Overproduction of VLDL ₁ Driven by Hyperglycemia Is a Dominant Feature of Diabetic Dyslipidemia

Abstract

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...

Overproduction of large VLDL particles is driven by increased liver fat content in man

“…There was a strong linear correlation between the ApoB and TG pools in all subjects (r=0.98, p<0.001). This finding is consistent with our earlier results [3] …”

“…Type 2 diabetic subjects produced significantly (p<0.01) more VLDL 1 TG and ApoB than non-diabetic subjects (Table 2), confirming our previous findings [3]. There was also a significant increase (p=0.04) in direct production of VLDL 2 , TG but no significant difference in direct production of VLDL 2 ApoB.…”

“…Previously, we reported that elevation of large VLDL particles is the major determinant of plasma TG levels in subjects with and without type 2 diabetes mellitus [2] and that the production rate of large VLDL 1 particles is increased in type 2 diabetic patients [3]. Thus, in diabetic dyslipidaemia, overproduction of large VLDL particles seems to initiate a sequence of lipoprotein changes that increase the risk of atherosclerosis, including an increase in smaller LDL and a decrease in HDL particles.…”

“…One subject did not have intra-abdominal or s.c. fat measured. Fifteen of the control subjects and six of the type 2 diabetic subjects were presented in a previous paper [3]. 2 , and the enrichment curves of leucine in plasma and leucine and glycerol in VLDL 1 and VLDL 2 were used as the data set for a multicompartment model that allowed simultaneous modelling of ApoB and TG kinetics as described [21].…”

Effect of pioglitazone on various parameters of insulin resistance including lipoprotein subclass according to particle size by a gel-permeation high-performance liquid chromatography in newly diagnosed patients with type 2 diabetes

“…The results of this study suggest that the hypoglycemic effect of pioglitazone is achieved mainly through improvement of hepatic insulin resistance, and that pioglitazone have an antiatherosclerotic effect by decreasing serum atherogenic modified-LDL and increasing adiponectin. [22][23][24]. Griffin and Packard [25,26] demonstrated that large VLDL1 is a precursor of small dense LDL, and that it is produced preferentially in the liver during development of insulin resistance.…”