Diabetes, Lipoproteins and Accelerated Vascular Disease
Diabetes, Lipoproteins and Accelerated Vascular Disease
To better understand the excess cardiovascular disease associated with diabetes mellitus.
BACKGROUND:

 Diabetes mellitus is associated with a 2-4 fold increase in risk for atherosclerotic
 cardiovascular disease. Atherosclerotic cardiovascular disease, particularly coronary artery
 disease, is the leading cause of death in diabetics. The study was a subproject within a
 program project grant, with Henry Ginsberg as principal investigator. The program project was
 part of an institute-initiated study on The Etiology of Excess Cardiovascular Disease in
 Diabetes Mellitus. The initiative originated after discussions between NHLBI and the Juvenile
 Diabetes Foundation International (JDFI). The Request for Applications (RFA) was originally
 issued in October 1994 and resulted in the award of one grant The RFA was reissued in
 December 1995 and resulted in the awarding of five program project grants, the one under
 discussion among them.

 DESIGN NARRATIVE:

 The study, subproject 3 within a program project grant, was entitled Atherogenic Triglyceride
 Rich Lipoproteins in Diabetes. The subproject examined the atherogenicity of
 hypertriglyceridemia in subjects with non-insulin dependent diabetes mellitus (NIDDM).
 Subproject 3 tested hypotheses concerning the impact of the size and number of
 triglyceride-rich lipoproteins (TGRL) on risk for atherosclerotic cardiovascular disease
 (ASCVD) in several human populations. A case-control study of diabetics with or without
 coronary artery disease determined if TGRL size and number differed between the groups. In
 this study, Whites, Blacks and Hispanics with documented coronary artery disease or with less
 than 50 percent coronary stenosis by angiography were recruited. The hypothesis was tested
 that increased apoB in small TGRL was associated with coronary artery disease. Fasting and
 postprandial blood samples were obtained for measurement of TGRL apoB level, TGRL TG:apoB
 ratio, the amount of apoB in apoE-rich TGRL, and retinyl palmitate clearance. Allelic
 differences in the apoB, apoE, LPL, and apoCIII genes were examined for effects on the size
 and number of TGRL: specific hypotheses were tested regarding the impact of these alleles.

 TGRL size and number were also compared in diabetics with and without carotid atherosclerosis
 in the Atherosclerosis Risk in Communities (ARIC) study, in Sioux and Pima Indian tribes that
 differed in ASCVD rates, and in Blacks, Whites and Hispanics with a range of insulin levels
 and insulin resistance in the Insulin Resistance and Atherosclerosis Study (IRAS). These
 studies served both to confirm findings in the case-control study and to provide the
 opportunity to investigate diverse populations. The collaboration with IRAS allowed
 determination of the effects of insulin resistance and insulin secretory capacity on TGRL
 size and number. Finally, experiments with cultured endothelial cells were performed to
 determine if small TGRL could cause endothelial dysfunction. PMI-1 and VCAM-1 were markers of
 TGRL effects. In the case-control study, plasma PMI and VCAM-1 were measured to examine their
 relationship to coronary artery disease and to TGRL size and number.

 Dollars awarded were estimated based on the CRISP assignment of $173,249 dollars in FY 1996
 for Subproject 3. This was approximately 25 percent of the total dollars awarded and was used
 to estimated committed dollars.
Inclusion criteria

 -  Patients with type 2 diabetes mellitus (DM), defined by medical record diagnosis,
 fasting glucose >140 mg/dl, or the use of diabetes medications

 -  Had a myocardial infarction (MI) any time in the past, a coronary angiogram within the
 previous year, or an exercise perfusion scan (stress thallium study) within one year

 -  Patients with CAD group, defined by the following criteria: documented prior MI,
 PTCA/stent, CABG, or >75% stenosis in any vessel by coronary angiography.

 -  Patients without CAD group, defined as: the absence of a prior MI and <50% stenosis in
 all vessels by coronary angiography within the past year, or the combination of a
 normal exercise perfusion scan and the absence of a prior MI or any interventional
 cardiac procedures.

 Exclusion criteria

 -  MI or cardiac procedures within the past 3 months

 -  Diagnoses of cancer, severe congestive heart failure (ejection fraction < 20%), kidney
 or liver disease, pancreatitis, other gastrointestinal conditions,

 -  Laboratory values of creatinine levels > 1.3, abnormal liver function tests, abnormal
 CBC, fasting TG > 400 mg/dl, urine protein > 2+ on urinalysis or > 1000 mg/24 h,
 abnormal thyroid function tests, body mass index (BMI) > 34 for men and > 37 for women
 or BMI < 20 for both sexes

 -  Age < 35 or > 75 years