ELEVATED FASTING GLUCOSE LEVELS IN OBESE CHILDREN AND ADOLESCENTS: PREVALENCE AND LONG-TERM CONSEQUENCES

Background: Obesity in childhood and adolescents is a major concern in Sweden, as in many parts of the world. Already during the pediatric years is obesity associated with several metabolic complications, which often persists into adulthood. An important metabolic concern is the disturbance of the glucose-insulin homeostasis. One early sign is impaired fasting glycaemia (IFG) which is considered a prediabetic stage as IFG is associated with markedly increased risk for development of type 2 diabetes mellitus (T2DM) in adults. IFG refers to elevated, but not yet diabetic, glucose levels in the fasting state. At present, two different cut-off values for IFG are used in parallel; the American Diabetes Association (ADA) suggest 5.6 mmol/L and the World Health Organization (WHO) promotes 6.1 mmol/L as the cut-off for IFG. In adults, IFG has been associated with increased risk for cardiovascular disease, cancer, and premature also in the absence of the development of T2DM. The prevalence of IFG in the obese pediatric population has been reported with vast differences across different countries and populations. Further, the long-term consequences of IFG in the obese pediatric population are not clear. However, obesity as well as obesity-induced dysglycemia, may affect several brain functions important for schooling. The aim of this thesis is to investigate the prevalence, risk groups, and consequences of IFG in obese children and adolescents. Method: All studies included in this thesis contains data from the Swedish Childhood Obesity Register – BORIS (Barn Obesitas Register I Sverige). BORIS is a national quality register for obesity treatment in childhood and adolescence and was initiated in 2005. In addition, data from Germany and Poland regarding children and adolescents who have been undergoing obesity treatment are included. Study I and II are cross-sectional observational studies and Study III and IV are prospective cohort studies, which in addition to BORIS data using data from several national registries. Results: The total prevalence of IFG among obese children in the German cohort according to the ADA was 5.7% and according to the WHO it was 1.1%. In Sweden, the corresponding prevalence was 17.1% and 3.9%, respectively. IFG risk was associated with increasing age, male sex and degree of obesity. Further, Swedish obese young children had higher glucose levels than Polish obese young children. The use of T2DM medication retrieved from the national prescribed drug registry was used as a proxy for the diagnosis of T2DM. The pediatric obese population in Sweden, based on the BORIS cohort, had a 24 times increased use of T2DM medications in early adulthood in relation to a population-based comparison group, regardless of gender and ethnicity. While the WHO-defined IFG predicted future use of T2DM medication in early adulthood with an adjusted hazard ratio of 3.84 compared with those who had fasting glucose levels <5.6mmol/L. A fasting glucose level of 5.66.0 mmol/L, i.e. the IFG glucose interval added by ADA, did not increase the use of T2DM medication in young adults more than pediatric obesity itself. Female gender and more severe degree of obesity increased the risk for future T2DM medication. In the obese cohort, 55.4% completed ≥12 years in school, compared with 76.2% in the comparison group. IFG did not correlate significantly with school completion; 50.8% for those with IFG according to ADA and 48.4% for those with IFG according to WHO completed school compared with 55.8% for non-IFG. When analyzing glucose as a continuous variable, a non-significant tendency on school completion could be seen (adjusted p=0.06). Conclusion: IFG is highly prevalent among obese children in Sweden compared with Poland and Germany. There are no known explanations for the large regional differences in both IFG prevalence and fasting glucose levels. IFG according to WHO, but not the additional interval added by ADA (5.6-6.0 mmol/L) can be considered as a prediabetic stage in the obese pediatric population. Thus, these studies indicate that risk markers identified in adults can not directly be transferred to children. Obesity in childhood and adolescence was associated with low educational level in early adulthood but IFG did not statistically significantly increase the risk for low education in obese individuals. SVENSK POPULARVETENSKAPLIG SAMMANFATTNING (SWEDISH LAY SUMMARY) Fetma hos barn och ungdomar hor till vara storsta hot mot folkhalsan. Hos vuxna okar fetma risken for en rad sjukdomar, bland annat hjartkarlsjukdom och typ 2 diabetes (T2D). Hos barn med fetma ar dessa foljdsjukdomar sallsynta, men forstadier till dem finns. Ett sadant tidigt tecken ar forhojt fasteblodsocker, eller engelskans impaired fasting glycemia (IFG), som hos vuxna ar ett forstadium till T2D. I dagslaget finns det tva olika granser for IFG: en lagre grans satt av American Diabetes Association (ADA) med blodsocker tagna efter en natts fasta pa ≥5,6 mmol/L och en hogre grans som ar satt av Varldshalsoorganisationen (WHO), ≥6,1 mmol/L. Vuxna individer med IFG har okad risk for hjartkarlsjukdom, cancer och fortidig dod, aven om diabetes inte utvecklas. Bade fetma i sig, T2D och forhojda fasteblodsocker kan paverka hjarnans mentala processer, sasom inlarning och minne. Huruvida IFG hos barn och ungdomar som lider av fetma medfor samma risker som IFG gor bland vuxna ar inte kant. Den har avhandlingens syften ar att utvardera 1. forekomsten av IFG hos barn och ungdomar som lider av fetma 2. om det gar att identifiera vilka barn som har hogst risk att fa IFG 3. huruvida de barn och ungdomar som har IFG utvecklar diabetes i vuxen alder 4. om IFG minskar chansen att avsluta gymnasieutbildning