This retrospective analysis of HbA1c
levels in 677 children and adolescents with type 1 diabetes over more than 3 years revealed a clear seasonal variability with 11–13 months periodicity. Similar results have been described in patients with diabetes by others [4
]. In our study, the lowest HbA1c
levels were observed in August and September, while peaks were found in November, December and February. Poland, situated on the northern hemisphere, has a moderate climate, and these months correspond to late summer and late autumn/early winter respectively. Mean summer temperatures in Poland are between 16.5 and 20.0°C, mean temperatures in winter are between −6.0 and 0°C. In the present study, winter–summer differences in HbA1c
levels for the study interval were from 0.44% in 2007 to 0.67 % in 2009. These values are high, compared with the results obtained by Gerstl et al. in a large cohort of young patients with diabetes observed over several years (mean values for September 7.86% vs January 8.08%) [11
], but comparable to the observation of Sakura et al. in adult patients with diabetes, where the differences reached 0.45% [7
Seasonal variations of HbA1c
can be attributed to several factors, which may be classified into two groups: (1) sun exposure/temperature-dependent factors such as physical activity, vitamin D deficiency, serum melatonin concentration; and (2) sun exposure /temperature-independent factors such as school stress, amount of leisure time, mild upper respiratory and other ‘seasonal’ infections, seasonal dietary patterns related to the seasonal availability of ‘healthy food’ and endogenous seasonal hormonal variations (e.g. cortisol) [13
]. Herbst et al., in their study including a cohort of 19,143 patients with type 1 diabetes (aged 3–20 years), showed that the frequency of regular physical activity is one of the most important factors influencing HbA1c
levels and that HbA1c
levels were lower in patients with greater regular weekly physical activity [14
]. In countries with moderate climates, both younger (5–6 years old) and older children (10–12 years old) spend more time outdoors in warmer months than in cooler months [15
]. Tucker et al. provided summaries of studies published up to 2009, which present evidence that quantitative measures of weather conditions correlate with physical activity of the general population, and particularly that of children [16
]. Physical activity of schoolchildren, especially from urban areas, depends on after-school access to school gymnasiums and athletic fields, and on participation in organised activities. Sport facilities, however, are not well maintained, are poorly supported and access to them often costs money. Therefore the main kind of physical activity, especially for boys, are self-organised outdoor activities such as football or basketball, which are highly restricted by daylight hours. In the region covered by this study, about 35% of the population lives in rural areas. In rural areas the traditional ‘manual labour’ has become more mechanised and gradually requires less and less physical effort. Furthermore, on many farms, children with a chronic disease are still stigmatised as weaker, and as a result are often less burdened by physical work. There is also the global problem of increasingly sedentary lifestyles of children, resulting from the ever greater amounts of time spent in front of the computer, video games and television. Thus patterns of physical activity of children and adolescents from rural and urban areas are gradually becoming similar. Based on all these data, daylight hours and ambient temperature are good surrogates of physical activity in Poland, and so we examined their association with HbA1c
levels. Our study found a significant negative correlation between HbA1c
levels and ‘good’ weather conditions in schoolchildren, but not in preschoolers. Younger children, attending kindergarten or staying at home, are more physically active, both indoors and outdoors, than schoolchildren. During the school year, students spend many hours indoors, due to school work, which affects their daily physical activity patterns. For schoolchildren, weather conditions, day length and the structure of the school year (especially summer holidays) strongly influence outdoor activities, while preschoolers, who are active all day and unrestricted by school-associated workload, seem to be less sensitive to these influences. An association between HbA1c
levels and quantified weather conditions, including sun exposure, has not been previously presented for children with diabetes. The data presented in this paper provide a physiological reason both for our findings of an annual pattern of HbA1c
levels and for similar results from other groups.
The trend in HbA1c
variation is consistent with seasonal variation of type 1 diabetes incidence [17
]. An inverse correlation with ultraviolet irradiance and diagnosis of type 1 diabetes has been observed in Newfoundland, Canada [19
]. Both phenomena could be dependent on vitamin D synthesis in human skin [20
]. The mechanism by which vitamin D possibly protects against type 1 diabetes is still unclear. Although there is some evidence suggesting that vitamin D may protect from cytokine-induced beta cell damage [21
], such a mechanism provides little explanation of its association with metabolic control in stable, long-standing type 1 diabetes in children.
On the other hand, melatonin, which is secreted by the pineal gland, synchronises biological rhythms and follows a circadian and circannual rhythm. Melatonin is secreted in darkness and its level increases during the night [22
] and in winter (December in the northern hemisphere) compared with daytime hours and summer (July) respectively [23
]. Melatonin decreases insulin sensitivity, can decrease insulin secretion and can increase blood glucose levels, while phototherapy sessions (which potentially decrease melatonin levels) have been shown to induce recurrent hypoglycaemia in a patient with type 1 diabetes [24
]. From these observations, one could conclude that higher melatonin levels persisting for a longer time during autumn and winter nights could contribute to higher blood glucose levels. Such an association seems to be even clearer than any relation between vitamin D deficiency and higher blood glucose levels observed in colder months in patients with overt type 1 diabetes.
Other seasonal factors such as different dietary habits (e.g. lower consumption of vegetables and greater fat intake in winter), seasonal changes in body fat content (higher in winter and decreased in summer), more frequent infections and higher cortisol or glucagon levels in autumn and winter than in summer, as well as school stress can also unfavourably influence HbA1c
levels through their effect on insulin sensitivity and blood glucose levels [5
]. In Poland dietary habits may play an important role. Although food supply is generally unrestricted in the major food markets, due to the regional vegetation pattern prices of fresh vegetables and fruit increase during winter and early spring. In many households, especially those of poorer economic status, this may be compensated by higher intake of food rich in carbohydrates and fat. This can contribute to less favourable glycaemic profiles in young patients with type 1 diabetes who do not adapt their insulin doses appropriately.
Factors that can interfere with the performance of HbA1c
assays are: haemoglobin variants and derivatives, shortened erythrocyte survival, vitamin C and E, iron deficiency anaemia, hypertriacylglycerolaemia, hyperbilirubinaemia, uraemia, chronic alcoholism, chronic ingestion of salicylates and opiate addiction (www.ngsp.org/factors.asp
; accessed 25 November 2010). Two of these could be speculated to promote a seasonal pattern in a paediatric population, namely vitamin C (as potentially related to seasonal changes in vegetable and fruit intake) and hypertriacylglycerolaemia (related to increased fat intake). However, according to the Bio-Rad Variant Hemoglobin A1c
manual (for hypertriacylglycerolaemia) and data from the literature (for pharmacological doses of vitamin C), none of these substances has any impact on HPLC-measured HbA1c
]. In respect to meteorological factors, neither the NGSP (www.ngsp.org/factors.asp
; accessed 25 November 2010) nor the manufacturer’s instruction manual mention ambient temperature, humidity or pressure as ‘factors that interfere with HbA1c
Irrespective of their origin, the documented seasonal variations of HbA1c levels should be considered in disease management schedules: adaptation of insulin doses, meal plans, advising and organising physical activity, prevention of physical activity-related fear of hypoglycaemia in young patients with type 1 diabetes and the use of HbA1c as a tool for diabetes diagnosis. This may also be an important consideration for short-time (i.e. running over several months) clinical trials measuring before and after intervention HbA1c levels. In patients using continuous subcutaneous insulin infusion (in many paediatric centres, including ours, more than 50% of patients use this), the basal rate is assessed and adjusted if needed at least every 3 months and could anticipate the observed seasonality of glycaemic control.
There are some limitations that may bias the results of the study. According to ADA recommendations, the HbA1c
test should be performed at least twice a year in patients with diabetes who are meeting glycaemic goals and at least four times a year in those who are not meeting treatment goals or whose therapy has changed [3
]. The mean number of measurements among our study participants was 1.8 per patient per year, as some patients dropped out upon reaching the age of 18 years and some were evaluated only as inpatients during scheduled metabolic control assessment. However, a small number of measurements per patient reduces the effect of within-patient variability, as patients with better control have fewer observations with less variability and those with higher HbA1c
and more frequent testing may weigh the analysis, causing false peaks of bad metabolic control. We would expect this effect to be randomly distributed across the year, thus not biasing any seasonal trend. Another limitation of our analysis is that HbA1c
measurements may be affected by factors independent of seasonal variations. HbA1c
measurements incorporate the potential biases of a different number of measurements per patient, this is in contrast to the measures of weather variation, which can be observed under consistent conditions. Thus, mean HbA1c
levels may depend on the number of measurements each month and sampling of particular patients, while average sun exposure and temperature do not have such variation and allows for a continuous time series composed of the same number of measurements each month. A slight time delay in autocorrelations of HbA1c
and weather conditions was also noted. It was probably due to the fact that the HbA1c
level is an intrinsically time-lagged variable and depends strongly on the previous 3 months of glycaemic control. Autocorrelations of HbA1c
were observed to dwindle faster, due to initial lower strength, which is typical for such autocorrelation effects. Although this may affect the direct relationship of seasonal changes and HbA1c
, the established pattern is still valid.
The strength of this study is that it covered a well documented, ethnically homogeneous (white) population with several long-running epidemiological projects such as the developing Nationwide Registry of Pediatric and Adolescent Diabetes and the Polish Registry of Neonatal Diabetes [29
]. From a geographic perspective, the region is characterised by the lack of mountains or seaside providing a stable temperate climate with daylight hours of sunshine varying continuously throughout the year and typically no natural disasters.
In conclusion, periodic changes of HbA1c are a biologically significant phenomenon in young patients with type 1 diabetes and should be considered in patient education and diabetes management schedules. They may affect the results of paired, time-dependent comparisons in clinical trials using HbA1c levels as their primary outcome and the HbA1c-based diagnosis of diabetes.