Features of diabetic dyslipidaemia in non-insulin-dependent diabetes mellitus (NIDDM), such as a low HDL cholesterol concentration, the preponderance of small dense LDL and postprandial fat intolerance are considered to be metabolic consequences of elevated plasma triglycerides [1]. The mechanism underlying hypertriglyceridaemia in NIDDM is still unclear. A majority of studies indicate that the elevation of plasma triglycerides in NIDDM result from an overproduction of VLDL triglyceride [2,3] and apo B [4,5] but it is unclear and a matter of controversy whether the increased production of VLDL particles is driven by a direct effect of hyperinsulinaemia or is a consequence of defective suppression of VLDL production by insulin [1]. In healthy subjects acute insulin administration suppresses VLDL apo B production [6][7][8]. Data on the suppression of VLDL production by insulin in insulin resistant states are controversial. Lewis et al. [6] showed an impaired suppression of VLDL apo B production in obese subjects while Cummings et al. [9] did not find any defect in the ability of insulin to suppress VLDL apo B production in patients with NIDDM.Two major subclasses of VLDL particles are recognised, large triglyceride-rich VLDL1 particles Diabetologia (1997) 40: 454-462 Defective regulation of triglyceride metabolism by insulin in the liver in NIDDM Summary Insulin administration to healthy subjects inhibits the production of very low density lipoprotein (VLDL)1 (Svedbergs flotation (Sf) rate 60-400) without affecting that of VLDL2 (Sf 20-60) subclass. This study was designed to test whether this hormonal action is impaired in non-insulin-dependent diabetes mellitus (NIDDM). We studied six men with NIDDM (age 53 ± 3 years, body mass index 27.0 ± 1.0 kg/m 2 , plasma triglycerides 1.89 ± 0.22 mmol/l) during an 8.5 h infusion of saline (control) and then in hyperinsulinaemic (serum insulin ∼ 540 pmol/l) conditions during 8.5 h infusions of glucose and insulin to give either hyper-and normoglycaemic conditions. [3-2 H]-leucine was used as tracer and kinetic constants derived using a non-steadystate multicompartmental model. Compared to the control study, patients with NIDDM reduced VLDL1 apo B production by only 3 ± 8 % after 8.5 h of hyperinsulinaemia (701 ± 102 vs 672 ± 94 mg/day respectively, NS) in hyperglycaemic conditions and by 9 ± 21 % under normoglycaemic conditions (603 ± 145 mg/day). In contrast, in normal subjects insulin induced a 50 ± 15 % decrement in VLDL1 apo B production (p < 0.05). Direct synthesis of VLDL2 apo B in patients with NIDDM was not markedly affected by insulin. We conclude that a contributory factor to hypertriglyceridaemia in NIDDM is the inability of insulin to inhibit acutely the release of VLDL1 from the liver, despite efficient suppression of serum nonesterfied fatty acids. [Diabetologia (1997) 40: 454-462]

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...

We consider laminar high-Reynolds-number flow through a long finite-length planar channel, where a segment of one wall is replaced by a massless membrane held under longitudinal tension. The flow is driven by a fixed pressure difference across the channel and is described using an integral form of the unsteady boundary-layer equations. The basic flow state, for which the channel has uniform width, exhibits static and oscillatory global instabilities, having distinct modal forms. In contrast, the corresponding local problem (neglecting boundary conditions associated with the rigid parts of the system) is found to be convectively, but not absolutely, unstable to small-amplitude disturbances in the absence of wall damping. We show how amplification of the primary global oscillatory instability can arise entirely from wave reflections with the rigid parts of the system, involving interacting travellingwave flutter and static-divergence modes that are convectively stable; alteration of the mean flow by oscillations makes the onset of this primary instability subcritical. We also show how distinct mechanisms of energy transfer differentiate the primary global mode from other modes of oscillatory instability.

The mechanism by which acute insulin administration alters VLDL apolipoprotein (apo) B subclass metabolism and thus plasma triglyceride concentration was evaluated in 7 normolipidemic healthy men on two occasions, during a saline infusion and during an 8.5-hour euglycemic hyperinsulinemic clamp (serum insulin, 490 +/- 30 pmol/L). During the insulin infusion, plasma triglycerides decreased by 22% (P < .05), and serum free fatty acid decreased by 85% (P < .05). The plasma concentration of VLDL1 apo B fell 32% during the insulin infusion, while that of VLDL2 apo B remained constant. A bolus injection of [3-(2)H]leucine was given on both occasions to trace apo B kinetics in the VLDL1 and VLDL2 subclasses (Svedberg flotation rate, 60-400 and 20-60, respectively), and the kinetic basis for the change in VLDL levels caused by insulin was examined using a non-steady-state multicompartmental model. The mean rate of VLDL1 apo B synthesis decreased significantly by 35% (P < .05) after 0.5 hour of the insulin infusion (523 +/- 87 mg/d) compared with the saline infusion (808 +/- 91 mg/d). This parameter was allowed to vary with time to explain the fall in VLDL1 concentration. After 8.5 hours of hyperinsulinemia, the rate of VLDL1 apo B synthesis was 51% lower (321 +/- 105 mg/d) than during the saline infusion (651 +/- 81 mg/d, P < .05). VLDL2 apo B production was similar during the saline (269 +/- 35 mg/d) and insulin (265 +/- 37 mg/d) infusions. No significant changes were observed in the fractional catabolic rates of either VLDL1 or VLDL2 apo B. We conclude that acute hyperinsulinemia lowers plasma triglyceride and VLDL levels principally by suppressing VLDL1 apo B production but has no effect on VLDL2 apo B production. These findings indicate that the rates of VLDL1 and VLDL2 apo B production in the liver are independently regulated.