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

Abstract

AIMS=HYPOTHESIS:Mechanisms responsible for the decreased high-density lipoprotein (HDL) cholesterol level associated with insulin resistance in obese patients are not clearly understood. To determine the influence of insulin resistance at an early stage on HDL metabolism, we performed a stable isotope kinetic study of apolipoprotein (apo) A-I, in five obese insulin resistant women with normal fasting triglycerides and without impaired glucose tolerance, and in five age-matched control women. METHODS: Each subject received a 16 h constant infusion of L-[1-13 C]leucine at 0.7 mg=kg=h following a primed bolus of 0.7 mg=kg. RESULTS: ApoA-I fractional catabolic rate (FCR) was significantly increased in insulin-resistant women compared to controls (0.316 AE 0.056 vs 0.210 AE 0.040 per day, P < 0.01), indicating a significant 50% increase of apoA-I catabolism, leading to an important reduction of plasma apoA-I residence time (3.25 AE 0.59 vs 4.92 AE 1.11, P < 0.01). ApoA-I production rate tended to be higher in insulin resistant women than in controls (364 AE 77 vs 258 AE 60 mg=l=day, P ¼ 0.13), but the difference was not statistically significant. ApoA-I FCR was correlated with triglycerides during the fed state (r ¼ 0.69; P ¼ 0.026) and HDL triglycerides -esterified cholesterol ratio (r ¼ 0.73; P ¼ 0.016), suggesting that alteration of apoA-I metabolism in insulin resistance may be partly related to HDL enrichment in triglycerides. CONCLUSIONS: Our kinetic study shows that patients, at an early stage of insulin resistance (without impaired glucose tolerance nor fasting hypertriglyceridaemia), already have a significant alteration of apoA-I metabolism (increased apoA-I catabolism), which is consistent with the increased risk of atherosclerosis in this population.

Biochemical and Molecular Studies on Subjects With Sedentary Lifestyle and Type 2 Diabetes.

“…Dyslipidemia has been reported as a risk factor for type 2 diabetes by several prospective studies High plasma triglycerides and low plasma HDL cholesterol levels are both seen in the insulin resistance syndrome, which is a prediabetic state suggesting that nonfasting triglycerides and HDL cholesterol levels reflect the degree of insulin resistance (Pont et al, 2002). Similarly the present study found that increased mean CBMN frequency (12.87) in subjects with H/o dyslipidemia.…”

Body Mass Index and High-Density Lipoproteins in Cherokee Indian Children and Adolescents

“…These findings can be explained by increased cholesterol uptake from HDL by SR-BI scavenger receptors, which is known to be selectively greater from LpA-I:A-II particles (34), making them susceptible to degradation. The fractional catabolic rate for apoA-I is increased in cases with insulin resistance (35) but not so for apoA-II (36). However, apoA-II production is considered to be a determinant of LpA-I:A-II (37) but is not different in the insulin-resistant state (36).…”

Thematic review series: Patient-Oriented Research. What have we learned about HDL metabolism from kinetics studies in humans?

“…A more controlled stable isotope kinetics study of apoA-I was performed in five obese, insulin-resistant women with normal fasting triglycerides without impaired glucose tolerance and in five age-matched control women in the postprandial state (46). In these obese individuals, apoA-I catabolism was increased markedly by 50% versus normal controls, resulting in a significant reduction in plasma apoA-I residence time.…”

“…Furthermore, plasma HDL-C levels were significantly correlated with the apoA-I FCR and not with the apoA-I production rate. Thus, the authors concluded that accelerated apoA-I catabolism, and not production, is the main factor responsible for the decrease in HDL-C levels observed in obese, insulin-resistant subjects (46).…”