1928 DIABETES, VOL. 47, DECEMBER 1998 In Vivo Evidence for Increased Apolipoprotein A-I Catabolism in Subjects With Impaired Glucose Toleran ce Jens Pietzsch, Ulrich Julius, Sigrid Nitzsche, and Markolf Hanefeld The in vivo kinetics of the HDL apolipoproteins ( apo) A-I and A-II were studied in six subjects with impaired glucose tolerance ( IGT) and six control subjects with normal glucose tolerance ( NGT) , using a stable isotope approach. During a 12-h primed constant infusion of L- [ring- 1 3 C 6 ]-phenylalanine, tracer enrichment was deter- mined in apoA-I and apoA-II from ultracentrifugally isolated HDL. The rates of HDL apoA-I and apoA-II production and catabolism were estimated using a one- compartment model-based analysis. Triglycerides were higher in IGT subjects (1.33 ± 0.21 vs. 0.84 ± 0.27 mmol/l, P < 0.05), but were within the normal range. HDL cholesterol and apoA-I levels were significantly lower in subjects with IGT (1.07 ± 0.15 vs. 1.36 ± 0.14 mmol/l, P < 0.05; 0.94 ± 0.10 vs. 1.34 ± 0.07 g/l, P < 0.01). In IGT subjects, HDL composition was signifi- cantly altered, characterized by an increase in HDL triglycerides (4.9 ± 1.9 vs. 3.2 ± 1.0% , P < 0.05) and HDL phospholipids (34.7 ± 2.6 vs. 27.5 ± 5.8%, P < 0.05) and a decrease in HDL cholesteryl esters (10.1 ± 2.0 vs. 12.7 ± 2.9%, P < 0.05) and HDL apoA-I (31.5 ± 4.4 vs. 43.2 ± 2.4%, P < 0.05) . The mean fractional catabolic rate (FCR) of HDL apoA-I was significantly higher in IGT subjects (0.34 ± 0.05 vs. 0.26 ± 0.03 day – 1 , P < 0.01), while the HDL apoA-I production rate (PR), as well as the PR and FCR of HDL apoA-II, showed no diff erences between the two groups. There were significant corre- lations between HDL apoA-I FCR and the following parameters: HDL apoA-I ( r = –0.902, P < 0.001), HDL cholesterol ( r = –0.797, P = 0.001) , plasma triglycerides ( r = 0.743, P < 0.01), HDL triglycerides ( r = 0.696, P < 0.01) , and cholesterol ester transfer protein activity ( r = 0.646, P < 0.01). We observed a strong positive asso- ciation between increased apoA-I catabolism and insulin ( r = 0.765, P < 0.01) and proinsulin ( r = 0.797, P < 0.01) concentrations. These data support the hypothesis that the decrease in HDL cholesterol and apoA-I levels in IGT is principally the result of an enhanced apoA-I catabolism. The latter seems to be an early metabolic finding in IGT even when other lipid parameters, espe- cially plasma triglycerides, still appear to be not or only weakly affected. Diabetes 47:1928–1934, 1998 L ow concentrations of HDL cholesterol appear to be an outstanding lipoprotein predictor of cardio- vascular diseases. A number of epidemiologic studies in nondiabetic people have demonstrated that HDL cholesterol and HDL apolipoprotein (apo) A-I con- centrations inversely correlate with the incidence of coronary artery disease (CAD) (1–4). Furthermore, in both patients with NIDDM and those with impaired glucose tolerance (IGT), reduced HDL levels (HDL cholesterol levels are typ- ically ~15–30% lower in these patients than in nondiabetic subjects) also have been found to be directly correlated with an increased risk of CAD (5–9). The true nature of the relationship between diabetic conditions and increased CAD still remains unclear, and the role of HDL has not been adequately proven. IGT, characterized by insulin resistance and hyperinsulinemia, has been suggested to be the transi- tional state between normal glucose tolerance (NGT) and NIDDM (10–12). In NIDDM, the altered insulin action influ- ences hormone-sensitive enzymes that are directly involved in HDL metabolism, e.g., lipoprotein lipase (LPL), hepatic triglyceride lipase (HTGL), and cholesterol ester transfer protein (CETP) (13–15), and should have early conse- quences on the turnover of HDL particles, and conclusively, on the metabolism of HDL apoA-I and apoA-II. Recently, Frenais et al. (16) reported an increased catabolism of HDL apoA-I to be completely responsible for the lower HDL con- centrations in NIDDM with a pronounced diabetic dyslipi- demia (hypertriglyceridemia and low HDL cholesterol) and poor metabolic control when compared with nondiabetic subjects. However, only a few data are available on the ear- lier stages of the metabolic decompensation, particularly changes in lipoprotein metabolism, in IGT. To explore whether subjects with IGT but without a distinct hyper- triglyceridemia already show alterations in their HDL metab- olism, we assessed the in vivo kinetics of HDL apoA-I and apo A-II in IGT using endo geno us labeling with L-[ring- 13 C 6 ]- phenylalanine. The kinetic parameters for apoA-I and apoA- II were subsequently estimated by one-compartment model- based analysis, using the SAAM II program. To gain further insight into the metabolic etiology of low HDL in IGT, we looked for relationships between kinetic parameters of apoA-I and apoA-II metabolism and specific markers of an insulin resistant and/or hyperinsulinemic situation. From the Institute and Policlinic of Clinical Metabolic Research, Medical Faculty ‘Carl Gustav Carus’, Technical University, Dresden, Germany. Address correspondence and reprint requests to Dr. Jens Pietzsch, Insti- tute and Policlinic of Clinical Metabolic Research, Medical Faculty ‘Carl Gustav Carus’, Technical University, Fetscherstrasse 74, D-01307 Dresden, Ge rm any. E-mail: julius@rcs.urz.tu-dresden.de. Received for publication 2 March 1998 and accepted in revised form 24 August 1998. apo, apolipoprotein; CAD, coronary artery disease; CETP, cholesterol ester transfer protein; FCR, fractional catabolic rate; FFA, free fatty acids; FSD, fractional standard deviation; FSR, fractional synthetic rate; HTGL, hepatic triglyceride lipase; IGT, impaired glucose tolerance; LpA-I, sub- class of HDL particles that contains only apoA-I; LpA-I:A-II, subclass of HDL particles that contains both apoA-I and apo A-II; LPL, lipoprotein lipase; NGT, normal glucose tolerance; OGTT, oral glucose tolerance test; PR, production rate; TPLA, total postheparin lipase activity; WHO, Wo rld Health Organization.