Overproduction of VLDL1 driven by hyperglycemia is a dominant feature of diabetic dyslipidemia.

OBJECTIVE: We sought to compare the synthesis and metabolism of VLDL1 and VLDL2 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 VLDL1 and VLDL2 after a bolus injection of [2H3]leucine and [2H5]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 VLDL1 apoB and TG. Direct production of VLDL2 apoB and TG was not influenced by diabetes per se. The production rates of VLDL1 apoB and TG were closely related, as were the corresponding pool sizes. VLDL1 and VLDL2 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 VLDL1 TG production rate. CONCLUSIONS: Insulin resistance and DM2 are associated with excess hepatic production of VLDL1 particles similar in size and composition to those in nondiabetic subjects. We propose that hyperglycemia is the driving force that aggravates overproduction of VLDL1 in DM2.

Improved Estimation of Human Lipoprotein Kinetics with Mixed Effects Models.

CONTEXT: Mathematical models may help the analysis of biological systems by providing estimates of otherwise un-measurable quantities such as concentrations and fluxes. The variability in such systems makes it difficult to translate individual characteristics to group behavior. Mixed effects models offer a tool to simultaneously assess individual and population behavior from experimental data. Lipoproteins and plasma lipids are key mediators for cardiovascular disease in metabolic disorders such as diabetes mellitus type 2. By the use of mathematical models and tracer experiments fluxes and production rates of lipoproteins may be estimated. RESULTS: We developed a mixed effects model to study lipoprotein kinetics in a data set of 15 healthy individuals and 15 patients with type 2 diabetes. We compare the traditional and the mixed effects approach in terms of group estimates at various sample and data set sizes. CONCLUSION: We conclude that the mixed effects approach provided better estimates using the full data set as well as with both sparse and truncated data sets. Sample size estimates showed that to compare lipoprotein secretion the mixed effects approach needed almost half the sample size as the traditional method.

Investigations of a compartmental model for leucine kinetics using non-linear mixed effects models with ordinary and stochastic differential equations.

Non-linear mixed effects (NLME) models represent a powerful tool to simultaneously analyse data from several individuals. In this study, a compartmental model of leucine kinetics is examined and extended with a stochastic differential equation to model non-steady-state concentrations of free leucine in the plasma. Data obtained from tracer/tracee experiments for a group of healthy control individuals and a group of individuals suffering from diabetes mellitus type 2 are analysed. We find that the interindividual variation of the model parameters is much smaller for the NLME models, compared to traditional estimates obtained from each individual separately. Using the mixed effects approach, the population parameters are estimated well also when only half of the data are used for each individual. For a typical individual, the amount of free leucine is predicted to vary with a standard deviation of 8.9% around a mean value during the experiment. Moreover, leucine degradation and protein uptake of leucine is smaller, proteolysis larger and the amount of free leucine in the body is much larger for the diabetic individuals than the control individuals. In conclusion, NLME models offers improved estimates for model parameters in complex models based on tracer/tracee data and may be a suitable tool to reduce data sampling in clinical studies.

Modelling of peripheral fluid accumulation after a crystalloid bolus in female volunteers - a mathematical study.

OBJECTIVE: To simultaneously model plasma dilution and urinary output in female volunteers. METHODS: Ten healthy female non-pregnant volunteers, aged 21-39 years (mean 29), with a bodyweight of 58-67 kg (mean 62.5 kg) participated. No oral fluid or food was allowed between midnight and completion of the experiment. The protocol included an infusion of acetated Ringer's solution, 25 ml/kg over 30 min. Blood samples (4 ml) were taken every 5 min during the first 120 min, and thereafter the sampling rate was every 10 min until the end of the experiment at 240 min. A standard bladder catheter connected to a drip counter to monitor urine excretion continuously was used. The data were analysed by empirical calculations as well as by a mathematical model. RESULTS: Maximum urinary output rate was found to be 19 (13-31) ml/min. The subjects were likely to accumulate three times as much of the infused fluid peripherally as centrally; 1/µ = 2.7 (2.0-5.7). Elimination efficacy, E(eff), was 24 (5-35), and the basal elimination k(b) was 1.11 (0.28-2.90). The total time delay T(tot) of urinary output was estimated as 17 (11-31) min. CONCLUSION: The experimental results showed a large variability in spite of a homogenous volunteer group. It was possible to compute the infusion amount, plasma dilution and simultaneous urinary output for each consecutive time point and thereby the empirical peripheral fluid accumulation. The variability between individuals may be explained by differences in tissue and hormonal responses to fluid boluses, which needs to be further explored.

A new combined multicompartmental model for apolipoprotein B-100 and triglyceride metabolism in VLDL subfractions.

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 steady-state 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.