METABOLIC HETEROGENEITY OF PLASMA VLDL & LDL IN DIABETES

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This study examines heterogeneity in the metabolic pathways of plasma very low density lipoproteins (VLDL) and low density lipoproteins (LDL) in man and evaluates the importance of this heterogeneity in the disorder(s) of lipid metabolism in diabetes. The specific Aim of the study is to test the hypotheses: 1) that the TG-poor subfraction (sf 60-20) of plasma VLDL is metabolically heterogenous being formed by both direct synthesis and as a result of the delipidation of less dense particles; 2) that this subfraction serves as a precursor pool for IDL and LDL, and as a remnant pathway through which incompletely formed and/or partially delipidated VLDL particles are cleared from the plasma; 3) that the LDL subfraction (sf 12-0) is derived from lipolysis of both large and small VLDL and from direct synthesis into IDL and LDL; 4) that the apo-B source in LDL determines the density range and catabolic rate of LDL particles; 5) that the metabolic heterogeneity of the TG-poor VLDL and LDL is influenced by: a) the rate of apo-B synthesis, b) hepatic coupling of TG to apo-B and possibly other apolipoproteins (apo-C's and apo-E's), c) the efficiency of the VLDL delipidation cascade, and d) the splanchnic uptake of remnant particles. Kinetic parameters of VLDL and LDL metabolism are determined utilizing pulse injections of radiolabeled VLDL1 (Sf 400-100), VLDL3 (sf 60-20) and LDL (sf 12-0). The data will then be used to develop a multicompartmental model describing the metabolic events. Studies are performed in healthy volunteers to establish control data. Regulation of VLDL or LDL channeling is evaluated in normal subjects on either a high or low carbohydrate diet and in patients with genetic hypertriglyceridemias. Finally, the abormalities which occur in noninsulin-dependent diabetic patients with and without hyperlipidemia, and the relationship of these abnormalities to the metabolic profile and the effect of diabetic control are defined.