Principal Investigator Prof. James Gibney
Research Title: To compare high-density lipoprotein function and composition in type 1 versus type 2 diabetes, and determine their relationship to early atherosclerosis.”
Meath Foundation Research Funding Awarded 2017
A progress report on a research project to compare high-density lipoprotein function and composition in type 1 versus type 2 diabetes, and determine their relationship to early atherosclerosis was presented by Prof. James Gibney, Consultant Endocrinologist, Tallaght University Hospital.
Prof. Gibney said HDL cholesterol (HDL-C) was a strong negative predictor of cardiovascular events in the general population. However, drugs that increased HDL-C levels had not been shown to reduce cardiovascular events. This observation had led to attempts to determine whether more complex measures of HDL structure and function were more important metrics than HDL-C levels.
A research project “HDL Cholesterol Efflux Capacity and Incident Cardiovascular Events” (Anand Rohatgi et al), published in the New England Journal of Medicine in 2014, concluded that cholesterol efflux capacity, a new biomarker that characterises a key step in reverse cholesterol transport, was inversely associated with the incidence of cardiovascular events in a population-based cohort.
This project found that Cholesterol Efflux Capacity (HDL-CEC), the effect of HDL particles to transfer cholesterol from macrophages in the arterial wall to the liver for excretion more accurately predicted cardiovascular events compared to HDL-C levels.
Prof. Gibney said that in 20015, he and colleagues had published a cross sectional study which demonstrated increased serum amyloid, a related inflammation in High Density Lipoproteins From subjects with Type 1 Diabetes Mellitus and how this Association was augmented by poor glycaemic control,” in the Journal of Diabetes Research.
The current research programme looked at understanding HDL structure and function in Type 1 diabetes. Considerable progress had been made with this.
They had made a cross-sectional comparison between 100 patients with T1DM and matched controls. This was complete and published in the journal, Diabetologia.
Sample collection and laboratory analysis of a cross-sectional evaluation of variables that influenced HDL function in 280 T1DM patient, was also complete.
A 5-year follow-up of 280 patients with Type 1 diabetes was in progress and samples had been collected on HDL structure and function in response to an acute inflammatory state – a study in COVID-19.
They had now designed a cross-sectional study of 4 groups of 75 participants to compare lipoprotein structure and HDL-cholesterol efflux capacity between people with T1DM and T2DM, matched for age and gender, and with respective matched non-diabetic cohorts. All groups were matched for age and gender.
The study design provided for Investigations – Lipoprotein particle size (Nuclear Magnetic Resonance Spectroscopy), HDL-cholesterol efflux capacity (ABCA1-dependent and ABCA1-independent), Lipidomic analysis and HDL proteome analysis and statistical analysis carried out between-group ANOVA with post hoc testing.
CEC was measured using a validated method used in the large efflux studies. They used Mouse J 774 macrophages cell line as cholesterol donor. These cells were incubated for 24 hours with radiolabel led cholesterol as a tracer. Participants serum was depleted form Apo B containing particles mainly LDL, IDL and VLDL and TG using polyethelyin glycol (PEG) precipitation. This resulted in HDL supernatant, which was incubated with cAMP over 4 hours. ABCA 1 independent efflux was measured in paltes without camp stimulation while the difference in efflux to HDL from stimulated and non-stimulated cells represented ABCA1 mediated efflux measured as a percentage.
Prof. Gibney said the results were that Triglyceride levels were lower in T1DM compared to all other groups and VLDL and chylomicron particle number and triglyceride concentration were lower in the T1DM group compared to all other groups.
LDL particle size was greater in T1DM compared to all other groups, and greater in lean non-diabetic participants compared to T2DM and overweight non-diabetic participants.
HDL-cholesterol was greater in T1DM compared to T2DM and overweight non-diabetic participants.
HDL particle size was greater in T1DM compared to all other groups, and also greater in lean compared to overweight non-diabetic participants.
HDL-CEC was greater in T1DM compared to all other groups. This was explained by increased ABCA1- dependent but not ABCA1- independent CEC in T1DM.
“In summary, in Type 1 diabetes, there is a unique lipid phenotype that is not seen in Type 2 diabetes or in BMI-matched non-diabetic participants. It includes:
- Lower triglyceride levels in plasma, and in chylomicrons and VLDL.
- Lower number of VLDL and chylomicron particles.
- Lower number of LDL particles but larger particles.
- Larger HDL particles.
- Increased total and ABCA1-dependent CEC.
- LDL and HDL particle size were also greater in lean non-diabetic participants compared to overweight participants with and without T2DM.
Prof. Gibney said the conclusions were that as these changes only occurred in Type 1 diabetes, it was likely that they reflected the effects of subcutaneous insulin administration, i.e. reduced insulin levels in the portal relative to the systemic circulation.
“It is not known whether these differences are protective or harmful, but some of the observed changes including improved HDL-CEC are considered to be protective.
“Establishing optimal strategies to reduce cardiovascular disease in Type 1 diabetes will require further understanding of the mechanisms through which it occurs,” he said.
This work was funded by research funding from The Meath Foundation and a legacy from the estate of the late Robert George Davies.