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Diabetes during Puberty Increases Risk of Complications

Girls with diabetes are at an even greater risk for excessive weight gain during puberty….

An increase in childhood diabetes warrants a closer look at the risk of complications in relation to puberty. Recent data suggests that there is a greater risk for severe vascular complications in those that have diabetes during puberty vs. those that develop diabetes after puberty. Studies have also shown that hemoglobin A1c levels are often higher during puberty. A review article by Cho et al. explores the many complications of diabetes and relates them to the physiological processes that occur during puberty to understand what adolescents with diabetes are at greatest risk of developing.
 
The FinnDiane study found that among 1117 patients, adults who developed diabetes when they were <15 had 1.8-fold greater likelihood of developing proliferative retinopathy than those with postpubertal onset of diabetes (age 15-40). Breaking the age up further, those who developed diabetes at age 0-5 had a 1.6-fold greater risk, whereas those with diabetes onset at age 5-14 had a 1.9-fold greater risk. Other studies that looked at earlier markers of retinopathy found that there was a longer time until development of complications in adolescents diagnosed before puberty compared to those diagnosed after puberty. The Berlin retinopathy study found that children diagnosed before age 10 had a median time of 12.1 years free of retinopathy, while those diagnosed at age 10-18 years had a median time of 6.6 years free of retinopathy.
 
In Finland, data from the Kidney Disease Register and Finnish Diabetes Register was used to study the contribution of prepubertal and pubertal diabetes duration on nephropathy. The study, which included more than 20,000 patients, found that those diagnosed before age 5 had the lowest risk of ESRD. Even though these patients would have gone through puberty with diabetes, the prepubertal period is assumed to have conferred protection to these patients. The group diagnosed at age 5-9 had 2.7-fold greater risk compared to the group diagnosed at age <5. The age group diagnosed at 10-14 had the highest relative risk of 3.3, while the group diagnosed at age 15-19 had a relative risk of 2.6. The youngest group, with diagnosis at <5 years, had 5 years longer duration until ESRD than the 5-9 year age group, and 10 years longer than the group diagnosed at age 10-14. The oldest group, diagnosed at age 15-19, took longer to develop ESRD than the 10-14 age group. This data suggests that pubertal diabetes duration may play a role in accelerating renal damage.
 
Regarding the effect of gender on vascular complications, females were found to be at greater risk during childhood and adolescence, whereas males were at greater risk as adults. In the longitudinal study of retinopathy, females were found to have a 29% higher risk of developing retinopathy. Females were also found to develop microalbuminuria earlier than males. Young adult women with type 1 diabetes are also seen to lose the cardiovascular protection that is normally seen in females, giving them similar rates of ischemic heart disease as men with type 1 diabetes. Change in adiposity and body composition, especially during puberty, may add to the risk of complications. Girls with diabetes are at an even greater risk for excessive weight gain during puberty, which may further exacerbate insulin resistance. BMI > +2 SDS showed a two-fold higher risk for albuminuria in a cohort study, while BMI> 95th percentile was associated with an increased risk in retinopathy. Another study of adolescent girls with type 1 diabetes found that lower SHBG (sex hormone-binding globulin), in addition to poor glycemic control, was associated with cardiac autonomic dysfunction. SHBG is also known to be associated with insulin resistance.
 
The growth hormone (GH)/ insulin-like growth factor (IGF-1) axis is thought to be involved with retinopathy as patients with retinopathy have been seen to have increased serum growth hormone levels. In GH-deficient patients, there is a lower prevalence of retinopathy, and improvement in retinopathy has been observed following pituitary ablation. Growth hormone is also thought to have a large impact on insulin resistance during puberty. Insulin resistance is found to occur during puberty in both diabetics and non-diabetics, with insulin sensitivity reduced by approximately 30-36% during this time period. For pre-pubertal diabetics that already have insulin sensitivity that is 42% lower than non-diabetic controls of the same age, this is a big problem. This increased insulin resistance is thought to be due to lower peripheral insulin action as a result of increased mean 24-h growth hormone levels (peak GH concentrations coincide with the pubertal growth spurts of males and females). This occurs because insulin is required to regulate hepatic GH receptors, and periods of hepatic insulin deficiency can lead to impaired IGF-1 production. Impaired IGF-1 production then causes a negative feedback loop that results in elevated GH levels.
 
ACEIs are used in adults with diabetes particularly for HTN and microalbuminuria. New evidence now suggests earlier use in adolescents, especially with new studies showing that they may increase insulin sensitivity. HMG-CoA reductase inhibitors may also be beneficial for their ability to improve vascular function. Metformin has emerging evidence that it too may have a benefit on vascular function in adults with type 1 diabetes.
 
Attention to diet and insulin are other key components to proper diabetes management. The available evidence points towards type 1 diabetes during puberty being an accelerator of risk for complications. Puberty is also the time for when gender really starts to play a role in the progression of diabetes and the development of its risks and complications. In recent years, improved glycemic control has helped to lower complications from this disease, though awareness and caution is still important, especially with increasing adiposity in today’s youth.
 
Practice Pearls:
  • Gender disparities for risk factors put females at higher risk for complications than males.
  • Improving insulin sensitivity is critical during puberty for adolescents with type 1 diabetes. Exercise programs tailored to increase insulin sensitivity and improve cardiac function should be utilized, along with proper insulin replacement.
Cho, YH. et al. "Puberty as an accelerator for diabetes complications" Pediatric Diabetes. 2014: 15(1): 18-26.