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Published on: October 12, 2017
Functional and proteomic alterations of plasma high density lipoproteins in type 1 diabetes mellitus
Shankarappa Manjunatha1, Klaus Distelmaier1, Surendra Dasari2
1Division of Endocrinology and Metabolism, Mayo Clinic, Rochester, MN, USA.
Insights
In type 1 diabetes mellitus (T1DM), high HDL-cholesterol (HDL-C) doesn't guarantee reduced cardiovascular risk. Altered HDL function, due to protein modifications, explains increased risk, not just HDL-C levels.
Area of Science:
- Biochemistry
- Cardiovascular Medicine
- Metabolic Disorders
Background:
- Higher high-density lipoprotein cholesterol (HDL-C) typically correlates with lower cardiovascular risk.
- However, individuals with type 1 diabetes mellitus (T1DM) with normal or high HDL-C experience increased cardiovascular events compared to non-diabetic controls (ND).
- This suggests that HDL function, not just concentration, may be compromised in T1DM.
Purpose of the Study:
- To investigate if altered HDL functions, despite normal HDL-C levels, contribute to increased cardiovascular risk in T1DM.
- To determine if irreversible posttranslational modifications (PTMs) of HDL-bound proteins are present in T1DM individuals with impaired HDL function.
Main Methods:
- Compared T1DM patients with poor (T1D-PC) and good (T1D-GC) glycemic control to age-, sex-, and BMI-matched NDs.
- Assessed HDL's cholesterol efflux capacity (CEC), antioxidant function, and PON1 activity.
- Utilized mass spectrometry and shotgun proteomics to analyze HDL-bound proteins and their PTMs.
Main Results:
- Both T1DM groups showed reduced HDL CEC and antioxidant function compared to NDs, despite similar HDL-C concentrations.
- Increased abundance of oxidative PTMs (e.g., on ApoA4, ApoE) and amadori modifications (on ApoD) were observed in T1DM groups.
- Specific modifications like deamidation of ApoA4 were higher in T1D-PC.
Conclusions:
- Compromised HDL function in T1DM, regardless of glycemic control, is linked to a higher prevalence of irreversible PTMs in HDL proteins.
- HDL quality, rather than quantity (HDL-C levels), appears to be a critical determinant of cardiovascular risk in T1DM.
- HbA1c and HDL-C measurements alone are insufficient biomarkers for assessing effective cardiovascular risk reduction in T1DM.
Objective:
Higher HDL-cholesterol (HDL-C) is linked to lower cardiovascular risk but individuals with type 1 diabetes mellitus (T1DM) with normal or high HDL-C have higher cardiovascular events compared to age matched non-diabetic controls (ND). We determined whether altered HDL functions despite having normal HDL-C concentration may explain increased cardiovascular risk in T1DM individuals. We also determined whether irreversible posttranslational modifications (PTMs) of HDL bound proteins occur in T1DM individuals with altered HDL functions.
Methods:
T1DM with poor glycemic control (T1D-PC, HbA1c≥8.5%, n=15) and T1DM with good glycemic control (T1D-GC, HbA1c≤6.6%, n=15) were compared with equal numbers of NDs, ND-PC and ND-GC respectively, matched for age, sex and body mass index (BMI). We measured cholesterol efflux capacity (CEC) of HDL in the serum using J774 macrophages, antioxidant function of HDL as the ability to reverse the oxidative damage of LDL and PON1 activity using commercially available kit. For proteomic analysis, HDL was isolated by density gradient ultracentrifugation and was analyzed by mass spectrometry and shotgun proteomics method.
Results:
Plasma HDL-C concentrations in both T1DM groups were similar to their ND. However, CEC (%) of T1D-PC (16.9±0.8) and T1D-GC (17.1±1) were lower than their respective ND (17.9±1, p=0.01 and 18.2±1.4, p=0.02). HDL antioxidative function also was lower (p<0.05). The abundance of oxidative PTMs of apolipoproteins involved in CEC and antioxidative functions of HDL were higher in T1D-PC (ApoA4, p=0.041) and T1D-GC (ApoA4, p=0.025 and ApoE, p=0.041) in comparison with ND. Both T1D-PC and T1D-GC groups had higher abundance of amadori modification of ApoD (p=0.002 and p=0.041 respectively) and deamidation modification of ApoA4 was higher in T1D-PC (p=0.025).
Conclusions:
Compromised functions of HDL particles in T1DM individuals, irrespective of glycemic control, could be explained by higher abundance of irreversible PTMs of HDL proteins. These results lend mechanistic support to the hypothesis that HDL quality rather than quantity determines HDL function in T1DM and suggest that measurements of concentrations of HbA1c and HDL-C are not sufficient as biomarkers of effective treatment to lower cardiovascular risk in T1DM individuals.
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