We found that youth with type 2 diabetes and a relatively short diabetes duration (average 1.5 years) have a higher prevalence of many CVD risk factors, including obesity and central fat deposition, elevated blood pressure, dyslipidemia, and elevated ACR, compared with nondiabetic youth of similar age, sex, and race/ethnicity. Moreover, youth with diabetes tend to have a cluster of multiple CVD risk factors, on average 2.9 vs. 1.0 in the control group. Data from the Bogalusa Heart Study (18
) showed that the risk of fibrous plaques in the coronary arteries in youth with three or four CVD risk factors was three to eight times higher than the risk with zero, one, or two risk factors.
Our data show that youth with type 2 diabetes have an atherogenic dyslipidemia characteristic of adults with type 2 diabetes, including low HDL cholesterol, high triglycerides, and apoB and increased levels of LDL particle density. There were no significant differences in LDL cholesterol between case and control youth in our study. Elevated levels of apoB in the presence of normal LDL cholesterol levels have been associated with acute myocardial infarction in adults (19
). Elevated apoB levels in the presence of normal LDL cholesterol levels may be explained by the increased concentration of triglyceride-rich apoB-containing lipoproteins and by the presence of dense LDL that is enriched in apoB relative to its cholesterol content. The association between type 2 diabetes and hypertension is well established in adults, and our findings support a similar relationship in youth.
Our findings suggest that adiposity and glycemic control account for much of the association between type 2 diabetes and an unfavorable CVD risk factor profile in youth. Excess adiposity, particularly visceral abdominal obesity, is a well-known risk factor for a cluster of metabolic abnormalities, including insulin resistance, dyslipidemia, and hypertension, and is in turn associated with the development of CVD. Consistent with data in adults (20
), we found that adiposity, as measured by BMI and waist circumference, has a strong effect on differences in HDL cholesterol, triglycerides, and blood pressure levels between diabetic and nondiabetic youth.
Accumulating evidence indicates that adipose tissue releases a number of bioactive mediators that play an important role in the regulation of metabolic, inflammatory, and thrombolytic pathways that are associated with CVD risk (21
). Most of these factors, including leptin, fibrinogen, IL-6, and CRP, are overproduced with obesity. Conversely, plasma levels of adiponectin, an insulin-sensitizing cytokine, are downregulated during obesity. We observed significantly higher levels of CRP, IL-6, fibrinogen, and leptin and lower levels of adiponectin in diabetic youth than in healthy control subjects. Consistent with a key role of obesity in the dysregulation of these adipocytokines and inflammatory factors in youth with type 2 diabetes, case-control differences disappeared (for adiponectin and leptin) or were even reversed (for CRP) on adjustment for adiposity. Nevertheless, fibrinogen and IL-6 remained significantly elevated in diabetic youth relative to nondiabetic youth, independent of demographic factors, adiposity, and glycemia, suggesting potential independent effects of fibrinogen and IL-6 on type 2 diabetes–related CVD risk in youth.
Although obesity is a major contributor to cardiometabolic risk, prospective studies suggest a possible independent effect of hyperglycemia (22
). Hyperglycemia accelerates the formation of advanced glycation end products, which can lead to atherogenic endothelial damage. Our results suggest smaller effects of hyperglycemia, relative to adiposity, on CVD risk profiles in youth with diabetes. However, the present data suggest that hyperglycemia may have important effects on lipoprotein risk factors, including apoB and LDL particle size. Previous data from the SEARCH study indicated that both apoB levels and LDL density increased significantly with increasing A1C in youth with either type 1 or type 2 diabetes (23
). Also, insulin therapy in adults with type 2 diabetes was shown to significantly reduce apoB levels (24
This study has several limitations. The cross-sectional data limits our ability to definitively identify which factors and pathways account for the unfavorable CVD risk profile observed in diabetic youth compared with nondiabetic youth. Also, the case-control design has an inherent limitation of potential selection bias; however, comparisons between eligible type 2 diabetic case subjects that did and did not participate in this study revealed no significant differences in diabetes duration, BMI z-scores, or waist circumference (P
> 0.05 for each comparison). Additionally, there is a lack of consensus regarding specific criteria and cutoff values for CVD risk factors, particularly in youth. Despite this limitation, our findings that the mean values and prevalence for a majority of CVD risk factors are significantly higher in type 2 diabetic youth is an important and timely observation about the potential burden of comorbidities in this population, especially given that many CVD risk factors encountered in youth track from childhood into adulthood (25
In summary, when compared with youth without diabetes, type 2 diabetic youth have a higher prevalence of many and multiple CVD risk factors. Adiposity and glycemia are both independent and interdependent contributors to a less favorable CVD risk profile for diabetic youth. Inflammatory and coagulation/prothrombotic factors may also play an important role. Because an earlier age of onset of type 2 diabetes will likely increase the lifetime incidence of CVD complications, early prevention and treatment strategies aimed at reducing the prevalence of CVD risk factors in these youth are needed.