Apolipoprotein-Based Lipoprotein Subclass Profiles and the Vascular Complications of Diabetes

Principal Investigator: Timothy J. Lyons, M.D., F.R.C.P. Professor & Chief, Section of Endocrinology

Abstract:

Objectives:To investigate apolipoprotein-based lipoprotein subclass profiles in diabetic and control subjects and their associations with diabetic retinopathy (DR) in Type 1 diabetes and the effect of statins in Type 2 diabetes.

Rationale: Vascular complications cause a majority of the morbidity and mortality of diabetes.Evidence suggests that dyslipidemia mediates risk for micro- and macro-vascular complications. There are no reports about the characterization of apolipoprotein-defined lipoprotein subclasses in Type 1 diabetes in relation to DR, and inadequate information about effects of commonly used lipid lowering drugs on subclasses in Type 2 diabetes. Since apolipoprotein-based particle analysis allows a new view of a complex system, this proposal will provide important new knowledge.

Hypotheses: Apolipoprotein-based plasma lipoprotein subclass profiles are associated with the development of the macro- and micro-vascular complications of diabetes, and may help identify at-risk patients for vascular complications.

Specific Aims:

To define (a) apolipoprotein-based profiles that are associated with retinopathy in patients with Type 1 diabetes, and (b) apolipoprotein-based lipoprotein subclass profiles that are associated with Type 1 diabetes (with and without retinopathy) compared with age-, gender-, and race matched non-diabetic control subjects.We will determine the apolipoprotein-based lipid profile in 50 Type 1 diabetic patients: 25 with retinopathy and 25 others, individually age-, sex-, and race-matched to the first group but without retinopathy, and in 25 healthy non-diabetic control subjects (individually matched by age and gender to the diabetic subjects).

To define (a) apolipoprotein-based profiles that are associated with statin treatment in patients with Type 2 diabetes, and (b) apolipoprotein-based lipoprotein subclass profiles that are associated with Type 2 diabetes (taking and not taking statins) compared with age-, gender-, and race matched non-diabetic control subjects.We will determine the apolipoprotein-based lipid profile in 50 Type 2 diabetic patients: 25 taking statins and 25 others, individually age-, sex-, and race-matched to the first group but not taking statins, and in 25 healthy non-diabetic control subjects (individually matched by age and gender to the diabetic subjects).

To investigate the relationship between apolipoprotein- based lipoprotein subclass profiles, in Type 1 and Type 2 diabetic and control subjects, and other characteristics known to be associated with dyslipidemia and the risk for atherosclerosis at least in non-diabetic subjects.The “secondary outcomes to be measured in this aim will allow accurate description and definition of other related vascular risks that may impact lipoprotein subclasses.They may also generate pilot data for future collaborative research studies.These “secondary outcome” characteristics will include:

• Other lipoprotein characteristics, including NMR, apoA1, B and Lp(a) by nephelometry, and conventional lipid profiles.
• Measures of oxidation status/oxidative stress
• Measures of endothelial dysfunction
• Measures of platelet function
• Growth factors
• In vivo vascular function
• Glycemia

Inclusion and exclusion criteria:

For Type 1 diabetic subjects:

Inclusion: Type 1 diabetes (C-peptide negative) of at least one year’s duration; age 18-70 years; male or female (genders to be equally represented); any race or ethnic group (composition to reflect local community as closely as possible); stable glycemic control (but no limit on HbA1c).We will select 25 patients with retinopathy (defined as history of laser therapy, i.e. ETDRS grades 10 - 23) and 25 individually age-, gender, and race-matched patients without retinopathy (ETDRS score < 4).For the latter assessment, we require recent documentation (within 6 months) by an ophthalmologist.

Exclusion:Evidence of significant cardiovascular complications, microalbuminuria (>40mg per 24hrs) or frank proteinuria, evidence of unstable glycemic control, or history of admission for hyperglycemia/ketoacidosis or hypoglycemia in the 6 months prior to recruitment; consumption of any medications (other than insulin) that might affect lipoprotein profiles; other significant renal, hepatic, cardiovascular, or neurological disease; cancer; pregnancy.

For Type 2 diabetic subjects:

Inclusion: Type 2 diabetes of at least one year’s duration; age 18-70 years; male or female (genders to be equally represented); any race or ethnic group (composition to reflect local community as closely as possible); stable glycemic control (but no limit on HbA1c).We will select 25 patients taking lipid-lowering (statin) therapy and 25 individually age-, gender, and race-matched patients not on lipid- lowering (statin) therapy.

Exclusion: Evidence of significant cardiovascular complications, microalbuminuria (>40mg per 24hrs) or frank proteinuria, evidence of unstable glycemic control, or history of admission for hyperglycemia or hypoglycemia in the 6 months prior to recruitment, other significant renal, hepatic, cardiovascular, or neurological disease; cancer; pregnancy.

For non-diabetic control subjects:

Inclusion: Healthy (taking no medications) non-diabetic control subjects, individually matched to each diabetic subject pair (both Type 1 and Type 2) for age (within three years of index case), gender, and race, will be recruited.

Exclusion: Evidence of significant cardiovascular complications, significant renal, hepatic, or neurological disease; cancer; pregnancy, diabetes, use of prescription medicines.

ParticipantCompensation: Yes

Contact Information:

Albina Gosmanova, MD, Endocrine Fellow, University of Oklahoma Health Sciences Center. (405) 271-xxxx or albina-gosmanova@ouhsc.edu When inquiring, please mention the Subclass Profiles Diabetes Study at the General Clinical Research Center