A 2 year physical activity and dietary intervention attenuates the increase in insulin resistance in a general population of children: the PANIC study

The Physical Activity and Nutrition in Children (PANIC) study is a non-randomised controlled trial on the effects of a combined physical activity and dietary intervention on cardiometabolic risk factors and other health outcomes in a population sample of children from the city of Kuopio, Finland [22, 23]. The Research Ethics Committee of the Hospital District of Northern Savo approved the study protocol in 2006 (Statement 69/2006). The parents or caregivers of the children gave their written informed consent, and the children provided their assent to participation. The PANIC study has been carried out in accordance with the principles of the Declaration of Helsinki as revised in 2008.

We invited 736 children aged 6–9 years who started the first grade in 16 primary schools of the city of Kuopio in 2007–2009 to participate in the study (Fig. 1). Altogether, 512 (70%) children (248 girls, 264 boys) accepted the invitation and participated in the baseline examinations between October 2007 and December 2009. The participants did not differ in sex, age, height-SD score (SDS) or BMI-SDS from all children who started the first grade in the city of Kuopio in 2007–2009. We excluded six children from the study at baseline either owing to their physical disabilities that could hamper participation in the intervention or withdrawal of the families because they had no time or motivation to attend the study. We also excluded data from two children whose parents or caregivers later withdrew their permission to use these data in the study. The final study sample thus included 504 children at baseline.

We allocated the children from nine schools to a combined physical activity and dietary intervention group (306 children, 60%) and the children from seven schools to a control group (198 children, 40%) to avoid contamination in the control group by any local or national health promotion programmes that could have been initiated in the study region during the follow-up period. We also proportionally matched the intervention and control group according to the location of the schools (urban vs rural) to minimise sociodemographic differences between the groups. We included more children in the intervention group than in the control group because of a larger number of dropouts expected in the intervention group and to retain a sufficient statistical power for comparison between the groups. The children, their parents or caregivers, or people carrying out the examination visits or doing the measurements were not blinded to the group assignment. A total of 261 children (85% of those invited) from the intervention group and 177 (89%) children from the control group participated in the 2 year follow-up examinations between November 2009 and January 2012. The median (interquartile range) of follow-up time was 2.1 (2.1–2.2) years in the intervention and control group.

Data on fasting serum insulin and HOMA-IR were available in the intervention group for 295 children at baseline and 252 children at 2 year follow-up and in the control group for 186 children at baseline and 165 children at 2 year follow-up. Data on fasting plasma glucose were available in the intervention group for 299 children at baseline and 256 children at 2 year follow-up and in the control group for 193 children at baseline and 168 children at 2 year follow-up. The partly incomplete data on these outcome variables were due either to missing fasting blood samples for the insulin and glucose analyses or to haemolysis that interfered with the insulin analyses.

The 2 year individualised and family-based physical activity and dietary intervention consisted of six intervention visits that occurred 0.5, 1.5, 3, 6, 12 and 18 months after baseline examinations. Each intervention visit included 30–45 min of physical activity counselling and 30–45 min of dietary counselling for the children and their parents or caregivers. The children and their parents or caregivers received individualised advice from a specialist in exercise medicine and a clinical nutritionist on how to increase physical activity, decrease sedentary time and improve the diet of the children in everyday conditions. Each visit had a specific topic of discussion (physical activity, sedentary time and diet; electronic supplementary material [ESM] Table 1) in accordance with the goals of the intervention (ESM Table 2) and included practical tasks on these topics for the children. The children and their parents or caregivers also received fact sheets on physical activity, sedentary time and diet, and verbal and written information on opportunities for exercising in the city of Kuopio. Some material support was also given for physical activity, such as exercise equipment and allowance for playing indoor sports. Of the 306 children in the intervention group who attended the baseline examination, 266 (87%) participated in all six visits, 281 (92%) in at least five visits, and 295 (96%) in at least four visits. The children in the intervention group, particularly those who did not attend organised sports or exercise, were also encouraged to participate in after-school exercise clubs organised at the nine schools by trained exercise instructors of the PANIC study. The children in the control group were not allowed to attend these exercise clubs to avoid a non-intentional intervention in the control group. Altogether, 254 (83%) of the 306 children in the intervention group participated in at least one of the after-school exercise clubs, and 124 (41%) participated at least once a month. In the control group, the children and their parents or caregivers received general verbal and written advice on health-improving physical activity and diet only at baseline with no further lifestyle counselling.

A research nurse took blood samples in the morning, after children had fasted overnight for at least 12 h. Serum insulin was analysed using an electrochemiluminescence immunoassay with the sandwich principle (Roche Diagnostics, Mannheim, Germany). The within-day and between-day coefficients of variation for the insulin analyses were 1.3–3.5% (76–1104 pmol/l) and 1.6–4.4% (132–681 pmol/l), respectively. A hexokinase method was used to analyse plasma glucose (Roche Diagnostics). The within-day and between-day coefficients of variation for the glucose analyses were 0.7–0.9% (5.1–11.9 mmol/l) and 1.5–1.8% (3.4–14.1 mmol/l), respectively. HOMA-IR was calculated as explained elsewhere [24].

The measures of physical activity and sedentary time, reflecting the goals of the intervention, including average daily total physical activity energy expenditure, light, moderate and vigorous physical activity and total sedentary time, were assessed using individually calibrated combined heart rate and body movement monitoring [25]. The methods used for the assessment of physical activity and sedentary time [26‐29] are explained in detail in ESM Methods. Average total physical activity energy expenditure was calculated in kJ/kg daily. Light, moderate and vigorous physical activity were defined as time spent at intensity >1.5 and ≤4.0 metabolic equivalents (METs), >4.0 and ≤7.0 METs and >7.0 METs, respectively, where one MET is defined as an energy expenditure of 71 J kg⁻¹ min⁻¹ or oxygen uptake of 3.5 ml kg⁻¹ min⁻¹. Moderate-to-vigorous physical activity was calculated by summing moderate and vigorous physical activity. Total sedentary time was defined as the time spent at intensity ≤1.5 METs, excluding sleep.

Dietary factors reflecting the goals of the intervention, including the consumption of vegetables, fruit and berries, high-fibre (≥5%) grain products, low-fibre (<5%) grain products, high-fat (≥60%) vegetable oil-based spreads, vegetable oils, butter-based spreads, high-fat (≥1%) milk, low-fat (<1%) milk, red meat, fish and foods with high sugar content, were assessed using 4 day food records [30]. (See ESM Methods for details.) We used the Finnish Children Healthy Eating Index (FCHEI) as an indicator of overall diet quality [31]. The index was calculated by summing the reported consumption of the following foods based on their quantiles in the present study population [30]: vegetables, fruit and berries (scored 1–10); high-fat (≥60%) vegetable oil-based spreads and vegetable oils (0–10); low-fat (<1%) milk (0–9); fish (0–6); and foods with high sugar content (10–1). The index thus ranged between 2 and 45, a higher score indicating higher overall diet quality.

Body height and weight were assessed, BMI was calculated, age- and sex-standardised height-SDS and BMI-SDS were calculated, overweight and obesity were defined, and BF% and lean body mass were measured [25, 30]. (See ESM Methods for details.)

A research physician assessed pubertal status according to breast development for girls (scored M 1–5) and according to testicular volume measured by an orchidometer for boys (scored G 1–5) using the Tanner staging method [32, 33].

We performed all statistical analyses using the IBM SPSS Statistics software, version 25.0 (IBM Corp., Armonk, NY, USA). A p value of <0.05 for a two-tailed test was used to indicate statistical significance. The outcome variables were normally distributed based on visual observation of the histograms. We compared baseline characteristics between the intervention and control group by linear mixed-effects models with cluster-robust SEs, except body weight status for which comparison was performed by generalised linear mixed-effects models with ordered structure, to account for the clustering effect of schools. Sample size calculations [22, 23] are explained in ESM Methods. We studied the effects of the combined physical activity and dietary intervention on insulin, glucose and HOMA-IR using the intention-to-treat principle by including all 504 children in the statistical analyses. We analysed the data using linear mixed-effects models according to a three-level data structure by clustering the repeated outcome variables at baseline and 2 year follow-up within children who were considered as being included in the mixed model structure and were clustered within schools. However, we did not use the three-level data structure in the final models because allowing for school-level clustering did not improve model fit based on the Bayesian information criterion, as presented in ESM Methods. We adjusted the data for sex, age at baseline, and pubertal status at baseline and 2 year follow-up and included main effects for time and for study group × time interaction in the models. The mixed-effects models assume that the data are missing at random. We found that this assumption was reasonable because there were only minor differences in the characteristics between children with the outcome data and children without these data at 2 year follow-up. We did not include study group as a separate variable in the models because there were no statistically significant differences in insulin, glucose and HOMA-IR between the intervention and control group at baseline. The formula for the linear mixed-effects model is presented in ESM Methods. We also examined whether 2 year changes in physical activity, sedentary time, diet, BF% and lean body mass might partly explain the observed intervention effects on insulin, glucose and HOMA-IR by calculating percentage changes in regression coefficients for differences in estimated changes in insulin, glucose and HOMA-IR between the intervention and control group after adding physical activity, sedentary time, diet, BF% and lean body mass at baseline and 2 year follow-up one-by-one as covariates into the linear mixed-effects models.

There were no differences in baseline characteristics between the groups, except that children in the combined physical activity and dietary intervention group consumed less high-fat milk than children in the control group (Table 1). Only 2–3% of the children at baseline (Table 1) and 23–24% of the children at 2 year follow-up (ESM Table 3) had entered puberty (Tanner stage ≥2). Altogether, 13% of the children in both groups were overweight or obese at baseline (Table 1), whereas 17% of the children in the intervention group and 18% of the children in the control group were overweight or obese at 2 year follow-up (ESM Table 3).

Fasting insulin increased 4.65 pmol/l less (absolute change +8.96 vs +13.61 pmol/l) and HOMA-IR increased 0.18 units less (+0.31 vs +0.49 units) over 2 years in the combined physical activity and dietary intervention group than in the control group (Table 2). These intervention effects on fasting insulin and HOMA-IR were statistically significant after adjustment for sex, age at baseline, and pubertal status at baseline and 2 year follow-up (Table 2). However, the intervention had no effect on fasting glucose (Table 2), BF% (regression coefficient β for intervention effect −0.02 [95% CI −0.39, 0.36], p = 0.926) or lean body mass (β for intervention effect 0.03 [95% CI −0.07, 0.13], p = 0.567) over 2 years.

The intervention effects over 2 years on fasting insulin and HOMA-IR, respectively, were explained by the following changes (β for intervention effect was changed by the % shown): total physical activity energy expenditure and moderate-to-vigorous physical activity 39% and 38%; light physical activity 33% and 33%; total sedentary time 30% and 31%; the reported consumption of high-fat (≥60%) vegetable oil-based spreads 21% and 23%; and FCHEI 12% and 11% (Table 3). However, 2 year changes in other dietary factors, BF% or lean body mass did not explain any of the intervention effects (Table 3).