=0.89 (AVR) (P<0.001, for all).

Physical fitness and physical activity

Physical fitness was measured by means of the Munich fitness test. This standardized test includes six items (step test, goal throwing, stand-and-reach, jump-and-reach, flexed arm hanging and ball bouncing) designed to evaluate cardiopulmonary fitness, coordination, muscle strength and flexibility in children. For each item, children received gender- and age-specific t-scores between 30 and 70 points. The sum of the six items divided by the number of items yielded the total t-score.36 The physical fitness tests were conducted by trained staff in the physical exercise lessons in the school gym on a separate examination day.

Physical activity was measured by a validated questionnaire concerning the amount of moderate-to-vigorous physical activity and sedentary behavior. The following standardized question was used to analyze physical activity: ‘Over a typical or usual week, on how many days are you physically active for a total of at least 60 min per day?’.37 Questionnaires were filled out in class.

Statistical analysis

Data analysis was performed using SPSS statistical software version 20 (SPSS Inc., Chicago, IL, USA). For qualitative data absolute and relative frequencies are presented. Quantitative data are described by mean±s.d. or by median (minimum–maximum) for skewed data. Comparisons of quantitative data between two independent groups were conducted by two-sample t-tests or the Mann–Whitney U-tests, respectively. The association between retinal vessel diameters and cardiometabolic risk markers, measures of physical fitness or activity was assessed with Pearson’s correlation coefficient r (for skewed data after log-transformation). In addition, associations between retinal vascular parameters and anthropometric and cardiometabolic risk parameters were evaluated in different linear regression models to adjust for possible confounders. We constructed three models: In Model one, we adjusted for age and gender. In Model two, we further adjusted for BMI and model three included additional adjustment for systolic and diastolic blood pressure.

For illustration of the relationship, quartiles of anthropometric and cardiometabolic risk parameters were used as independent variables and estimated means and standard errors of retinal vascular parameters are presented for each quartile. P-values of these regression analyses are denoted as ‘P for trend’. The difference for retinal vessel parameter according to physical activity was compared in tertiles (less active <2 days per week (d/wk), moderate active=3–4 d/wk, active >5 d/wk, according to international recommendations of physical activity for children (WHO Europe 200938). The detection value of IL-6 was 1.49 pg ml−1, therefore the differences in retinal vascular parameter in relation to IL-6 were compared between two groups (below and above the threshold (1.49 pg ml−1; >1.49 pg ml−1). For all statistical tests a two-sided level of significance of α=5% was used.

Results

Population and anthropometrics

Out of 792 children in 32 school classes, 623 children (78.7%) had written informed consent from their parents. 587 children (age: 11.1±0.6 years, height: 147.1±7.6 cm; weight: 42.0±10.9 kg; BMI: 19.2±3.6 kg m−2) took part in physical examination, 36 children were ill or absent at the day of examination. A total of 387 children had blood samples. Anthropometric and blood data were obtained from 381 children (158 girls/223 boys) (Figure 1). No relevant differences in anthropometric data between children with or without blood samples were observed. The average BMI of children with complete data was 19.3±3.7 kg m−2. Out of the 381 children enrolled in this analysis, 7.9% were underweight, 66.7% had normal weight and 25.4% of the children were overweight or obese according to national reference data. Compared with the international obesity task force cut off points, 8.1% of the children were underweight, 61.9% had normal weight and 30.0% of the children were overweight or obese. The application of the international obesity task force cut off points reclassified 17 normal weight children (according to national reference data) as overweight children and 6 obese children (according to national reference data) as overweight. Girls had higher BMI (19.8±3.7 kg m−2 vs 19.0±3.7 kg m−2, P=0.042) as compared with boys.

Figure 1
figure1

Flowchart of the recruitment and enrollment process of the study including number of children in weight groups.

Serum biomarkers

Median leptin concentration was 8.0 (0.6–49.9) ng ml−1, median adiponectin level was 6.1 (0.2–43.2) μg ml−1, median insulin level was 9.4 (2.6–97.2) μU ml−1 and median IL-6 concentration was 1.5 (1.5–16.9) pg ml−1 (Table 1). Leptin levels (11.6 vs 6.5 ng ml−1, P<0.001), IL-6 concentration (1.50 vs 1.49 pg ml−1, P=0.002) and insulin levels (10.9 vs 8.4 μU ml−1, P<0.001) were higher in girls compared with boys. Adiponectin levels were comparable between boys and girls (P=0.760). Overweight children (n=58) had higher leptin levels (17.3 vs 7.2 ng ml−1, P<0.001), higher insulin levels (10.6 vs 8.6 μU ml−1, P<0.001) and lower adiponectin levels (5.1 vs 6.4 μg ml−1, P=0.005) compared with normal weight children (n=254). No significant difference in IL-6 concentration was found with respect to body weight (P=0.105). In obese children (n=39) higher leptin levels (24.2 vs 7.2 ng ml−1, P<0.001), higher insulin levels (18.3 vs 8.6 μU ml−1, P<0.001), higher IL-6 concentration (2.2 vs 1.5 pg ml−1, P<0.001) and lower adiponectin levels (5.2 vs 6.4 μg ml−1, P=0.013) were measured compared with normal weight children.

Table 1 Baseline characteristics of the study population

Physical fitness/physical activity

The mean physical fitness score for all children (n=356) was 48.0±3.9 points (pts) (Table 1). 36.1% of all children (n=333) reported to be active for >60 min/day on 3 or 4 days a week, 19.8% of the children were more active (>5 d/wk), 44.1% of the children reported to be less active (<3 d/wk). No significant difference in physical fitness was observed between girls and boys (47.6±3.8 vs 48.4±4.0 pts, P=0.051). Boys showed a higher amount of regular physical activity per day than girls (3.3 d/wk compared with 2.6 d/wk, P<0.001). Physical fitness was lower in overweight children (46.1±3.3 pts) and obese children (46.1±4.1 pts) compared with normal weight children (48.7±3.9 pts, P<0.001, for both). No significant difference in the amount of physical activity was observed between overweight (2.6 d/wk, P=0.089) or obese children (3.1 d/wk, P=0.852) and normal weight peers (3.1 d/wk).

Retinal vessel diameters

The mean retinal arteriolar diameter was 208.2±15.8 μm, the mean venular diameter was 236.9±15.9 μm, and the mean AVR was 0.88±0.06 (Table 1). Mean arteriolar and venular diameter were wider in girls compared with boys (CRAE: 211.8 vs 205.6 μm, CRVE: 240.3 vs 234.4 μm, P<0.001, for both). Overweight children had lower AVR than normal weight peers (0.87 vs 0.89, P=0.041). In obese children, lower AVR (0.85 vs 0.89, P<0.001) and wider venules (241.3 vs 235.9 μm, P=0.041) were observed. In Table 2, retinal vascular parameters of the 1st to 4th quartile in relation to the anthropometric and cardiometabolic risk parameters are presented after adjusting for age and gender. Retinal vascular parameters in relation to physical activity were compared in tertiles (less active <2 d/wk, moderate active=3–4 d/wk, active >5 d/wk) and in relation to IL-6 concentration in two groups (below and above the threshold: 1.49 pg ml−1; >1.49 pg ml−1). AVR was lower in the 4th quartile of BMI compared with the 1st quartile (−0.03, P for trend: 0.006). Similar results were found for BMI-SDS quartiles (P=0.004). The CRVE was significantly wider in the 4th quartile of leptin compared with the 1st quartile (mean difference between the 1st and 4th quartile: 7.1 μm, P for trend: 0.009; Table 2).

Table 2 Retinal vessel diameter and AVR in relation to anthropometric parameters and cardiovascular risk factors

Regression analysis

The association between retinal vessel diameters, cardiometabolic risk markers and physical fitness/physical activity are presented in Table 3. There was a significant association between CRVE and BMI after adjusting for age and gender (0.44 μm increase in CRVE per unit increase of BMI, P=0.046). No significant association between CRVE and BMI-SDS was observed (P=0.119). AVR significantly decreased with every unit of BMI (β: −0.003; P<0.001) and BMI-SDS (β: −0.008; P=0.006). Wider CRVE (β: 0.20 μm, P=0.032) and lower AVR (β: −0.001; P=0.010) were associated with higher leptin levels after adjusting for age and gender. This association failed to maintain significance after adjusting for BMI or BMI-SDS. A significant increase in CRAE (β: 0.15 μm, P=0.045) was observed per unit increase of insulin after adjustment for BMI. A comparable increase in CRVE was observed per unit increase with adjustment for age and gender (β: 0.20 μm, P=0.005) and with adjustment for age, gender and BMI (β: 0.16 μm, P=0.034). The association between CRAE and insulin remained significant after adjustment for systolic and diastolic blood pressure. After adjustment for BMI-SDS, the association between CRAE and insulin failed to maintain significant (Model 2: P=0.089; Model 3: P=0.096). The association between CRVE and insulin remained significant after adjustment for BMI-SDS instead of BMI (Model 2: P=0.020; Model 3: P=0.033). No significant association between physical activity, physical fitness and retinal vascular parameters was observed (Table 3). Nevertheless, children with higher physical fitness level had lower BMI (r=−0.31, P<0.001), lower leptin levels (r=− 0.42, P<0.001) and lower insulin levels (r=−0.18, P<0.001). The association between physical fitness and leptin levels (r=−0.33, P<0.001) remained significant after adjustment for BMI and age.

Table 3 Regression analysis of retinal vessel diameter and AVR in relation to cardiometabolic risk factors, inflammation markers, physical fitness and activity

Discussion

Our study provides new data on the relationship of metabolic peptides and retinal microvasculature caliber in school–aged children. Our data suggest a direct association between insulin and wider retinal venular diameters, whereas the association between higher leptin levels and retinal venular dilatation seems to be strongly linked to BMI. Especially insulin seems to be a good target marker for the cardiometabolic risk assessment in children.

Our data confirm previous findings indicating that adverse changes to the microvascular structure were associated with adiposity even in childhood.9, 39 We found that higher BMI was associated with wider retinal venular diameter (0.44 μm increase in CRVE per unit increase of BMI, P=0.046) and lower AVR (β: −0.003; P<0.001). The association between AVR and BMI remained after adjustment for blood pressure (P=0.003), whereas no significant association between CRVE and BMI was found after adjustment for blood pressure. Children in the highest quartile of BMI had wider CRVE in comparison to those with BMI in the lowest quartile (239.3 μm compared with 234.7 μm) with a significant group difference between obese and normal weight children (P=0.041).

In previous studies, inflammation, oxidative stress, hyperleptinemia and nitric oxide dysregulation have all been discussed as potential pathways for the link between obesity and larger retinal venules. Our study is the first to assess the direct association between different metabolic peptides and retinal vessel diameter. The linear regression analysis showed a significant association between higher leptin levels and wider retinal venular diameters, which was, however, not independent of BMI. These results confirm the direct association between higher BMI and wider retinal venular diameters. Potential pathophysiological mechanisms that may explain wider retinal venular vessel diameters in the context of overweight and increased leptin levels are low-grade inflammation and leptin-induced endothelial activation by increased nitric oxide production modulating venular caliber at an early age.17, 16

In our study, children with higher insulin levels had significantly wider retinal venular diameters after adjustment for BMI or BMI-SDS. It appears that insulin can independently regulate retinal venular diameters.40 Data from the Blue Mountains eye study showed that individuals with larger retinal venules had a higher risk to become obese in the follow-up, supporting the role of microvascular function in the development of overweight and obesity.41

Furthermore, we observed an association between higher insulin levels and wider arteriolar diameter, even after adjustment for BMI and blood pressure. In adults, insulin has been shown to act as an arterial vasodilator in brachial42 as well as renal and ophthalmic arteries.43 It has been suggested that insulin has direct dilatory effects on arterioles and venules in order to improve glucose disposal and direct blood flow to nutritive capillary beds in the periphery.44, 45 The vasodilatory effects of insulin seem to be mediated in large part by the stimulation of nitric oxide (NO) release. Therefore, insulin may induce retinal arteriolar dilatation in children by means of increasing NO production. The potential interaction between leptin and insulin may be another potential mechanism involving NO. Leptin enhances nitric oxide (NO) production via Akt phosphorylation in endothelial cells. Previous data show a direct interaction between leptin and insulin in the arterial tree. Insulin potentiates leptin-induced NO release by enhancing leptin-stimulated phosphorylation of Akt and endothelial NO synthase.40 This mechanism may be one of the reasons for the association of insulin with wider retinal arterioles in obesity.

Previous investigations have shown a strong association between retinal arteriolar narrowing and hypertension, higher risk of cardiovascular disease and stroke. These impairments have primarily been discussed as functional phenomena, which may be caused by increased sympathetic activity.11 Endothelial and smooth muscle dysfunction seem to induce vasoconstriction or, as in chronic hypertension, structural adaptations of the endothelium and vessel wall causing a loss of arteriolar lumen diameter. Wider arteriolar and venular diameters have inconsistently been reported in type 2 diabetes mellitus. Possible mechanisms are a disruption of the endothelial surface layer followed by a reduced vascular reactivity and endothelial dysfunction, that are induced mainly by concomitant systemic inflammation.46 These mechanisms may help explain wider retinal venular and wider retinal arteriolar diameters in children with higher insulin levels. Further investigations are necessary to examine the short-term or chronic effects of insulin levels on retinal vessels diameter in adulthood as well as in childhood.

In adults, the role of IL-6 and adiponectin in endothelial dysfunction or retinal vessel diameter have been investigated,47, 48 whereas no data for children exist to date. We found no association between adiponectin or IL-6 levels and retinal vessel diameters in children. Nevertheless, obese children at this early age showed an unfavorable inflammatory profile with lower adiponectin and higher IL-6 levels than normal weight peers. These results confirm early signs of chronic low-grade inflammation in this age group.

Physical activity and physical fitness seem to counteract alterations of the retinal microvasculature in obese adults and children, whereas inactivity such as TV time and media use seem to aggravate retinal vascular abnormalities.5, 28, 29, 39 In this study, no significant association between physical fitness and retinal microvasculature was observed. This may be explained by the physical fitness assessment used, which primarily measured different motor abilities. The study design with a focus on a practical and applicable approach did not allow the use of ergometry tests in the school setting. Nevertheless, the independent association of lower leptin levels with higher physical fitness suggests that regular exercise has the potential to influence low-grade inflammation and sustain health in childhood. Intervention programs may need to focus more on cardiorespiratory fitness rather than a variety of motor skills.

The analysis of retinal vessel diameters allows the noninvasive assessment of the association between cardiometabolic risk factors and microvascular end-organ impairments. The current analysis is cross-sectional and no causal association relating to physical fitness and health, cardiometabolic risk factors and retinal vessel diameter can be assessed. A prospective long-term follow-up is warranted to proof the associations between physical fitness and activity, cardiometabolic risk and the retinal microvasculature. Furthermore, pubertal development was not assessed by Tanner stage, which was not feasible in our school-based setting. To determine pubertal stages, we analyzed estradiol and testosterone levels. Nevertheless we did not find any association between sex steroid levels and retinal vessel diameters (data not shown).

In conclusion, our data present leptin and insulin as cardiovascular risk factors in overweight and obese school children, which are associated with early changes in retinal microvasculature. Especially insulin seems to be a good marker for the cardiometabolic risk assessment in children since elevated insulin levels are independently associated with microvascular end-organ alterations at an early stage. With respect to the clinical implications it is important to note that insulin and leptin are single circulating biomarkers acting on a complex vascular system. We therefore postulate the use of retinal vessel diameters as a tissue biomarker to determine the cumulative subclinical effects of circulating risk factors on the microvasculature in children. The available data and present study emphasize the importance and relevance of retinal vessel analysis in childhood obesity. Early diagnosis of vascular impairments can improve cardiovascular risk stratification, ensures sufficiently early initiation and monitoring of treatment strategies such as lifestyle modifications and, thereby, has the potential to improve prevention of childhood obesity and associated cardiovascular disease manifestations later in life.

References

  1. 1

    Lobstein T . Summary: the rising crisis. Obes Rev 2004; 5: 4–85.

  2. 2

    Dietz WH . Childhood weight affects adult morbidity and mortality. J Nutr 1998; 128: 411S–414S.

  3. 3

    Skilton MR, Celermajer DS . Endothelial dysfunction and arterial abnormalities in childhood obesity. Int J Obes (Lond) 2006; 30: 1041–1049.

  4. 4

    Bibbins-Domingo K, Coxson P, Pletcher MJ, Lightwood J, Goldman L . Adolescent overweight and future adult coronary heart disease. N Engl J Med 2007; 357: 2371–2379.

  5. 5

    Ikram MK, Ong YT, Cheung CY, Wong TY . Retinal vascular caliber measurements: clinical significance, current knowledge and future perspectives. Ophthalmologica 2012; 229: 125–136.

  6. 6

    Wang JJ, Liew G, Klein R, Rochtchina E, Knudtson MD, Klein BE et al. Retinal vessel diameter and cardiovascular mortality: pooled data analysis from two older populations. Eur Heart J 2007; 28: 1984–1992.

  7. 7

    Wong TY, Klein R, Sharrett AR, Schmidt MI, Pankow JS, Couper DJ et al. Retinal arteriolar narrowing and risk of diabetes mellitus in middle-aged persons. JAMA 2002; 287: 2528–2533.

  8. 8

    Nguyen TT, Wang JJ, Sharrett AR, Islam FM, Klein R, Klein BE et al. Relationship of retinal vascular caliber with diabetes and retinopathy: the Multi-Ethnic Study of Atherosclerosis (MESA). Diabetes Care 2008; 31: 544–549.

  9. 9

    Cheung N, Saw SM, Islam FM, Rogers SL, Shankar A, de HK et al. BMI and retinal vascular caliber in children. Obesity (Silver Spring) 2007; 15: 209–215.

  10. 10

    Gopinath B, Flood VM, Wang JJ, Smith W, Rochtchina E, Louie JC et al. Carbohydrate nutrition is associated with changes in the retinal vascular structure and branching pattern in children. Am J Clin Nutr 2012; 95: 1215–1222.

  11. 11

    Mitchell P, Cheung N, de HK, Taylor B, Rochtchina E, Islam FM et al. Blood pressure and retinal arteriolar narrowing in children. Hypertension 2007; 49: 1156–1162.

  12. 12

    Hanssen H, Siegrist M, Neidig M, Renner A, Birzele P, Siclovan A et al. Retinal vessel diameter, obesity and metabolic risk factors in school children (JuvenTUM 3). Atherosclerosis 2012; 221: 242–248.

  13. 13

    Deboer MD . Obesity, systemic inflammation, and increased risk for cardiovascular disease and diabetes among adolescents: a need for screening tools to target interventions. Nutrition 2013; 29: 379–386.

  14. 14

    Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO III, Criqui M et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003; 107: 499–511.

  15. 15

    Ciccone M, Vettor R, Pannacciulli N, Minenna A, Bellacicco M, Rizzon P et al. Plasma leptin is independently associated with the intima-media thickness of the common carotid artery. Int J Obes Relat Metab Disord 2001; 25: 805–810.

  16. 16

    Koh KK, Park SM, Quon MJ . Leptin and cardiovascular disease: response to therapeutic interventions. Circulation 2008; 117: 3238–3249.

  17. 17

    Beltowski J . Leptin and atherosclerosis. Atherosclerosis 2006; 189: 47–60.

  18. 18

    Hall JE, da Silva AA, do Carmo JM, Dubinion J, Hamza S, Munusamy S et al. Obesity-induced hypertension: role of sympathetic nervous system, leptin, and melanocortins. J Biol Chem 2010; 285: 17271–17276.

  19. 19

    Venner AA, Lyon ME, Doyle-Baker PK . Leptin: a potential biomarker for childhood obesity? Clin Biochem 2006; 39: 1047–1056.

  20. 20

    Esler M, Straznicky N, Eikelis N, Masuo K, Lambert G, Lambert E . Mechanisms of sympathetic activation in obesity-related hypertension. Hypertension 2006; 48: 787–796.

  21. 21

    Sinaiko AR, Gomez-Marin O, Prineas RJ . Relation of fasting insulin to blood pressure and lipids in adolescents and parents. Hypertension 1997; 30: 1554–1559.

  22. 22

    McGill HC Jr, McMahan CA, Tracy RE, Oalmann MC, Cornhill JF, Herderick EE et al. Relation of a postmortem renal index of hypertension to atherosclerosis and coronary artery size in young men and women. Pathobiological determinants of atherosclerosis in youth (PDAY) research group. Arterioscler Thromb Vasc Biol 1998; 18: 1108–1118.

  23. 23

    Telford RD, Cunningham RB, Telford RM, Kerrigan J, Hickman PE, Potter JM et al. Effects of changes in adiposity and physical activity on preadolescent insulin resistance: the Australian LOOK longitudinal study. PloS One 2012; 7: e47438.

  24. 24

    Gil-Campos M, Canete RR, Gil A . Adiponectin, the missing link in insulin resistance and obesity. Clin Nutr 2004; 23: 963–974.

  25. 25

    Spranger J, Kroke A, Mohlig M, Bergmann MM, Ristow M, Boeing H et al. Adiponectin and protection against type 2 diabetes mellitus. Lancet 2003; 361: 226–228.

  26. 26

    Gilardini L, McTernan PG, Girola A, da Silva NF, Alberti L, Kumar S et al. Adiponectin is a candidate marker of metabolic syndrome in obese children and adolescents. Atherosclerosis 2006; 189: 401–407.

  27. 27

    Metcalf BS, Jeffery AN, Hosking J, Voss LD, Sattar N, Wilkin TJ . Objectively measured physical activity and its association with adiponectin and other novel metabolic markers: a longitudinal study in children (EarlyBird 38). Diabetes Care 2009; 32: 468–473.

  28. 28

    Hanssen H, Nickel T, Drexel V, Hertel G, Emslander I, Sisic Z et al. Exercise-induced alterations of retinal vessel diameters and cardiovascular risk reduction in obesity. Atherosclerosis 2011; 216: 433–439.

  29. 29

    Gopinath B, Baur LA, Wang JJ, Hardy LL, Teber E, Kifley A et al. Influence of physical activity and screen time on the retinal microvasculature in young children. Arterioscler Thromb Vasc Biol 2011; 31: 1233–1239.

  30. 30

    Siegrist M, Hanssen H, Lammel C, Haller B, Halle M . A cluster randomised school-based lifestyle intervention programme for the prevention of childhood obesity and related early cardiovascular disease (JuvenTUM 3). BMC Public Health 2011; 11: 258.

  31. 31

    Kromeyer-Hauschild K, Wabitsch M, Kunze D, Geller F, Geis HC, Hesse V et al. Perzentile für den Body Mass Index für das Kindes- und Jugendalter unter Heranziehung verschiedener deutscher Stichproben. Monatsschr Kinderheilkd 2001; 149: 807–818.

  32. 32

    Cole TJ . The LMS method for constructing normalized growth standards. Eur J Clin Nutr 1990; 44: 45–60.

  33. 33

    Cole TJ, Lobstein T . Extended international (IOTF) body mass index cut-offs for thinness, overweight and obesity. Pediatr Obes 2012; 7: 284–294.

  34. 34

    National High Blood Pressure Education Program Working Group on High Blood in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 2004; 114: 555–576.

  35. 35

    Hubbard LD, Brothers RJ, King WN, Clegg LX, Klein R, Cooper LS et al. Methods for evaluation of retinal microvascular abnormalities associated with hypertension/sclerosis in the Atherosclerosis Risk in Communities Study. Ophthalmology 1999; 106: 2269–2280.

  36. 36

    Rusch H, Irrgang W . Münchner Fitnesstest. Haltung und Bewegung 1994; 14: 4–11.

  37. 37

    Prochaska JJ, Sallis JF, Long B . A physical activity screening measure for use with adolescents in primary care. Arch Pediatr Adolesc Med 2001; 155: 554–559.

  38. 38

    Carroquino Salto M Percentage of Physically Active Children and Adolescents. http://www.euro.who.int/__data/assets/pdf_file/0012/96987/2.4.-Percentage-of-physically-active-children-EDITED_layoutedV2.pdf 2013. Fact Sheet 2.4. Accessed: 15-2-2013.

  39. 39

    Gopinath B, Baur LA, Teber E, Liew G, Wong TY, Mitchell P . Effect of obesity on retinal vascular structure in pre-adolescent children. Int J Pediatr Obes 2011; 6: e353–e359.

  40. 40

    Vecchione C, Aretini A, Maffei A, Marino G, Selvetella G, Poulet R et al. Cooperation between insulin and leptin in the modulation of vascular tone. Hypertension 2003; 42: 166–170.

  41. 41

    Wang JJ, Taylor B, Wong TY, Chua B, Rochtchina E, Klein R et al. Retinal vessel diameters and obesity: a population-based study in older persons. Obesity (Silver Spring) 2006; 14: 206–214.

  42. 42

    Scherrer U, Randin D, Vollenweider P, Vollenweider L, Nicod P . Nitric oxide release accounts for insulin's vascular effects in humans. J Clin Invest 1994; 94: 2511–2515.

  43. 43

    Schmetterer L, Muller M, Fasching P, Diepolder C, Gallenkamp A, Zanaschka G et al. Renal and ocular hemodynamic effects of insulin. Diabetes 1997; 46: 1868–1874.

  44. 44

    Bouskela E, Cyrino FZ, Wiernsperger N . Effects of insulin and the combination of insulin plus metformin (glucophage) on microvascular reactivity in control and diabetic hamsters. Angiology 1997; 48: 503–514.

  45. 45

    Kraemer-Aguiar LG, Maranhao PA, Cyrino FZ, Bouskela E . Waist circumference leads to prolonged microvascular reactive hyperemia response in young overweight/obese women. Microvasc Res 2010; 80: 427–432.

  46. 46

    Ikram MK, de Jong FJ, Vingerling JR, Witteman JC, Hofman A, Breteler MM et al. Are retinal arteriolar or venular diameters associated with markers for cardiovascular disorders? The Rotterdam Study. Invest Ophthalmol Vis Sci 2004; 45: 2129–2134.

  47. 47

    Bachmayer C, Kemmer A, Ehrmann N, Hasenberg T, Lammert A, Hammes HP . Adipokines and endothelial dysfunction in obesity WHO degrees III. Microvasc Res 2013; 89: 129–133.

  48. 48

    Wong TY, Islam FM, Klein R, Klein BE, Cotch MF, Castro C et al. Retinal vascular caliber, cardiovascular risk factors, and inflammation: the multi-ethnic study of atherosclerosis (MESA). Invest Ophthalmol Vis Sci 2006; 47: 2341–2350.

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Acknowledgements

We would like to express our gratitude to the children and the staff of the participating schools. We are grateful for the help of the medical technical assistants (MTAs) of the Department of Prevention, Rehabilitation and Sports Medicine of the Technische Universität München, who performed the anthropometric measurements and organized the handling of the blood samples as well as the MTAs of the Department of Internal Medicine II, and the Department of Clinical Chemistry, University of Munich, Grosshadern Campus, who analyzed inflammatory markers. This work has been funded by a grant from the Bavarian State Ministry of the Environment and Public Health (Gesund.Leben.Bayern.) (LP 00001-FA 08).

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Correspondence to M Siegrist.

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Siegrist, M., Hanssen, H., Neidig, M. et al. Association of leptin and insulin with childhood obesity and retinal vessel diameters. Int J Obes 38, 1241–1247 (2014). https://doi.org/10.1038/ijo.2013.226

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Keywords

  • childhood obesity
  • leptin
  • cardiovascular risk
  • retinal microcirculation
  • physical fitness

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