Individuals who are overweight or obese not only constitute a group who are at increased risk for coronary heart disease (CHD) but also display features of Metabolic Syndrome (MSX) and diminished endothelial vasodilatory function many years prior to their normal-weighted counterparts. In our studies of at-risk and healthy cohorts, we have observed that central obesity is a primary predictor of insulin and glucose metabolic dysregulation and is linked with diminished vasodilatory function, an early indicator of CHD risk. The literature has focused more on insulin resistance as the primary deficit in MSX but there is a growing body of evidence that suggests that glycemic dysregulation, as indexed by postprandial indicators, may be independently predictive of GHD risk and vascular dysfunction. Although methodology was previously unavailable, the development of a device to continuously measure glucose levels has now been introduced that would permit assessments of meal-related glycemic regulation over prolonged periods of time and under various conditions. The primary objective of the proposed research is to use this technology, systematically manipulate glucose content of meals over the course of a two-day in-patient visit, and then as function of CHD risk status examine indices of meal-related glycemic functioning and its impact on vascular functioning, in the context of postprandial metabolic mediators i.e., insulinemia, triglyceridemia and free fatty acids. The study will enroll 281 (of 400 screened) persons to obtain complete data on 184 subjects. We will compare 92 high risk men and women who meet MSX diagnostic criteria and have body mass >25 kg/m2 with 92 low risk age-, sex- and ethnicity-matched individuals who do not have MSX (as per NCEP ATP III criteria) and whose body mass is ? 25 kg/m2. Subjects will be screened with an exercise stress test and will have no diagnosed cardiovascular conditions. The study will include two contiguous 24 hour periods of in-patient stay. Subjects will have an oral glucose tolerance test (OGTT) and 4 meals/day of equivalent caloric content but the glucose content will be manipulated such that on one day the glucose content will be 300 calories/meal (as in an OGTT) and the other day the glucose content will be 600 calories/meal. The order of low and high glucose load days will be counterbalanced across subjects. Measures of metabolic mediators will be derived following overnight fasts, OGTTs, and meals for the low and high caloric days. Echocardiographic measures of carotid intimal media thickness and cardiac structure and function will be obtained as well as measures of endothelial-dependent vasodilatory function and arterial stiffness (using the brachial artery reactive hyperemia test before and 1 hour after meals). A measure of insulin sensitivity will be derived using a euglycemic hyperinsulinemia clamp. Measures of central obesity (waist girth, and CT measures of visceral adipose mass, subcutaneous adipose mass) will also be obtained. In sum, the study postulates that high risk overweight and obese persons with MSX relative to low risk controls will exhibit greater meal-related glycemic dysregulation that worsens over the day and worsens with increasing glucose load;more corresponding meal-related decrease in vasodilatory function and enhancement of arterial stiffness will be predicted. This research is an essential step toward understanding in persons with MSX the role of postprandial glycemic regulation in accelerated CHD pathogenesis.
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