Chronic hyperglycemia and insulin resistance (IR) is associated with cardiac function and increase the risk of heart failure (HF). Hyperglycemia has been linked to an excess of advanced glycation end products, alterations in myocardial calcium handling, and modifications of the extracellular matrix. These changes contribute to increased ventricular stiffness, impaired relaxation, and ultimately diastolic dysfunction. ^,,,, Meanwhile, IR affects substrate metabolism, promotes cellular injury, and contributes to microvascular dysfunction, as well as sympathetic and neurohormonal hyperactivity, leading to functional and structural changes in the heart. ^, However, despite the biological link between chronic hyperglycemia and IR and the development of HF, epidemiologic evidence has been mostly extrapolated from older adult cohorts. ^, Early-onset type 2 diabetes (T2D, diagnosed <age 40) has been shown to be disproportionately associated with HF. Yet ,; little is known about the cumulative effect of hyperglycemia and IR on cardiac dysfunction among young adults with early-onset T2Dor those with prediabetes (pre-DM). We evaluated the effects of glucose and IR accumulated over 20 years and cardiac dysfunction among individuals with early-onset T2D or pre-DM and compared the effects among those with euglycemic status.

Data source: The Coronary Artery Risk Development in Young Adults (CARDIA) study is a prospective study of 5,115 healthy young adults enrolled in 1985 across 4 U.S. field centers. We used data from CVD-free nonpregnant participants with early-onset T2D/pre-DM or euglycemia (age-, sex-, and race-matched) (Supplemental Figure 1). CARDIA data were obtained from the National Heart, Lung, and Blood Institute, Biologic Specimen, and Data Repository Information Coordinating Center (BioLINCC).

Early-onset T2D was defined by self-reported diabetes or antidiabetic medication (every examination), fasting glucose (FG) ≥126 mg/dL (CARDIA years 0, 7, 10), or 2-hour oral glucose tolerance test (OGTT) ≥200 mg/dL (year 10) at or before year 10 (maximum age 40). Pre-DM was defined by FG 100 to 125 mg/dL or OGTT 140 to 199 mg/dL at or before year 10. Insulin users were excluded from the study.

Euglycemic controls (matched 1:2 to cases based on sex, age, and race at the ‘onset of hyperglycemia’) were selected based on the absence of elevated glucose levels throughout the study period and the availability of 4 or more risk factor measurements, which was necessary for applying a robust quadratic random-effects model (see Analysis section for details). Risk factors: Glucose and insulin assay methods were described previously. ^, The index of HOMA‐IR was expressed by the formula: fasting insulin (µU/dL) × fasting glucose (mg/dL)/405.

Outcomes: At Year 25, doppler echocardiography and 2D-guided M-mode echocardiography were performed (Toshiba Medical Systems, Otawara, Japan) by trained sonographers. Left ventricular (LV) systolic function was estimated with ejection fraction and global longitudinal strain. The strain was calculated as the change in segment length relative to its end-diastolic length, and the peak systolic value was recorded. More negative values of strain indicate greater shortening or better function. Peak early diastolic mitral annular velocity (e’) was calculated from the average of the septal and lateral mitral annular velocities. E/e′ ratio was calculated as an index of LV filling pressures.

We used the area under the growth curve (AUC) between year 10 and year 25 derived from quadratic random-effects models of ≥4 repeated FG and HOMA-IR measures to estimate their cumulative burden. The AUC, computed from longitudinal growth curve models, uses multiple measurements of risk factors throughout time to reduce within-person variability and has been widely adopted for estimating risk burden in life-course cohorts. ^, Because the growth curves of the risk factors may be cubic models, a minimum of 4 measures were needed. This model computes all participants’ maximum likelihood estimates of curve parameters. We selected the most parsimonious model using p-values (<0.05) of the independent variable (age). We calculated the AUCs using an integral calculus formula based on the fixed and random-effect parameters of the model during follow-up for each subject, dividing them by follow-up years to reflect the varying follow-up intervals between participants. ^, We computed AUC to characterize the overall risk factor from the first recorded risk factor to the last recorded risk factor.

For individual i:

where β = (β0, β1, β2, β3) is a vector of fixed-effect parameters, b _i = (b0 _i , b1 _i , b2 _i , b3 _i ) is a vector of random-effect parameters, and ɛ _i is an unknown error for individual i. We performed linear regressions to examine the associations of the total AUC of FG or HOMA-IR with cardiac functional outcomes, adjusting for sex, race, field center, mid-life (year 25) age, education, smoking, oral antidiabetic medications, lipid-lowering medications, and resting heart rate. We further adjusted for the cumulative burden of hypertension and obesity (AUC of SBP or BMI) because of their confounding role in the association of interest.

Among individuals with early-onset T2D/pre-DM, the mean onset age was 32 years. Sociodemographic and lifestyle factors were comparable in the 2 glycemic groups at baseline (year of diagnosis) ( Table 1 ). At year 25, the mean age of 2 groups was 51 years. The mean of e’ was significantly lower, but e/e’ and longitudinal peak systolic strain were significantly higher in the early-onset DM/pre-DM group than in the euglycemic group (9.8 vs. 10.9, P =.001 and 8.4 vs.7.6 %, and −14.6 vs. −15.3, P ≤.0002, respectively) at year 25. Total AUCs of FG and HOMA-IR were higher in the early-onset T2D/pre-DM than in the euglycemic group ( Table 1 ).