Objective-We sought to compare the synthesis and metabolism of VLDL 1 and VLDL 2 in patients with type 2 diabetes mellitus (DM2) and nondiabetic subjects. Methods and Results-We used a novel multicompartmental model to simultaneously determine the kinetics of apolipoprotein (apo) B and triglyceride (TG) in VLDL 1 and VLDL 2 after a bolus injection of [ 2 H 3 ]leucine and [ 2 H 5 ]glycerol and to follow the catabolism and transfer of the lipoprotein particles. Our results show that the overproduction of VLDL particles in DM2 is explained by enhanced secretion of VLDL 1 apoB and TG. Direct production of VLDL 2 apoB and TG was not influenced by diabetes per se. The production rates of VLDL 1 apoB and TG were closely related, as were the corresponding pool sizes. VLDL 1 and VLDL 2 compositions did not differ in subjects with DM2 and controls, and the TG to apoB ratio of newly synthesized particles was very similar in the 2 groups. Plasma glucose, insulin, and free fatty acids together explained 55% of the variation in VLDL 1 TG production rate. Conclusion-Insulin resistance and DM2 are associated with excess hepatic production of VLDL 1 particles similar in size and composition to those in nondiabetic subjects. We propose that hyperglycemia is the driving force that aggravates overproduction of VLDL 1 in DM2. Key Words: diabetes Ⅲ dyslipidemia Ⅲ VLDL Ⅲ apolipoprotein B Ⅲ triglycerides Ⅲ compartmental modeling Ⅲ kinetics Ⅲ stable isotope B y 2025, Ͼ300 million people worldwide will have type 2 diabetes mellitus (DM2). Because atherosclerosis is an important complication of DM2, this will contribute significantly to an expected increase in cardiovascular disease worldwide. 1 One important cardiovascular risk factor associated with DM2 is a dyslipidemia characterized by high levels of triglyceride (TG)-rich VLDL, low levels of HDL cholesterol, small, dense LDL, and impaired and prolonged postprandial hyperlipidemia. 2 These abnormalities are present for years before DM2 is diagnosed clinically.The discovery of heterogeneity within the major lipoprotein classes (VLDL, LDL, and HDL) has opened new avenues to identify specific perturbations of diabetic dyslipidemia. 3 VLDL particles secreted from the liver vary in size and composition and can be classified by their density (0.94 to 1.06 g/mL), diameter (20 to 75 nm), and flotation [Svedberg flotation rate (Sf) 20 to 400]. VLDL can be separated into 2 main classes: large, buoyant VLDL 1 particles (Sf 60 to 400) and small, dense VLDL 2 particles (Sf 20 to 60). VLDL 1 particles contain more TG than VLDL 2 particles and are rich in apolipoprotein (apo) CIII and apoE. 4 Large VLDL 1 particles are the major subclass of endogenous TG-rich lipoproteins and seem to be the major determinant of the plasma TG concentration in normolipidemic subjects. 5 Although elevation of plasma TG is a consistent feature of diabetic dyslipidemia, little attention has focused on the VLDL subclass distribution in DM2. However, emerging data indicate a higher increase of VLDL 1 particles than of VL...
The use of stable isotopes in conjunction with compartmental modeling analysis has greatly facilitated studies of the metabolism of the apolipoprotein B (apoB)-containing lipoproteins in humans. The aim of this study was to develop a multicompartment model that allows us to simultaneously determine the kinetics of apoB and triglyceride (TG) in VLDL 1 and VLDL 2 after a bolus injection of [ 2 H 3 ]leucine and [ 2 H 5 ]glycerol and to follow the catabolism and transfer of the lipoprotein particles. Here, we describe the model and present the results of its application in a fasting steadystate situation in 17 subjects with lipid values representative of a Western population. Analysis of the correlations showed that plasma TG was determined by the VLDL 1 and VLDL 2 apoB and TG fractional catabolic rate. Furthermore, the model showed a linear correlation between VLDL 1 TG and apoB production. A novel observation was that VLDL TG entered the circulation within 21 min after its synthesis, whereas VLDL apoB entered the circulation after 33 min. These observations are consistent with a sequential assembly model of VLDL and suggest that the TG is added to a primordial apoB-containing particle in the liver. Regulation of the metabolism of VLDL subfractions has been an area of active interest that received fresh impetus from the introduction of stable isotope-based techniques in the late 1980s (1, 2). The use of tracer models has generated direct information on lipoprotein synthetic rates, which previously could only be inferred from the turnover of radiolabeled lipoproteins. One common approach is to inject a bolus of radioactive tracer, such as [ 3 H, 14 C]glycerol, and determine the subsequent monoexponential slope of the decline in plasma VLDL-specific radioactivity. A disadvantage of this approach is that it can underestimate the true VLDL turnover rate because it does not account for recycling of the injected bolus of tracer (3). Multicompartmental modeling improves the accuracy by attempting to account for tracer recycling (3-8). Such studies have revealed that VLDL 1 apolipoprotein B-100 (apoB-100) production and VLDL 2 apoB-100 production are independently regulated (9-11), indicating that regulatory steps in the assembly of VLDL govern the lipid content of the secreted particles. However, it is still unclear how the liver regulates the triglyceride (TG) content of VLDL particles to produce large VLDL 1 or small VLDL 2 . VLDL assembly is thought to involve at least two steps in which nascent VLDL particles are formed and then TG is added, resulting in larger particles (12,13).Several studies have analyzed VLDL TG turnover kinetics using stable isotopically labeled glycerol or palmitate tracers and mathematical modeling. However, VLDL subclasses were not analyzed in those studies, and VLDL apoB was not included in the models (3,14,15). To enhance our understanding of the pathways leading to VLDL 1 and VLDL 2 and of the metabolic fate of these particles, we developed for the first time a multicompartmental m...
This paper is devoted the the study of the mean field limit for many-particle systems undergoing jump, drift or diffusion processes, as well as combinations of them. The main results are quantitative estimates on the decay of fluctuations around the deterministic limit and of correlations between particles, as the number of particles goes to infinity. To this end we introduce a general functional framework which reduces this question to the one of proving a purely functional estimate on some abstract generator operators (consistency estimate) together with fine stability estimates on the flow of the limiting nonlinear equation (stability estimates). Then we apply this method to a Boltzmann collision jump process (for Maxwell molecules), to a McKean-Vlasov drift-diffusion process and to an inelastic Boltzmann collision jump process with (stochastic) thermal bath. To our knowledge, our approach yields the first such quantitative results for a combination of jump and diffusion processes.
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