Testosterone Concentrations and Cardiovascular Disease in Men with Type 1 Diabetes
In men, low endogenous levels of testosterone (T) are associated with increased risk of cardiovascular disease (CVD). It is unclear whether this relationship is independent of age, obesity, and conventional CVD risk factors such as levels of blood pressure and lipids. The majority of studies are cross-sectional and cannot examine changes in T or risk factor levels. Prospective studies of T and CVD risk are needed particularly for men with type 1 diabetes (T1D) for several reasons. Men with T1D may have as much as a 10-fold increased risk for CVD mortality compared to men without diabetes. This risk may be compounded by the lower bioavailable T levels in men with T1D compared to men without diabetes; as many as 1 in 5 men with T1D may have low bioavailable T. The need to understand T and its risks is more urgent due to the tripling in prescriptions for exogenous T over the past decade. We propose to address these important clinical questions by leveraging the extensive resources of DCCT/EDIC, a large randomized trial of intensive glycemic control in T1D and its observational follow-up to complete these aims: 1) to examine how changes in T levels predict changes in CVD risk factors among men with T1D. We hypothesize that decreases in T levels will predict increases in blood pressure, triglycerides, hemoglobin A1c, and decreases in high-density lipoprotein, before and after adjustment for age and obesity; 2) to examine how T levels predict cardiac structure and function on cardiac MRI among men with T1D. We hypothesize that lower T levels will predict lower values of left ventricular mass and end-diastolic volume, before and after adjustment for age, obesity, hemoglobin A1c, blood pressure, and lipid levels; and 3) to examine how changes in Tlevels predict CVD events among men with T1D. We hypothesize that lower T levels will predict a greater incidence of CVD events, before and after adjustment for age, obesity, hemoglobin A1c, blood pressure, and lipid levels. By examining a cohort at high-risk for CVD and which has serial measures of CVD risk factors as well as structure, function, and adjudicated events, we can examine whether T is related to CVD in the type 1 population, as well as illuminating the relationships between T and risk factors generally.

Sexual Function and Neuropathy in Pre-Diabetes and Type 2 Diabetes
A common health problem among both men and women, sexual dysfunction increases with advancing age and markedly reduces quality of life (QOL). Our team’s findings from people with type 1 diabetes (T1DM) in the Epidemiology of Diabetes, Interventions and Complications (EDIC) study–the observational extension of the Diabetes Control and Complications Trial (DCCT)–showed that 45% of men reported erectile dysfunction (ED) and 42% of women reported female sexual dysfunction (FSD). Poor glycemic control and cardiac autonomic neuropathy significantly increased risk of ED and FSD in this cohort. Although our findings in EDIC have begun to shed light on the role of prevalent T1DM on sexual dysfunction, data defining the burden, and risk reduction strategies among people who are at risk for type 2 diabetes (T2DM) are limited. The Diabetes Prevention Program (DPP), a randomized controlled trial of overweight and obese men and women at high risk for T2DM, and its observational follow up, the Diabetes Prevention Program Observational Study (DPPOS) now in its 18th year, demonstrated that intense lifestyle intervention and metformin both delayed the onset and progression of T2DM and its complications. At year 15, DPPOS participants completed the International Index of Erectile Function (IIEF) and Female Sexual Function Index (FSFI) yielding validated measures of sexual dysfunction for both genders. We hypothesize that sexual dysfunction in men and women with prediabetes and T2DM is highly prevalent and less favorable trajectories of glycemia and neuropathy predict those at highest risk. Accordingly, we propose to utilize existing data from DPPOS to test these hypotheses. By fully leveraging data in an existing, NIH-funded study, we avoid costs associated with primary data collection and facilitate generation of new knowledge that (1) builds on a growing body of research on the urological complications of DM and (2) has been defined as a high priority to the NIH and other stakeholders.

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