Evidence of increased secretion of apolipoprotein B-48-containing lipoproteins in subjects with type 2 diabetes

Patients with type 2 diabetes have high levels of triglyceride-rich lipoproteins (TRLs), including apolipoprotein B-48 (apoB-48)-containing TRLs of intestinal origin, but the mechanism leading to overaccumulation of these lipoproteins remains to be fully elucidated. Therefore, the objective of this study was to examine the in vivo kinetics of TRL apoB-48 and VLDL, intermediate density lipoprotein (IDL), and LDL apoB-100 in type 2 diabetic subjects (n = 11) and nondiabetic controls (n = 13) using a primed-constant infusion of l-[5,5,5-D3]leucine for 12 h in the fed state. Diabetic subjects had significantly higher fasting glycemia, higher fasting insulinemia, higher plasma triglyceride, and lower HDL-cholesterol levels than controls. Compared with controls, diabetic subjects had increased TRL apoB-48, VLDL apoB-100, and IDL apoB-100 pool sizes as a result of increased production rates (PRs) and reduced fractional catabolic rates of these lipoprotein subfractions. Furthermore, multiple linear regression analyses revealed that the diabetic/control status was an independent predictor of TRL apoB-48 PR and represented nearly 35% of its variance. These results suggest that the overaccumulation of TRLs seen in patients with type 2 diabetes is attributable to increased PRs of both intestinally derived apoB-48-containing lipoproteins and TRL apoB-100 of hepatic origin and to decreased catabolism of these subfractions. Patients with type 2 diabetes have high levels of triglyceride-rich lipoproteins (TRLs), including apolipoprotein B-48 (apoB-48)-containing TRLs of intestinal origin, but the mechanism leading to overaccumulation of these lipoproteins remains to be fully elucidated. Therefore, the objective of this study was to examine the in vivo kinetics of TRL apoB-48 and VLDL, intermediate density lipoprotein (IDL), and LDL apoB-100 in type 2 diabetic subjects (n = 11) and nondiabetic controls (n = 13) using a primed-constant infusion of l-[5,5,5-D3]leucine for 12 h in the fed state. Diabetic subjects had significantly higher fasting glycemia, higher fasting insulinemia, higher plasma triglyceride, and lower HDL-cholesterol levels than controls. Compared with controls, diabetic subjects had increased TRL apoB-48, VLDL apoB-100, and IDL apoB-100 pool sizes as a result of increased production rates (PRs) and reduced fractional catabolic rates of these lipoprotein subfractions. Furthermore, multiple linear regression analyses revealed that the diabetic/control status was an independent predictor of TRL apoB-48 PR and represented nearly 35% of its variance. These results suggest that the overaccumulation of TRLs seen in patients with type 2 diabetes is attributable to increased PRs of both intestinally derived apoB-48-containing lipoproteins and TRL apoB-100 of hepatic origin and to decreased catabolism of these subfractions. Type 2 diabetes is a complex disease known to increase triglyceride (TG) levels, decrease HDL-cholesterol levels, and promote the formation of small, dense LDL particles. Recent studies indicate that type 2 diabetes is associated with increased levels of triglyceride-rich lipoproteins (TRLs), including apolipoprotein B-48 (apoB-48)-containing TRLs of intestinal origin, in both the fasted and postprandial states (1.Schaefer E.J. McNamara J.R. Shah P.K. Nakajima K. Cupples L.A. Ordovas J.M. Wilson P.W. Elevated remnant-like particle cholesterol and triglyceride levels in diabetic men and women in the Framingham Offspring Study.Diabetes Care. 2002; 25: 989-994Crossref PubMed Scopus (106) Google Scholar, 2.Curtin A. Deegan P. Owens D. Collins P. Johnson A. Tomkin G.H. Elevated triglyceride-rich lipoproteins in diabetes. A study of apolipoprotein B-48.Acta Diabetol. 1996; 33: 205-210Crossref PubMed Scopus (83) Google Scholar). This is of interest because substantial evidence exists indicating that high levels of intestine-derived lipoproteins are associated with increased cardiovascular disease risk (3.Kolovou G.D. Anagnostopoulou K.K. Daskalopoulou S.S. Mikhailidis D.P. Cokkinos D.V. Clinical relevance of postprandial lipaemia.Curr. Med. Chem. 2005; 12: 1931-1945Crossref PubMed Scopus (116) Google Scholar). Chylomicrons are too large to be able to enter the subendothelial space, but once hydrolyzed by the lipoprotein lipase, chylomicron remnants of <700 Å are small enough to enter into the intima and to participate in atherosclerotic lesion development (4.Nordestgaard B.G. Tybjaerg-Hansen A. IDL, VLDL, chylomicrons and atherosclerosis.Eur. J. Epidemiol. 1992; 8: 92-98Crossref PubMed Scopus (66) Google Scholar). Chylomicron remnants have been shown to impair normal endothelial function (5.Doi H. Kugiyama K. Ohgushi M. Sugiyama S. Matsumura T. Ohta Y. Nakano T. Nakajima K. Yasue H. Remnants of chylomicron and very low density lipoprotein impair endothelium-dependent vasorelaxation.Atherosclerosis. 1998; 137: 341-349Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar), to be chemically modified, and to accumulate in the subendothelial space in the same way as apoB-100-containing lipoproteins do (6.Twickler T.B. Dallinga-Thie G.M. Cohn J.S. Chapman M.J. Elevated remnant-like particle cholesterol concentration: a characteristic feature of the atherogenic lipoprotein phenotype.Circulation. 2004; 109: 1918-1925Crossref PubMed Scopus (144) Google Scholar, 7.Proctor S.D. Mamo J.C. Intimal retention of cholesterol derived from apolipoprotein B100- and apolipoprotein B48-containing lipoproteins in carotid arteries of Watanabe heritable hyperlipidemic rabbits.Arterioscler. Thromb. Vasc. Biol. 2003; 23: 1595-1600Crossref PubMed Scopus (98) Google Scholar). However, the mechanisms underlying the overaccumulation of apoB-48-containing TRLs in type 2 diabetes have not been fully characterized. Studies have suggested a mixed contribution of VLDL overproduction leading to competition for the removal of apoB-48-containing TRLs, impaired lipoprotein lipase activity, modified composition of TRLs, and reduced recognition by hepatic receptors (8.Haffner S.M. Foster D.M. Kushwaha R.S. Hazzard W.R. Retarded chylomicron apolipoprotein-B catabolism in type 2 (non-insulin-dependent) diabetic subjects with lipaemia.Diabetologia. 1984; 26: 349-354Crossref PubMed Scopus (26) Google Scholar, 9.Mamo J.C. Hirano T. Sainsbury A. Fitzgerald A.K. Redgrave T.G. Hypertriglyceridemia is exacerbated by slow lipolysis of triacylglycerol-rich lipoproteins in fed but not fasted streptozotocin diabetic rats.Biochim. Biophys. Acta. 1992; 1128: 132-138Crossref PubMed Scopus (33) Google Scholar, 10.Brunzell J.D. Hazzard W.R. Porte Jr., D. Bierman E.L. Evidence for a common, saturable, triglyceride removal mechanism for chylomicrons and very low density lipoproteins in man.J. Clin. Invest. 1973; 52: 1578-1585Crossref PubMed Scopus (365) Google Scholar). Furthermore, a recent study (11.Duez H. Lamarche B. Uffelman K.D. Valero R. Cohn J.S. Lewis G.F. Hyperinsulinemia is associated with increased production rate of intestinal apolipoprotein B-48-containing lipoproteins in humans.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 1357-1363Crossref PubMed Scopus (146) Google Scholar) suggested that hyperinsulinemia was associated with an increased production rate (PR) of apoB-48-containing lipoproteins of intestinal origin in insulin-resistant humans. That study, however, did not specifically examine the impact of insulin resistance on TRL apoB-48 metabolism in subjects with type 2 diabetes. Therefore, the objectives of this study were to determine whether intestinal apoB-48-containing lipoprotein secretion and catabolism are impaired in patients with type 2 diabetes and severe hypertriglyceridemia and to examine correlations between apoB-48 and apoB-100 kinetics. Eleven men with type 2 diabetes and severe hypertriglyceridemia and 13 normolipidemic nondiabetic controls were included in this study. Diabetic subjects had to suffer from type 2 diabetes as defined by the American Diabetes Association (12.The Expert Committee on the Diagnosis and Classification of Diabetes MellitusReport of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.Diabetes Care. 2004; 27: 5-10Google Scholar) and to have a clinical requirement for an oral hypoglycemic agent. All diabetic patients were treated with either metformin or a combination of metformin and a sulfonylurea. Three subjects received a thiazolidinedione. For all subjects, exclusion criteria were as follows: history of cardiovascular disease; microalbuminuria; a genetic condition affecting lipid metabolism (e.g., familial hypercholesterolemia, type III hyperlipidemia, LPL deficiency, etc.); body mass index (BMI) of <18.0 or >35.0 kg/m2; uncontrolled hypothyroidism; nephrotic syndrome; anorexia nervosa; history of alcohol or drugs abuse; persistent increased alanine aminotransferase, aspartate aminotransferase, or creatine phosphokinase; uncontrolled endocrine or metabolic disease; poor mental condition; or a positive test for human immunodeficiency virus. All diabetic subjects had to receive stable doses of oral hypoglycemic agents for at least 3 months before the study to achieve glycosylated hemoglobin (HbA1C) values of <9%. Lipid-lowering medications were withdrawn for at least 6 weeks before the kinetic study. Upon their entry into the study, subjects met with a dietician and were instructed to maintain their usual nutritional habits throughout the entire intervention. A standardized food frequency questionnaire was also administered to participants to estimate their diet composition, and no significant difference was observed between the two groups. Fasting plasma insulin and glucose levels were measured to compute the insulin resistance index based on the homeostasis model assessment model (13.Wallace T.M. Matthews D.R. The assessment of insulin resistance in man.Diabet. Med. 2002; 19: 527-534Crossref PubMed Scopus (526) Google Scholar). The research protocol was approved by the Laval University Medical Center review committee, and written informed consent was obtained from each subject. To determine the kinetics of TRL apoB-48 and VLDL, intermediate density lipoprotein (IDL), and LDL apoB-100, participants underwent a primed-constant infusion of l-[5,5,5-D3]leucine while they were in a constantly fed state. Starting at 7 AM, the subjects received 30 identical small cookies every half-hour for 15 h, each equivalent to 1/30th of their estimated daily food intake based on the Harris-Benedict equation (14.Harris, J., and F. Benedict. 1919. A Biometric Study of Basal Metabolism in Man. Carnegie Institution, Washington, DC.Google Scholar), with 15% of calories as protein, 45% as carbohydrate, and 40% as fat (7% saturated, 26% monounsaturated, and 7% polyunsaturated) and 85 mg of cholesterol/1,000 kcal. At 10 AM, with two intravenous lines in place, one for the infusate and one for blood sampling, l-[5,5,5-D3]leucine (10 μmol/kg body weight) was injected as a bolus and then by continuous infusion (10 μmol/kg body weight/h) over a 12 h period. Blood samples (20 ml) were collected at 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, and 12 h. Before the kinetic studies, 12 h fasting venous blood samples were obtained from an antecubital vein into Vacutainer tubes containing EDTA (0.1% final concentration). Samples were then immediately centrifuged at 4°C for 10 min at 3,000 rpm to obtain plasma and were stored at 4°C until processed. Plasma VLDL (d < 1.006 g/ml) were isolated by preparative ultracentrifugation, and the HDL fraction was obtained after precipitation of LDL in the infranatant (d > 1.006 g/ml) with heparin and MnCl2. The cholesterol and TG contents of the infranatant fraction were measured before and after the precipitation step. Cholesterol and TG levels were determined using an Olympus AU400e analyzer (Melville, NY) using reagents and calibrators provided by the manufacturer. ApoB concentrations were measured by nephelometry (Dade Behring, Mississauga, Ontario, Canada) in plasma and in TRL and LDL fractions using reagents and calibrators provided by the manufacturer. Venous blood samples were obtained from an antecubital vein into Vacutainer tubes containing EDTA (0.1% final concentration) at various time intervals during the kinetic study. ApoB concentrations were determined in the TRL fraction by noncompetitive ELISA using immunopurified polyclocal antibodies (Alerchek, Inc., Portland, ME) to calculate the pool size (PS). The coefficient of variation for this apoB assay was between 6% and 10%, depending on the region of the standard curve. ApoB-100 and apoB-48 were separated by SDS 3–10% one-dimensional polyacrylamide gradient gel electrophoresis to standardized of and in human triglyceride-rich Full Text PDF PubMed Google Scholar), using of each was in the TRL fraction on the that apoB-48 and apoB-100 both have the same the of each apolipoprotein was by a of the the TRL from time to calculate the and to estimate the concentrations of apoB-100 and apoB-48 in the TRL fraction using the TRL apoB and apoB-100 were from the and hydrolyzed in at for h E.J. apolipoprotein B-48 and apoB-100 kinetics with stable Thromb. Vasc. Biol. 19: PubMed Scopus Google Scholar). the tubes were centrifuged and to of the The were then into using the by D. G.F. K.D. of for a and for stable kinetic studies of 2002; Full Text Full Text PDF PubMed Google Scholar). The were on a and were from the observed The of in the apolipoprotein was as using standardized D.M. R. to kinetic in stable J. PubMed Google Scholar). of apoB-48 and apoB-100 were derived by a model as Lamarche B. Cohn J.S. J.C. P. of on the in vivo kinetics of apoB-48 and apoB-100 in men with Thromb. Vasc. Biol. 2006; 26: PubMed Scopus Google Scholar). a of the pool and either the TRL apoB-48 or the VLDL apoB-100 as the function to the of into apoB-48 and apoB-100, E.J. apolipoprotein B-48 and apoB-100 kinetics with stable Thromb. Vasc. Biol. 19: PubMed Scopus Google Scholar). the fractional catabolic rate is equivalent to the fractional ApoB PRs were determined by the PR = apoB plasma J. D. Cohn S. J. of very low density and low density lipoprotein apolipoprotein and high density lipoprotein production in human subjects using of fasting and Clin. Invest. PubMed Scopus Google Scholar). Plasma was estimated as of body The was to the model to the observed from the two were using for and for continuous Plasma TG levels were to their were determined to the of between multiple linear regression was to the of these All analyses were using the and of subjects to their diabetic/control Diabetic subjects were significantly than controls = was no significant difference in between the two groups. Diabetic subjects had higher fasting glucose levels < higher fasting insulin levels = and higher homeostasis model = The in was and of subjects to model hemoglobin body mass insulin All subjects were in a body mass insulin All subjects were 2 the fasting of subjects to their Diabetic subjects had significantly higher plasma TG < higher TRL cholesterol < higher TRL TG < higher TRL apoB = and lower HDL-cholesterol = of subjects to apolipoprotein triglyceride-rich in a apolipoprotein triglyceride-rich 3 the kinetics of TRL apoB-48 to Diabetic subjects had higher plasma apoB-48 concentrations than controls < Compared with controls, TRL apoB-48 was also increased in diabetic subjects < as a result of an increase in TRL apoB-48 PR < and a decrease in TRL apoB-48 = in these linear regression was to the independent contribution of metabolic and to the of TRL apoB-48 and diabetic/control status were included in the shown in 4, the diabetic/control status represented nearly 35% of the in TRL apoB-48 to the of TRL apoB-48 for and diabetic/control was not to significantly TRL apoB-48 of TRL apoB-48 in controls and type 2 diabetic (n = (n = fractional catabolic production pool in a linear regression independent of and diabetic/control status to the of TRL apoB-48 in a fractional catabolic production pool the kinetics of apoB-100 to had higher VLDL apoB-100 < as a result of a decreased VLDL apoB-100 = and a an increased VLDL apoB-100 PR = IDL apoB-100 was increased in diabetic subjects < as a result of a decreased IDL apoB-100 = and an increased IDL apoB-100 PR = significant difference in LDL apoB-100 was seen between the two attributable to the increase in both LDL apoB-100 and PR in increased LDL apoB-100 however, significant after for and TRL apoB-48 was with apoB-48 PR in controls = = and in = = significant was between TRL apoB-48 and both VLDL apoB-100 was with = = = = but not with PR = = = = TRL apoB-48 and PR were with VLDL apoB-100 = < = = in controls but not in = = = = the between plasma TG levels and TRL apoB-48 PR and VLDL apoB-100 in diabetic significant was between TRL apoB-48 and catabolism of IDL apoB-100 in both groups. was no significant difference between controls and in either = or = of IDL, and LDL apoB-100 in controls and type 2 diabetic (n = (n = intermediate density in a IDL, intermediate density This study on the between TRL apoB-48 and VLDL, IDL, and LDL apoB-100 kinetics in type 2 diabetic with in plasma TG levels and 13 nondiabetic controls. have that these diabetic men had higher plasma concentrations and PR as as lower of intestinally derived apoB-48-containing lipoproteins than with lower insulin levels and insulin multiple linear regression analyses revealed that the of diabetes on TRL apoB-48 PR and independent of and results indicate that the higher in the diabetic did not significantly to the observed in TRL apoB-48 PR and and the results of a recent study by (11.Duez H. Lamarche B. Uffelman K.D. Valero R. Cohn J.S. Lewis G.F. Hyperinsulinemia is associated with increased production rate of intestinal apolipoprotein B-48-containing lipoproteins in humans.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 1357-1363Crossref PubMed Scopus (146) Google Scholar) a positive between TRL apoB-48 PR and fasting insulin concentrations in nondiabetic insulin-resistant Therefore, these results evidence that diabetic be associated with overproduction and reduced of both intestinally derived and TRL apoB-100-containing studies have shown that both chylomicrons and VLDL increase after the of a J. D. Cohn S. J. of very low density and low density lipoprotein apolipoprotein and high density lipoprotein production in human subjects using of fasting and Clin. Invest. PubMed Scopus Google Scholar, J. Johnson J. Cohn S. R. Y. R. of apoB-48 and apoB-100 triglyceride-rich lipoproteins to postprandial in the plasma of TRL and Full Text PDF PubMed Google Scholar). is also that diabetic have high levels of TRLs, including apoB-48-containing TRLs, in both the fasted and postprandial states (1.Schaefer E.J. McNamara J.R. Shah P.K. Nakajima K. Cupples L.A. Ordovas J.M. Wilson P.W. Elevated remnant-like particle cholesterol and triglyceride levels in diabetic men and women in the Framingham Offspring Study.Diabetes Care. 2002; 25: 989-994Crossref PubMed Scopus (106) Google Scholar, in nondiabetic and diabetic to Care. PubMed Scopus Google Scholar). The that TRL apoB-48 is with TRL apoB-48 PR and not indicate that the increase in apoB-48-containing lipoproteins is attributable to increased These results are in with and by (11.Duez H. Lamarche B. Uffelman K.D. Valero R. Cohn J.S. Lewis G.F. Hyperinsulinemia is associated with increased production rate of intestinal apolipoprotein B-48-containing lipoproteins in humans.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 1357-1363Crossref PubMed Scopus (146) Google Scholar) that intestinal secretion of apoB-48-containing lipoproteins is increased in insulin-resistant with study was not to the mechanisms underlying the increased production of apoB-48-containing lipoproteins by the in with type 2 diabetes. However, recent studies using from insulin-resistant have an increased secretion of apoB-48-containing lipoproteins by increased apoB-48 lipid and higher of TG mass M. F. Uffelman K.D. R. Lewis G.F. K. Fasting and postprandial overproduction of intestinally derived lipoproteins in an model of insulin Evidence that in the is by intestinal and lipoprotein Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, G.F. Uffelman K. M. M. K. lipoprotein a of insulin is by the insulin studies in the 2005; PubMed Scopus Google Scholar). Therefore, is that intestinal an in the secretion of apoB-48-containing lipoproteins by the in subjects with type 2 diabetes. lines of evidence also indicate that increased from to the the hepatic and secretion of apoB-100-containing lipoproteins in insulin-resistant subjects G.F. A. K. A. fat and in the of insulin resistance and type 2 2002; 23: PubMed Scopus Google Scholar, G.F. Uffelman K.D. B. between and insulin in the of very low density lipoprotein production in Clin. Invest. PubMed Google Scholar). recent studies using in that the secretion of apoB-48-containing lipoproteins K. and secretion of apolipoprotein B48-containing lipoprotein in the fasting evidence for by insulin resistance and 2005; Full Text Full Text PDF PubMed Scopus Google Scholar) and that intestinal lipoprotein production was increased by an increase of plasma in G.F. M. Uffelman K. K. lipoprotein production is by an of plasma in the fasting studies in insulin-resistant and 2004; PubMed Scopus Google Scholar). studies are to the between increased from to the and the intestinal production of TRL apoB-48 in humans. E.J. apolipoprotein B-48 and apoB-100 kinetics with stable Thromb. Vasc. Biol. 19: PubMed Scopus Google Scholar), this study also that VLDL apoB-100 is with the catabolism of VLDL apoB-100 and not PR in both controls and the increase in VLDL apoB-100 after the of a is to decreased catabolism of VLDL in LPL have been in patients with type 2 diabetes in nondiabetic and diabetic to Care. PubMed Scopus Google Scholar), and this significantly to decreased TRL study an between TRL apoB-48 and PR and VLDL apoB-100 in controls with low TG levels, a by in E.J. apolipoprotein B-48 and apoB-100 kinetics with stable Thromb. Vasc. Biol. 19: PubMed Scopus Google Scholar, J. S. A. P. P. A. of apolipoprotein and VLDL remnants during postprandial in normolipidemic patients with PubMed Scopus Google Scholar). However, the of between TRL apoB-48 and PR and VLDL apoB-100 in with severe hypertriglyceridemia that the competition between TRL apoB-48 and VLDL apoB-100 for the same catabolic be on the of is that high plasma concentrations of TRLs the catabolic and the of apoB-48-containing lipoproteins to with TRL apoB-100 for Furthermore, because both IDL and chylomicron remnants are by the same catabolic one a between of TRL apoB-48 and IDL However, was no significant between TRL apoB-48 and catabolism of IDL apoB-100 in both groups. These results are in with of a study E.J. apolipoprotein B-48 and apoB-100 kinetics with stable Thromb. Vasc. Biol. 19: PubMed Scopus Google Scholar) correlations between apoB-48 and apoB-100 kinetics in subjects and suggest the of significant between IDL and chylomicron and human studies in the of IDL and chylomicron catabolism are to this this study, observed that LDL apoB-100 PR and were higher in subjects with type 2 diabetes than in controls. in LDL apoB-100 however, significant after for and This with results of studies with type 2 both a decrease in LDL catabolism to the of apoB-100 of lipoproteins to an to that seen in diabetes their 1984; 33: PubMed Scopus Google Scholar) and a in the of LDL D.P. A.K. of by insulin in human J. PubMed Scopus Google Scholar) as as a reduced LDL F. P. B. of apolipoprotein lipoproteins in a stable kinetic J. Clin. Invest. Google Scholar). this is that the increased LDL apoB-100 PR observed in diabetic was attributable to increased VLDL and IDL apoB-100 associated with normal and is that the difference in LDL apoB-100 PR between and controls is no significant after for VLDL apoB-100 or plasma TG Therefore, studies including and controls with plasma TG levels are to the of type 2 diabetes on LDL apoB-100 kinetics. this study, diabetic subjects were and had higher with controls, and the that these have to the observed increase in TRL apoB-48 PR or have for these two however, type 2 diabetes was to be associated with increased TRL apoB-48 Furthermore, is to that diabetic subjects included are on to an that is not of diabetic subjects, with hemoglobin of <9%. Therefore, the that as or plasma TG levels, is studies with diabetic patients TG levels are to examine the between plasma TG levels and TRL apoB-48 this study evidence that type 2 diabetes associated with severe hypertriglyceridemia is also associated with both increased production and decreased catabolism of intestinally derived apoB-48-containing studies are to the mechanisms for the increased TRL apoB-48 PR in this condition and to the contribution of these lipoproteins to the development of in these The are to the participants for their is the of a from the and of is the of a from the is in and from the

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