Our data show that as IS decreases in adolescents with T1D, CVD risk factors become more atherogenic. Reduced IS is well-accepted as a CVD risk factor in other populations (8
), but the role of insulin resistance in T1D is less appreciated, in part due to the difficulty of estimating IS in people with T1D (3
). Our data are significant in that monitoring and controlling IS may be an important therapeutic target to reduce CVD risk in T1D, especially given that both potential lifestyle (diet (11
) and exercise (12
)) and pharmacologic options (such as metformin (13
)) are available to improve IS.
There have been previous studies in adults, but not in adolescents, focusing on estimates of IS as determined by glucose disposal rate (GDR) from hyperinsulinemic-euglycemic clamps. Williams et al generated an estimated GDR based on hyperinsulinemic-euglycemic clamps in T1D in a study with 24 adults (14
), which has been applied in a number of studies of adults with T1D. For example, Chillaron et al applied this estimate to 91 adults with T1D and showed a link between vascular complications and decreased IS (15
). Data from the DCCT as reported by Kilpatrick found that quantifying insulin resistance via estimated GDR using the Williams equation identified adults with T1D at higher risk to develop both microvascular and macrovascular complications (16
). Expanding upon these studies of adults, our study shows the link between decreased IS and CVD risk earlier in the physiologic pathway and with shorter duration of diabetes, in a relatively large cohort of adolescents with T1D and those without. Although there have been related studies of estimated GDR in adult cohorts, this study is the first study of its kind to apply a pediatric specific estimated GDR to adolescents with T1D to characterize the association of IS with CVD risk factors.
It is well established that IS is impaired in T1D and associated with vascular risk with the original description of this phenomenon being published over 40 years ago (17
). DeFronzo (18
), Yki-Jarvinen (19
), Amiel (20
) and Arslanian (21
) all described decreased IS historically in people with T1D, but mean glycemia was higher, as they were performed prior to the DCCT results leading to recommendations to lower target HbA1c, and insulin regimens differed from those typically used today (22
). More recently, hyperinsulinemic-euglycemic clamp studies continue to demonstrate significant insulin resistance in both adolescents (mean HbA1c=8.7±1.6%) (2
) and adults (mean HbA1c=7.5±0.9%) (3
) with T1D as compared with age, sex, pubertal stage, habitual level of physical activity, and BMI similar non-DM controls, despite lower HbA1c than pre-DCCT studies. These data also demonstrate that although IS decreases with increasing obesity, IS is decreased in both adolescents and adults with T1D as compared with non-DM controls at similar BMI. Moreover, the CACTI study showed that directly measured IS was associated with coronary artery calcification (3
), a surrogate marker of coronary artery disease predictive of future cardiovascular disease outcomes, and adolescent studies show that decreased IS is the strongest predictor of reduced exercise capacity (2
), a cardiovascular functional marker and predictor of mortality. Because cardiovascular disease is the leading cause of death in T1D with earlier mortality, such data are important for health outcomes for people with T1D and potentially can help provide insights into the pathogenesis of CVD in T1D.
We did not directly perform a hyperinsulinemic-euglycemic clamp in this study, the means of determining IS clinically via the ISS was validated by the hyperinsulinemic-euglycemic clamp procedure, which is considered a gold-standard measure of IS (explained 74% of the variance in GDR) (4
). Estimation of insulin sensitivity among patients with insulin-treated diabetes is problematic, as fasting levels of glucose and insulin reflect insulin treatment rather than underlying insulin and glucose metabolism, and so are unreliable indicators of insulin sensitivity. Moreover, insulin deficient patients with T1D are unable to produce insulin in response to glucose challenges in oral or intravenous glucose tolerance tests. In non-DM individuals, fasting levels of both insulin and glucose reflect insulin sensitivity, and methods have been developed to estimate IS based on these values, including the homeostasis model (HOMA) (23
) and the Quantitative Insulin Sensitivity Check Index (Quicki) equation (24
In summary, decreased IS is common in T1D and has a significant association to more atherogenic CVD risk factors. However, adolescents with T1D who are the most IS have similar CVD risk factors as non-DM adolescents, whereas decreased IS is associated with more atherogenic CVD risk factors. This finding suggests that decreased IS might be a modifiable therapeutic target for lowering CVD risk in adolescents with T1D.