Effect of Insulin Therapy on Metabolic Fate of Apolipoprotein B–Containing Lipoproteins in NIDDM

Abstract

Non-insulin-dependent diabetic (NIDDM) subjects exhibit abnormalities in their plasma lipid and lipoprotein profiles that increase the risk of ischemic heart disease. This study was designed to examine the metabolic behavior of very-low-density (VLDL), intermediate-density (IDL), and low-density (LDL) lipoproteins in NIDDM patients before treatment and after 4 wk of insulin therapy. Basal turnover studies of 131I-labeled VLDL1 (svedberg units [Sf] 60-400) and 131I-labeled VLDL2 (Sf 20-60) apolipoprotein B (apoB) were conducted in a group of seven NIDDM patients who had been off oral therapy for 1 wk. The subjects exhibited higher than normal transport rates for VLDL1 and a diminished input of apoB into the VLDL2 density range. These observations are concordant with the hypothesis that NIDDM patients overproduce VLDL triglyceride but not apoB. VLDL1 and VLDL2 were converted to IDL and ultimately to LDL at approximately normal rates, although the delipidation pathway by which apoB-containing particles were processed exhibited different properties from that seen in control subjects. Insulin therapy reduced plasma triglyceride by 38%, and this was associated with a 41% fall in VLDL1 mass (P less than 0.01). VLDL2 was less affected (19% reduction, P less than 0.05), IDL was unchanged, and LDL fell 17% (P less than 0.05). Repeat metabolic studies revealed that the major effects of insulin were to reduce VLDL1-apoB transport (from 811 to 488 mg/day) and increase the direct input of VLDL2 into the plasma (from 182 to 533 mg/day, P less than 0.05). These alterations in VLDL production led to normalization of apoB kinetics in IDL and LDL. The fractional catabolic rate of LDL increased 19% (P less than 0.05), whereas direct input into this fraction, which had been high before treatment, was reduced. Postheparin plasma lipoprotein lipase (LPL) and hepatic lipase levels were unaffected by insulin, although the hormone did increase LPL in adipose tissue. This lack of effect on lipase activities correlated well with the observation that the rates of catabolism of apoB in VLDL1, VLDL2, and IDL were not significantly affected by insulin therapy.

Defective regulation of triglyceride metabolism by insulin in the liver in NIDDM

“…This finding confirms a similar observation made in earlier study using radioiodinated tracers in which the VLDL1 and VLDL2 apo B production rates were 811 ± 233 and 182 ± 253 mg/day respectively [12]. We observed a small decrease in VLDL2 apo B production during the hyperglycaemic clamp.…”

“…Isolation of lipoproteins. VLDL1 and VLDL2 were isolated from plasma by cumulative flotation gradient ultracentrifugation using a six-step discontinuous salt gradient as previously described [12,13,14]. Pool sizes for apo B were calculated from the product of plasma volume (assumed to be 4.5 % of body weight) times the plasma concentration of apo B in VLDL1 and VLDL2.…”

Diabetic dyslipidaemia: from basic research to clinical practice*

“…The determination of apo B 100 and apo B 48 allows separation of particles from endogenous and exogeneous origins. Reproduced from reference [8] tionally higher increase of VLDL 1 particles compared with VLDL 2 particles in a small group of Type 2 diabetic patients [17]. Likewise another study [18] reported a relatively higher increase of VLDL 1 than that of VLDL 2 particles in a small cohort of Type 2 diabetic subjects.…”

High-density lipoprotein apolipoprotein A-I kinetics in obese insulin resistant patients. An in vivo stable isotope study

“…25 The daily food intake was divided into small equal portions taken by the subjects every 2 h, as previously performed by several groups. 7,8 With this protocol plasma lipid and apolipoprotein values remained constant throughout the kinetic study.…”

“…Food intake, with a leucine-poor diet (1700 kcal=day, 55% carbohydrates, 39% fats and 7% proteins), was fractionated in to small equal portions which were provided every 2 h, starting 6 h prior to the tracer infusion up to the end of the study, in order to avoid important variations in apolipoprotein plasma concentration, as previously performed by other groups. 7,8 To determine the kinetics of apolipoprotein A-I, the subjects received an intravenous injection of a 0.7 mg=kg bolus of L-[1-13 C]leucine (99% 13 C, Eurisotop, Saint Aubin, France), immediately followed by a 16 h constant infusion at 0.7 mg=kg=h. Blood samples (16 ml) were collected at hours 0, 0.25, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 15 and 16.…”