Diabetes and puberty : studies on hormonal factors of importance to the blood glucose control

Abstract: It is well known that, in children with type 1 diabetes, metabolic control often deteriorates during puberty. Better understanding of the mechanisms that cause deterioration of blood glucose control can lead to improved therapeutic approaches. Preliminary observations suggest that one component of the impaired glycemic control is a large variation in blood glucose. Several of the hormonal changes during puberty affect insulin sensitivity and could, in addition to lifestyle factors, also cause blood glucose variation. A marker of hormonal activity during puberty is linear growth, which thus can be affected by the metabolic control. The aim of this thesis was to study hormonal changes during puberty in children with type 1 diabetes in relation to blood glucose level as well as blood glucose variability, with special focus on anabolic hormones and linear growth as a mirror of hormonal and nutritional status. In summary, we have demonstrated that in children with type 1 diabetes, there is during puberty increased long-term variability in blood glucose and elevated blood glucose. The long-term blood glucose variability was related to linear growth and mean 24 hours GH level. Linear growth velocity can be used as a biological marker of the GH-IGF-I system. We showed that there was both hepatic growth hormone and insulin resistance during mid-puberty. However, the blood glucose levels during a 24 hour period was not correlated to GH but to IGFBP-1 confirming the importance of free IGF-I in the regulation of the glucose homeostasis. This correlation was dependent on insulin during mid-puberty but was independent of insulin in Tanner stage 5 patients. Neither cortisol, testosterone nor leptin could explain the blood glucose levels. However, we found a correlation between blood glucose and IGFBP-3 protease activity during mid-puberty. We speculate, the increased protease activity is a compensatory mechanism to restore free IGF-I concentrations to normalise glucose homeostasis. Low IGF-I levels and high IGFBP-1 levels were found in diabetic boys both during the mid-pubertal and the post-pubertal stages. These findings were correlated to low insulin concentrations and elevated HbA1c or blood glucose. Leptin, a hormone reflecting nutritional status, was elevated in diabetic boys with a correlation to BMI ratio but not to insulin. The importance of increased leptin levels is not fully understood but could serve as a marker of incomplete insulin treatment and increased risk of later diabetic complications, e.g. cardiovascular disease. In conclusion the IGF-I - IGFBP system is important in the regulation of glucose homeostasis in diabetic boys both during and after puberty. Bioavailable IGF-I levels determine blood glucose levels partly independent of insulin. The blood glucose variability measured as standard deviation of blood glucose over a longer period can be an additive marker of metabolic control in diabetic children. To achieve optimal metabolic control the treatment should be aimed to lower the blood glucose variability and to normalise the changes in the GH-IGF-I-IGFBP system.