Reduced HDL function in children and young adults with type 1 diabetes

Abstract

Background: Patients with type 1 diabetes (T1D) are at increased risk of cardiovascular disease (CVD). Measures of high-density lipoprotein (HDL) function provide a better risk estimate for future CVD events than serum levels of HDL cholesterol. The objective of this study was to evaluate HDL function in T1D patients shortly after disease onset compared with healthy control subjects.

Methods: Participants in the atherosclerosis and childhood diabetes study were examined at baseline and after 5 years. At baseline, the cohort included 293 T1D patients with a mean age of 13.7 years and mean HbA1c of 8.4%, along with 111 healthy control subjects. Their HDL function, quantified by HDL-apoA-I exchange (HAE), was assessed at both time points. HAE is a measure of HDL's dynamic property, specifically its ability to release lipid-poor apolipoprotein A-I (apoA-I), an essential step in reverse cholesterol transport.

Results: The HAE-apoA-I ratio, reflecting the HDL function per concentration unit apoA-I, was significantly lower in the diabetes group both at baseline, 0.33 (SD = 0.06) versus 0.36 (SD = 0.06) %HAE/mg/dL, p < 0.001 and at follow-up, 0.34 (SD = 0.06) versus 0.36 (SD = 0.06) %HAE/mg/dL, p = 0.003. HAE-apoA-I ratio was significantly and inversely correlated with HbA1c in the diabetes group. Over the 5 years of the study, the mean HAE-apoA-I ratio remained consistent in both groups. Individual changes were less than 15% for half of the study participants.

Conclusions: This study shows reduced HDL function, quantified as HAE-apoA-I ratio, in children and young adults with T1D compared with healthy control subjects. The differences in HDL function appeared shortly after disease onset and persisted over time.

Keywords: Atherosclerosis; HDL function; HDL-apoA-I exchange; High-density lipoprotein; Type 1 diabetes.

Fig. 1

Cholesterol transport in the intima and measurements of HDL function. To facilitate cholesterol efflux from cholesterol-laden macrophages (MΦ), lipid-poor apoA-I binds to ABCA1. During its association with ABCA1, apoA-I acquires free cholesterol (FC) and phospholipid (PL) to form discoidal alpha HDL (red arrow). These particles are acted upon by LCAT and converted to cholesterol ester core containing alpha HDL. ApoA-I is liberated from alpha HDL by the action(s) of phospholipid transfer protein (PLTP), cholesterol ester transfer protein (CETP), lipoprotein lipase (LPL) and hepatic lipase (HL) to generate lipid-poor apoA-I and preβ HDL (green arrows). The formation of lipid-poor apoA-I and preβ by HDL is a rate-limiting step of this process. These processes can be quantified by the CEC (red arrow) and HAE (green arrows) assays

Fig. 2

The relationship between  %HAE and apoA-I at baseline. N = 293 T1D patients. N = 111 for healthy control subjects. All resided in the South East region of Norway and had a mean age of 13.7 years. The average  %HAE for the T1D subjects was 50.7 and 52.4 for controls. T1D subjects differed significantly from healthy controls in %HAE-apoA-I (p < 0.001)

Fig. 3

Frequency distribution for delta HAE-apoA-1 ratio in diabetes patients. The delta value is calculated by subtracting the baseline value from the follow-up value of HAE-apoA-I ratio for each participant. N = 218. The values for most patients are close to zero, indicating little change in HAE-apoA-I ratio over the 5 years of the study