Postprandial lipemia is a distinct feature of diabetic dyslipidemia and may partly explain the atherogeneity of the lipid profile in type 2 diabetes (1). Several genetic factors contribute to the elevation of triglyceride-rich lipoproteins (TRLs). The role of apolipoprotein (apo)C-III as a regulator of TRL metabolism is well documented (2). Recently, apoA-V has been identified as a novel regulator of triglyceride metabolism. When the human APOA5 gene was expressed in transgenic mice, plasma triglyceride concentration was decreased by 70%, whereas apoA5 gene knockout mice had fourfold elevation of plasma triglyceride levels (3). Inherited apoA-V deficiency results in severe hypertriglyceridemia in humans (4). A mutation in the APOA5 gene causes hypertriglyceridemia due to decreased lipoprotein lipase (LPL) mass and activity (5). Thus, previous studies have proposed that apoA-V decreases triglycerides by stimulating lipolysis.

The present study focused on the response of apoA-V and apoC-III during postprandial lipemia and the associations between apoA-V and apoC-III and postheparin plasma LPL and hepatic lipase activities in type 2 diabetes.

The present study cohort was comprised of 39 men and 8 women with type 2 diabetes who were enrolled in the previously published nateglinide study with the same inclusion and exclusion criteria (6). A total of 17 patients were treated with diet alone, 20 with sulfonylurea, and 11 with metformin. The study protocol was approved by the ethics committee of the Helsinki University Hospital, and all patients gave informed consent.

The test meal was served after an overnight 12-h fast, and it contained 63 g fat (polyunsaturated fat/saturated fat ratio 0.08), 490 mg cholesterol, 25 g carbohydrate, and 35 g protein as previously described (6). Blood samples were drawn from a catheter placed in an antecubital vein before the meal and at 3, 4, 6, and 8 h. Concentrations of cholesterol, triglycerides, and HDL cholesterol, as well as apoB-100 and apoB-48 concentrations in the plasma lipoprotein fractions isolated by density-gradient ultracentrifugation, were analyzed as previously described (7). Postheparin LPL and hepatic lipase were analyzed by an established method (8). ApoA-V was analyzed by enzyme-linked immunosorbent assay (9). ApoC-III was determined by using a commercially available kit (10).

Data were analyzed using SPSS software (version 13.0; SPSS, Chicago, IL). Postprandial responses over the 8-h period were calculated as incremental areas under the curve (IAUCs) as previously described (11). The significance of the postprandial response of different variables was calculated by using ANOVA of repeated measurements. Spearman rank correlations were calculated to study the associations between variables, and P value <0.05 (two tailed) was considered statistically significant.

The patients were middle-aged (62.8 ± 8.5 years [mean ± SD]), overweight (BMI 28.4 ± 3.4 kg/m2), and mildly dyslipidemic (total cholesterol 5.3 ± 0.7 mmol/l, triglyceride 1.8 ± 0.6 mmol/l, and HDL cholesterol 1.31 ± 0.28 mmol/l). The mean A1C level averaged 7.6 ± 1.0%, and the mean fasting glucose level averaged 10.1 ± 2.7 mmol/l. ApoA-V and apoAC-III concentrations averaged 268 ± 98 ng/ml (range 119–557) and 3.91 ± 1.8 mg/dl (1.0–9.7), respectively.

The responses of both apoA-V and apoC-III closely paralleled the postprandial triglyceride response, particularly in VLDL1 fraction (Figure). The IAUC of apoA-V during oral fat load was positively associated with IAUCs of serum triglyceride (r = 0.571, P > 0.001), chylomicron triglyceride (r = 0.520, P < 0.001), VLDL1-triglyceride (r = 0.691, P < 0.001), chylomicron apoB-48 (r = 0.525, P < 0.001), and VLDL1-apoB-100 (r = 0.558, P < 0.001). Similarly, the IAUC of apoC-III showed significantly positive correlations with these lipoprotein parameters (data not shown). Importantly, the IAUC of apoA-V correlated significantly with that of apoC-III (r = 0.562, P < 0.001). Postheparin plasma LPL activity negatively correlated with IAUCs of VLDL1 triglycerides, VLDL1-cholesterol, and VLDL1- apoB-100 (data not shown).

Fasting ApoA-V concentration did not correlate with postheparin plasma LPL or hepatic lipase activities. The concentration of apoC-III showed no relationship with LPL or hepatic lipase activities. The baseline concentration of apoC-III correlated significantly with triglyceride in fasting plasma (r = 0.866, P < 0.001), chylomicrons (r = 0.769, P < 0.001), VLDL1 (r = 0.888, P < 0.001), and VLDL2 (r = 0.741, P < 0.001). No relationship existed between IAUC of apoA-V and postheparin plasma LPL or hepatic lipase activity.

Despite the lack of correlation between the fasting apoA-V and lipid parameters, the postprandial increase of apoA-V paralleled those of plasma and VLDL1 triglyceride as well as apoC-III, reaching its maximum at 4 h after oral fat load. Since apoA-V is associated with VLDL and chylomicron particles (12), the increase of apoA-V may reflect the increase of VLDL particles during the postprandial phase in analogy with apoC-III overproduction (2). Another potential explanation is that apoA-V production in the liver is increased as a regulatory mechanism to cover the increased need of postprandial lipolysis. Both hypotheses are consistent with the two recent reports showing elevated apoA-V concentrations in patients with severe hypertriglyceridemia (1314).

Although apoA-V has been reported to play an important role in lipolysis (3,1516), we found no association between postprandial apoA-V values and LPL activity. This could be explained by the fact that ApoA-V is present in plasma at very low concentrations, far lower than other lipoprotein levels (14). In contrast, animal studies (3,13) have used transgenic models manifesting higher concentrations of apoA-V than seen physiologically in plasma. To summarize, apo A-V response to oral fat load closely parallels those of TRLs and apo CIII in individuals with type 2 diabetes.

Figure 1—

Postprandial response of VLDL1 triglycerides (A) VLDL1- apoB-100 (B), chylomicron triglycerides (Chylo-triglyceride) (C), chylomicron apo B-48 (Chylo-apoB-48) (D), apoA-V (E), and apoC-III (F). The postprandial responses were calculated and presented as IAUCs (means ± SD). The significance of the postprandial change in each variable was calculated by using ANOVA of repeated measurements.

Figure 1—

Postprandial response of VLDL1 triglycerides (A) VLDL1- apoB-100 (B), chylomicron triglycerides (Chylo-triglyceride) (C), chylomicron apo B-48 (Chylo-apoB-48) (D), apoA-V (E), and apoC-III (F). The postprandial responses were calculated and presented as IAUCs (means ± SD). The significance of the postprandial change in each variable was calculated by using ANOVA of repeated measurements.

Close modal

This study was supported by grants from the Finnish Cardiovascular Research Foundation, Special State Grants for health science research, The Biomedicum Helsinki Foundation, The Finnish Medical Society Duodecim, The Paulo Foundation, the Sigrid Juselius Foundation, and Aarne Koskelo Foundation.

We thank Helinä Perttunen-Nio, Hannele Hilden, and Virve Naatti for their excellent technical assistance.

Mero N, Malmström R, Steiner G, Taskinen MR, Syvänne M: Postprandial metabolism of apolipoprotein B-48- and B-100-containing particles in type 2 diabetes mellitus: relations to angiographically verified severity of coronary artery disease.
Chan DC, Watts GF, Nguyen MN, Barrett HR: Apolipoproteins C-III and A-V as predictors of very-low-density lipoprotein triglyceride and apolipoprotein B-100 kinetics.
Arterioscler Thromb Vasc Biol
Pennacchio LA, Olivier M, Hubacek Ja, Cohen JC, Cox DR, Fruchart J-C, Krauss RM, Rubin EM: An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.
Oliva CP, Pisciotta L, Volti GL, Sambataro MP, Cantafora A, Bellocchio A, Catapano A, Tarugi P, Bertolini S, Calandra S: Inherited apolipoprotein A-V deficiency in severe hypertriglyceridemia.
Arterioscler Thromb Vasc Biol
Marcais C, Verges B, Charrière S, Pruneta V, Merlin M, Billon S, Perrot L, Drai J, Sassolas A, Pennacchio LA, Fruchart-Najib J, Fruchart J-C, Durlach V, Moulin P: Apoa5 Q139X truncation predisposes to late-onset hyperchylomicronemia due to lipoprotein lipase impairment.
J Clin Invest
Vakkilainen J, Mero N, Schweizer A, Foley JE, Taskinen M-R. Effects of nateglinide and glibenclamide on postprandial lipid and glucose metabolism in type 2 diabetes.
Diabetes Metab Res Rev
Mero N, Syvänne M, Eliasson B, Smith U, Taskinen MR: Postprandial elevation of ApoB-48-containing triglyceride-rich particles and retinyl esters in normolipemic males who smoke.
Arterioscler Thromb Vasc Biol
Huttunen JK, Ehnholm C, Kinnunen PKJ, Nikkilä EA: An immunochemical method for the selective measurement of two triglyceride lipases in human postheparin plasma.
Clin Chim Acta
Fruchart-Najib J, Bauge E, Niculescu LS, Pham T, Thomas B, Romens C, Majd Z, Brewer B, Pennachio LA, Fruchart J-C. Mechanism of triglyceride lowering in mice expressing human apoliporotein AV.
Biochem Biophys Res Commun
Hiukka A, Fruchart-Najib J, Leinonen E, Hilden H, Fruchart J-C, Taskinen MR: Alterations of lipids and lipoprotein CIII in very low density subspecies in type 2 diabetes.
Matthews JNS, Altman DG, Campbell MJ, Royston P: Analysis of serial measurements in medical research.
O'Brien PJ, Alborn WE, Sloan JH, Ulmer M, Boodhoo A, Knierman MD, Schultze A, Konrad RJ: The novel apolipoprotein A5 is present in human serum, is associated with VLDL, HDL, and chylomicrons, and circulates at very low concentrations compared with other apolipoproteins.
Clin Chem
Henneman P, Schaap FG, Havekes LM, Rensen PCN, Frants RR, van Tol A, Hattori H, Smelt AHM, van Dijk KW: Plasma apoA-V levels are markedly elevated in severe hypertriglyceridemia and positively correlated with the apoA5S19W polymorphism.
Schaap FG, Nierman MC, Berbée JFP, Hattori H, Talmud PJ, Vaessen SFC, Rensen PCN, Chamuleau RAFM, Kuivenhoven JA, Groen AK: Evidence for a complex relationship between apoA-V and apoC-III in patients with severe hypertriglyceridemia.
J Lipid Res
Schaap FG, Rensen PCN, Voshol PJ, Vrins C, van der Vliet HN, Chamuleau RAFM, Havekes LM, Groen AK, van Dijk KW: ApoA-V reduces plasma triglycerides by inhibiting very-low density lipoprotein-triglyceride (VLDL-triglyceride) production and stimulating lipoprotein lipase-mediated VLDL-triglyceride hydrolysis.
J Biol Chem
Grosskopf I, Baroukh N, Lee S-J, Kamari Y, Harats D, Rubin EM, Pennacchio LA, Cooper AD: Apolipoprotein A-V deficiency results in marked hypertriglyceridemia attributable to decreased lipolysis of triglyceride-rich lipoproteins and removal of their remnants.
Arterioscler Thromb Vasc Biol

Published ahead of print at on 7 May 2007. DOI: 10.2337/dc07-0100.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C Section 1734 solely to indicate this fact.