Insulin sensitivity and arterial stiffness in youth with type 1 diabetes: the SEARCH CVD study

https://doi.org/10.1016/j.jdiacomp.2015.02.004Get rights and content

Abstract

Aims

Decreased insulin sensitivity is a cardiovascular risk factor (CVRF) in youth with type 1 diabetes (T1D). Whether baseline insulin sensitivity is independently associated with changes in early arterial stiffness (pulse wave velocity (PWV)) over time in youth with T1D is not known.

Methods

Two hundred ninety-eight youth with T1D in the SEARCH CVD study had PWV measured ~ five years apart. Insulin sensitivity and other CVRFs were measured at baseline. The association between baseline insulin sensitivity with PWV over time was explored using linear mixed models. Models were adjusted for baseline age, sex and race, with subsequent adjustment for CVRFs.

Results

There was a significant interaction (p = 0.0326) between baseline insulin sensitivity and time on PWV, independent of CVRFs, indicating that higher insulin sensitivity levels were associated with lower rate of change in PWV over time. Other significant predictors of PWV change were baseline age [β = 0.007 (p = 0.03) increase in logPWV/year increase in age] and mean arterial blood pressure (MAP) [β = 0.005 (p < 0.01) increase in logPWV/mmHg increase in MAP] and smoking status (current vs. never smoker).

Conclusions

Lower insulin sensitivity at baseline appears to be an important risk factor for increased arterial stiffness over time in youth with T1D. This identifies a potentially modifiable therapeutic target.

Introduction

Cardiovascular disease (CVD) is the leading cause of death in adults with type 1 diabetes (T1D) and is associated with a tenfold increase in CVD-related mortality compared to the general population (Soedamah-Muthu et al., 2006). This process begins early in life, and there is evidence that subclinical vascular changes indicative of future CVD, such as increased arterial stiffness, are present among children and teens with T1D (Urbina et al., 2010). Vessel thickening or stiffness is due to a combination of deposition of glycosylated end products, endothelial damage and dysfunctional repair, as well as structural changes characterized by an overproduction of abnormal collagen and diminished quantities of normal elastin, in addition to deposition of lipids, calcium or other metabolic products (Rask-Madsen & King, 2013). Vessel stiffness can be quantitated by pulse wave velocity (PWV), the gold standard measure of peripheral vascular stiffness (Laurent et al., 2006). PWV is strongly correlated with cardiovascular events and all-cause mortality (Vlachopoulos, Aznaouridis, & Stefanadis, 2010).

Insulin resistance (decreased insulin sensitivity) is a well-accepted benchmark for type 2 diabetes (T2D), and is associated with worsening cardiovascular outcomes. Insulin resistance is less studied as risk factor in the development of macrovascular complications in T1D (Nadeau & Reusch, 2011), but recent studies show youth with T1D have increased insulin resistance compared to healthy youth (Nadeau et al., 2010). The presence of insulin resistance in T1D may explain at least some of the elevated CVD risk not associated with hyperglycemia (Snell-Bergeon & Nadeau, 2012).

In a previous cross-sectional study in youth without diabetes, insulin sensitivity assessed using the Homeostatic Model Assessment (HOMA-IR) was not independently associated with PWV (Urbina, Gao, Khoury, Martin, & Dolan, 2012). However, HOMA-IR is not usable for interpretation in insulin-treated patients (Dabelea, D'Agostino, et al., 2011). The aim of this study was to characterize the association between a validated marker of insulin sensitivity (Dabelea, D'Agostino, et al., 2011) and changes in PWV over time in youth with T1D participating in the longitudinal component of the SEARCH CVD study. Our hypothesis was that higher insulin sensitivity (less insulin resistance) at baseline will be associated with a slower increase in PWV from baseline to follow up. In addition, we hypothesized that these associations will be independent of demographic and other CVD risk factors.

Section snippets

Study design and participants

SEARCH CVD was an ancillary study to the SEARCH for Diabetes in Youth study (Group, S.S, 2004). The longitudinal component of SEARCH CVD included a cohort of 298 youth with provider diagnosed T1D from Colorado and Ohio who had data on arterial stiffness measured approximately 5 years apart, in 2004–05 and 2009–11, starting when youth were on average 14.5 (SD = 2.8) years old and had a mean duration of diabetes of 4.8 (SD = 3.8) years. All participants had demographics, anthropometric and metabolic

Results

Table 1 presents the characteristics of SEARCH CVD participants at baseline. The average age of the study participants at baseline was 14.5 years (SD 2.8), their diabetes duration was 4.8 years (SD 3.8) and the majority were NHW. BMIz at baseline indicates that the group, on average, was not overweight or obese. Approximately 9% had microalbuminuria, 3.4% were current smokers, 8.0% were former smokers and 88.6% were nonsmokers. Seventy-five percent were positive for either IA-2 or GAD. The

Discussion

This results of our study indicate that baseline insulin sensitivity, assessed using a validated surrogate marker based on routine clinical measures, influences the progression in PWV over an average follow up period of 5 years among youth with relatively short duration of T1D, such that the lower the baseline insulin sensitivity (the more insulin resistant), the greater the increase in PWV over time. This association was independent of demographics, BMIz, lipid and blood pressure levels,

Acknowledgements

The SEARCH CVD Study is indebted to the many youth and their families, and their health care providers, whose participation made this study possible. We also would like to thank all of the SEARCH for Diabetes in Youth investigators and study staff whose help was essential in moving this project forward.

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    Conflict of interest statement: There are no conflicts of interest to report.

    Sources of Funding: SEARCH CVD was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, R01DK078542, PI Dabelea). This work was also funded in part by the National Institute of Health Heart, Lung and Blood Institute (NHLBI, K23HL118132, PI Shah).).

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