Type 1 Diabetes Mellitus (T1D) affects 1.4 million people in the U.S. and its incidence is increasing by 3- 5% annually. While numerous promising therapeutic modalities are being investigated, currently no cure exists and the patients succumb prematurely to long-term complications, especially coronary artery disease (CAD). Excess risk of CAD seen in T1D is not fully explained by traditional risk factors identified in non-DM individuals and those with type 2 diabetes. Hyperglycemia, hypertension, dyslipidemia, albuminuria, obesity, inflammation, and low adiponectin levels clearly play a role. Insulin resistance may be the primary problem, underlying the above risk factors, but is more difficult to quantify in T1D subjects. In this application, I am proposing a series of studies with the overarching dual goal of acquiring advanced research skills while translating findings and methods of investigation of the pathogenesis of CAD in T1D adults to diabetic children -the ultimate target population for primary prevention. The goal of this training grant is to pursue the following specific aims to develop research skills within the framework of the Coronary Artery Calcification in Type 1 Diabetes (CACTI) Study to test hypotheses specific to this application: 1) to disentangle the inter-relationship between hyperglycemia, kidney function, hypertension, and insulin resistance (defined by visceral obesity, low adiponectin levels and dyslipidemia) in the development of premature CAD using the baseline and follow-up data from the CACTI cohort;2) To perform euglycemic hyperinsulinemic clamp studies in young adults in CACTI to develop an accurate estimate of insulin sensitivity based on easy to measure traditional and novel markers in T1D subjects;and 3) To establish a cohort of 120 adolescents (ages 12-19) with T1D (n=60) and non-DM (n=60). Formation and analysis of cardiovascular risk factors in this cohort at the Barbara Davis Center for Childhood Diabetes will provide pilot data for a future R01 application. These goals have been identified to translate research on CVD in T1D from young adults to adolescents. Although guidelines for CVD risk factors in adults are established, screening and intervention in adolescents with T1D are either absent or based on extrapolation from adult data. The general hypothesis for this research is that greatly elevated CVD risk factors are present in youth with T1D and screening and treatment thresholds need to be determined.
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