Atherosclerosis 197 (2008) 154–158
Remarkable increase of apolipoprotein B48 level in diabetic patients with end-stage renal disease Toshiyuki Hayashi a , Tsutomu Hirano a,∗ , Takayasu Taira b , Anna Tokuno a , Yusaku Mori a , Shinji Koba c , Mitsuru Adachi a a
First Department of Internal Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan b Department of Nephrology, Yokohama Daiichi Hospital, Yokohama, Japan c Third Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan Received 17 August 2006; received in revised form 28 February 2007; accepted 6 March 2007 Available online 25 April 2007
Abstract Apolipoprotein (apo) B48 is a structural protein of chylomicrons. Fasting serum levels of apoB48 suggest the presence of small number of remnant chylomicron particles which are thought to be an atherogenic lipoprotein. In view of the high incidence of coronary heart disease (CHD) in patients with diabetic nephropathy, we decided to measure the plasma apoB48 level in type 2 diabetics with diabetic nephropathy at various stages to ascertain how apoB48 relates to the progression of diabetic nephropathy. Patients with type 2 diabetes (n = 105) were stratified into four groups: normo-albuminuria, micro-albuminuria, overt-proteinuria, and patients with end-stage renal disease (ESRD) receiving hemodialysis. Age-matched-diabetic hypertensive patients (n = 24) and non-diabetic ESRD patients on hemodialysis (n = 47) were also enrolled. Plasma triglyceride (TG) levels rose as diabetic nephropathy progressed to overt-proteinuria. No further elevation in TG was observed in diabetic ESRD, however, and the TG levels were normal in non-diabetic ESRD. A similar pattern was observed for remnant-like particle-cholesterol (RLP-C). In contrast to the changes observed for TG and RLP-C, the levels of apoB48 increased steadily as the diabetic nephropathy progressed (control, 3.7; normo, 5.7; micro, 6.9; overt, 10.6 mg/l, respectively). ApoB48 peaked in the diabetic ESRD (19 mg/l) and was also markedly elevated in non-diabetic ESRD (10.1 mg/l). The apoB48/TG and apoB48/total-apoB ratios were substantially elevated in both diabetic and non-diabetic ESRD. These results are the first to demonstrate remarkable elevations of plasma apoB48 in patients with both diabetic and non-diabetic ESRD. The remarkably high level of apoB48 in diabetic ESRD seems to be attributable to dyslipidemia induced by both diabetic nephropathy and ESRD. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Apolipoprotein B48; Diabetic nephropathy; Dyslipidemia; End-stage renal disease
1. Introduction Patients with diabetes suffer from high rates of coronary heart disease (CHD), and the rates climb even higher in those with diabetic nephropathy [1–3]. A recent prospective cohort study of patients with type 2 diabetes mellitus has demonstrated that diabetic nephropathy is significantly associated with subsequent mortality from CHD even before end-stage renal disease (ESRD) occurs [4]. It has also been well estab∗
Corresponding author. Tel.: +81 3 3784 8722; fax: +81 3 3784 8742. E-mail address:
[email protected] (T. Hirano).
0021-9150/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2007.03.015
lished that high incidences of CHD and stroke substantially worsen the long-term prognosis for diabetic patients with ESRD. Among the multiple factors known to play roles in the pathogenesis of CHD in diabetic nephropathy, dyslipidemia is thought to be a powerful risk factor for coronary atherosclerosis [3–8]. Although lipid metabolism has been extensively investigated in diabetes, little information is available on the influence of nephropathy on diabetic dyslipidemia. Several studies, including our own, have suggested that atherogenic lipoprotein profiles – namely, a reduced level of high-density lipoprotein (HDL)-cholesterol in combination with elevated levels of very low-density lipoprotein
T. Hayashi et al. / Atherosclerosis 197 (2008) 154–158
(VLDL), intermediate-density lipoprotein (IDL), and small dense low-density lipoprotein (LDL) – are more prominent in type 2 diabetics with diabetic nephropathy [5–10]. Chylomicrons (CMs) are synthesized in the intestine for the transport of dietary TG in the circulation. CMs are promptly hydrolyzed with lipoprotein lipase (LPL), which results in a subsequent production of CM remnant. An accumulating body of evidence suggests that enhanced levels of CM remnant play a role in the pathogenesis of atherosclerosis [11–14]. The atherogenic nature of these particles is thought to be due to their ability to infiltrate the arterial wall, either directly or indirectly, by influencing the composition and metabolic fate of other lipoprotein classes via neutral lipid exchange [15]. Although CM remnant is quickly taken up by the liver via the remnant receptors, some of the CM remnants remain in the circulation in the fasting state. Apolipoprotein (apo) B48 is essential for the formation of CMs. As one CM particle contains one molecule of apoB48, the plasma level of apoB48 indicates the number of CM particles [15]. The physiopathologic role of TG-rich lipoprotein (TGRL)-apoB48 lipoparticles in atherosclerosis has been documented [16,17]. Sakai et al. [18] recently developed monoclonal antibodies against apoB48 and established the ELISA system. Their preliminary study demonstrated that fasting apoB48 levels were closely correlated with the area under the curve after an oral fat-loading [19]. If this is so, the fasting apoB48 will be useful as a predictor of postprandial increases in apoB48. Our group previously reported that the postprandial increase of TGRL was markedly higher in patients with diabetic nephropathy than in diabetics without nephropathy or in patients with non-diabetic kidney diseases [20]. We also reported elevations in remnant-like particle (RLP)-cholesterol (C) in the advanced stage of diabetic nephropathy [21]. To proceed further in the direction mapped out in previous studies, we examined plasma apoB48 levels in type 2 diabetic patients at various stages of diabetic nephropathy, including end-stage renal disease (ESRD), and tried to determine how diabetic nephropathy affects CMs and their remnants.
2. Subjects and methods Study subjects included 101 type 2 diabetic patients with diabetic nephropathy at different stages, 47 non-diabetic ESRD patients on hemodialysis, and 24 non-diabetic controls currently receiving anti-hypertensive agents for essential hypertension. Subjects treated with lipid-lowering agents were excluded. The average albumin/creatinine index in urine (u-alb/cr) was calculated from spot urine samples collected on three different days. Urine specimens contaminated with bacteria, white blood cells, or red blood cells were excluded. The diabetic patients were classified into the following subgroups based on the urinary albumin concentrations measured by the latex turbidimetric immunoassay method using a commercially available kit (LA-system; AIC Co.; Tokyo, Japan): normo-albuminuria (normo), u-alb/cr
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less than 29 mg/g; micro-albuminuria (micro), u-alb/cr of 30–299 mg/g; overt-proteinuria (overt), u-alb/cr greater than 300 mg/g; ESRD patients undergoing HD therapy. All of the diabetic patients with overt diabetic nephropathy had been diagnosed with diabetes more than 10 years before the start of the study, and all suffered from diabetic retinopathy as well. Every diabetic patient enrolled in the study, with or without nephropathy, was fed with an isocaloric diet (26–27 kcal/kg ideal body weight) consisting of 17% protein, 23% fat, and 60% carbohydrate. The dietary therapy was supervised by a dietitian and exercise therapy was prescribed by a physician according to the recommendations of the Japanese Diabetes Association. The diet and exercise therapies were the sole treatments administered during the course of the study for 14 normo-albuminuric, 4 micro-albuminuric, 6 proteinuric, and 16 ESRD diabetics. Three normo-albuminuric, five microalbuminuric, four proteinuric, and four ESRD diabetics were on insulin therapy. The other diabetic patients were treated with oral-hypoglycemic agents concomitantly with the diet and exercise therapies (sulfonylureas, alpha-glucosidase inhibitors, metformin, pioglitazone, or combination of these drugs). Metformin administered for six normo-albuminuric, eight micro-albuminuric, five proteinuric diabetics, while pioglitazone administered for four normo-albuminuric, four micro-albuminuric, four proteinuric, and two ESRD diabetics. There was no statistically significant difference in the frequency of metformin users between normo-albuminuric, micro-albuminuric, and proteinuric diabetics. There were no statistically significant differences in the frequency of insulin and pioglitazone users among the diabetic groups. Informed consent was obtained from all subjects, and the study was approved by the local ethics committee. Blood samples were obtained after an overnight fast. The plasma apoB48 level was measured by the enzyme immunoassay method (Lumipulse apoB48, Fujirebio, Tokyo, Japan) according to the method of Sakai et al. [18]. Remnantlike particle-cholesterol (RLP-C) was measured by the method of Nakajima et al. [22]. ApoAI, B, CII, and CIII were measured by immunoturbidimetry (Daiichi Pure Chemical Co.). LDL-C and HDL-C were measured by direct assay using commercially available kits (Cholestest LDL and Cholestest N-HDL; Daiichi Pure Chemical Co.). Totalcholesterol (TC), TG, Lp(a), glucose, hemoglobin (Hb)A1c, glycoalbumin, albumin and creatinine were measured by standard laboratory procedures. Significant differences between the four groups were determined by one-way ANOVA with the Bonferroni/Dunn test. Statistical significance was accepted at P < 0.05.
3. Results As shown in Table 1, age and gender were comparable between the controls, the diabetics with diabetic nephropathy at various stages, and the non-diabetic ESRD patients. Body mass index (BMI) was significantly greater in normo-
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Table 1 General characteristics of non-diabetic control subjects, type 2 diabetic subjects with various stages of nephropathy and non-diabetic patients with end-stage renal disease (ESRD)
Number (male/female) Age (year) Body mass index U-albumin/creatinine (mg/g) Plasma albumin (g/dl) Plasma creatinine (mg/dl) Plasma glucose (mg/dl) Glycoalbumin (%) HemoglobinA1c (%)
Controls
Normo
Micro
Overt
ESRD (DM)
ESRD (non-DM)
24 (15/9) 61 ± 15 22 ± 4 8±2 4.0 ± 0.7 0.7 ± 0.1 87 ± 9 NA NA
33 (21/12) 61 ± 13 26 ± 7 a 11 ± 6 4.0 ± 0.3 0.6 ± 0.1 195 ± 54 a 28 ± 9 10.2 ± 2.1
28 (17/11) 60 ± 13 23 ± 4 123 ± 78 ab 4.0 ± 0.3 0.7 ± 0.2 206 ± 49 a 32 ± 9 10.9 ± 2.2
21 (14/7) 56 ± 11 24 ± 3 1240 ± 1770 abc 3.4 ± 0.7 abc 1.3 ± 0.9 abc 165 ± 60 bc 26 ± 10 c 9.3 ± 2.2
23 (13/10) 65 ± 9 23 ± 4 NA 3.6 ± 0.2 abc 10.5 ± 1.9 abcd 161 ± 63 bc NA NA
47 (31/16) 61 ± 11 21 ± 3 a NA 3.6 ± 0.3 abc 12.1 ± 2.6 abcd 97 ± 11 NA NA
Data represent mean ± S.D. Normo, normo-albuminuric diabetes; micro, micro-albuminuric diabetes; overt, overt-proteinuric diabetes. NA, not available. Significance (P < 0.05) was determined by ANOVA: (a) vs. control; (b) vs. normo; (c) vs. micro; (d) vs. overt.
albuminuric diabetes group than in the control group or the non-diabetic ESRD group. The diabetics with proteinuria, the diabetics with ESRD, and the patients with non-diabetic ESRD had lower albumin concentrations and significantly higher plasma creatinine levels than the controls. The albumin concentrations and plasma creatinine levels in the normoalbuminuric and micro-albuminuric diabetic patients were comparable to those of the controls. The fasting plasma glucose and HbA1c levels were very high, as expected, in view of the poor diabetic control among the patients enrolled. However, both of these values were comparable among the normo-albuminuric, micro-albuminuric, and overt-proteinuric subgroups. Glycoalbumin is slightly but statistically lower in the overt-proteinuric group than in the micro-albuminuric group. Table 2 shows the levels of serum lipids and apolipoproteins in each group. Plasma triglyceride (TG) rose as the diabetic nephropathy progressed, but the level in the diabetic ESRD patients was comparable to that in the patients with proteinuric diabetes. In contrast, the TG level in the non-diabetic ESRD patients was no higher than that in the controls. Though unable to measure RLP-C in all of the subjects, we did observe a moderate rise in RLP-C as the diabetic nephropathy progressed. As with the TG, the RLPC level showed no further elevation in diabetic ESRD, hence it remained comparable between the patients with protein-
uric diabetes and those with diabetic ESRD. No elevation in RLP-C was found in the patients with non-diabetic ESRD. TC and LDL-C levels were significantly higher in diabetics, but was elevated neither in patients with diabetic ESRD nor non-diabetic ESRD. Lp(a) was comparable among the controls, the diabetics with nephropathy, and the diabetics without nephropathy. HDL-C and apoAI levels were selectively lower in ESRD, irrespective of the presence of diabetes. The apoB levels were elevated in the diabetics without ESRD, unchanged in the diabetics with ESRD, and moderately decreased in the patients with non-diabetic ESRD. ApoCII levels were significantly decreased in the patients with both diabetic and non-diabetic ESRD. ApoCIII rose moderately as the diabetic nephropathy progressed and peaked in the patients with diabetic ESRD. The apoCIII also exceeded the control level in non-diabetic ESRD. Fig. 1 shows the serum concentrations of apoB48. The apoB48 level rose steadily as the diabetic nephropathy progressed (control, 3.7; normo, 5.7; micro, 6.9; overt, 10.6) and peaked in the patients with diabetic ESRD (19 mg/l). The apoB48 level was also substantially elevated in non-diabetic ESRD (10.1 mg/l). Table 3 shows the ratios of plasma apoB48/TG and apoB48/total apoB. The ratios were not elevated for normo-albuminuric and micro-albuminuric diabetic groups, whereas these ratios were elevated significantly in overt-
Table 2 Plasma levels of lipids and apolipoproteins in control subjects, type 2 diabetic subjects with various stages of nephropathy, and non-diabetic patients with ESRD Controls TG (mg/dl) RLP-C (mg/dl) Total-C (mg/dl) LDL-C (mg/dl) Lp(a) (mg/dl) HDL-C (mg/dl) ApoA1 (mg/dl) ApoB (mg/dl) ApoCII (mg/dl) ApoCIII (mg/dl) ApoB48 (mg/l)
114 4.8 173 97 13 52 143 82 4.3 8.5 3.7
± ± ± ± ± ± ± ± ± ± ±
65 3.0 (n = 8) 38 26 10 13 25 24 2.5 2.3 2.3
Normo 136 5.6 214 137 12 50 129 107 5.8 10.4 5.7
± ± ± ± ± ± ± ± ± ± ±
Micro 77 3.0 (n = 9) 38 a 37 a 7 11 23 a 26 a 2.3 3.8 a 2.9 a
170 5.8 197 119 19 45 122 100 6.3 10.7 6.9
± ± ± ± ± ± ± ± ± ± ±
Overt 113 a 1.3 (n = 11) 40 a 35 a 20 11 17 a 28 a 3.2 5.4 a 5.7 a
188 10.7 235 131 21 58 143 113 6.8 12.3 10.6
± ± ± ± ± ± ± ± ± ± ±
ESRD (DM) 125 a 15.3 (n = 9) 54 ac 37 a 14 19 33 c 37 a 2.8 4.2 a 10.9 ab
178 9.6 177 95 23 39 110 85 3.8 13.1 19.3
± ± ± ± ± ± ± ± ± ± ±
13 a 14.3 a (n = 23) 35 d 21 b 20 14 abd 25 ad 22 bcd 1.7 bcd 3.1 abc 13.9 abcd
ESRD (non-DM) 96 5.0 149 79 16 43 112 67 2.5 10.9 10.1
± ± ± ± ± ± ± ± ± ± ±
43 de 2.3 e (n = 47) 30 de 25 bcd 14 12 abd 21 ad 20 abcde 1.3 abcde 3.7 a 5.7 abce
Data represent mean ± S.D. Normo, normo-albuminuric diabetes; micro, micro-albuminuric diabetes; overt, overt-proteinuric diabetes; NA, not available. Significance (P < 0.05) was determined by ANOVA: (a) vs. control; (b) vs. normo; (c) vs. micro; (d) vs. overt; (e) vs. diabetic ESRD.
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Table 3 The ratios of serum apoB48/TG and total-apoB in control subjects, type 2 diabetic subjects with various stages of nephropathy, and non-diabetic patients with ESRD
ApoB48/TG ApoB48/ApoB
Controls
Normo
Micro
Overt
ESRD (DM)
ESRD (non-DM)
0.040 ± 0.028 0.049 ± 0.033
0.041 ± 0.017 0.051 ± 0.024
0.042 ± 0.021 0.067 ± 0.053
0.060 ± 0.035 ab 0.091 ± 0.071 ab
0.112 ± 0.043 abcd 0.227 ± 0.143 abcd
0.108 ± 0.052 abcd 0.158 ± 0.104 abcd
Data represent mean ± S.D. Normo, normo-albuminuric diabetes; micro, micro-albuminuric diabetes; overt, overt-proteinuric diabetes; NA, not available. Significance (P < 0.05) was determined by ANOVA: (a) vs. control; (b) vs. normo; (c) vs. micro; (d) vs. overt.
Fig. 1. Fasting plasma apoB48 level in non-diabetic control subjects, type 2 diabetic subjects with various stages of nephropathy and non-diabetic patients with end-stage renal disease (ESRD). Normo, normo-albuminuric diabetes; micro, micro-albuminuric diabetes; overt, overt-proteinuric diabetes. Significance (P < 0.05) was determined by ANOVA: (a) vs. control; (b) vs. normo; (c) vs. micro; (d) vs. overt; (e) vs. diabetic ESRD.
proteinuric diabetic groups and markedly elevated in both diabetic and non-diabetic ESRD. There were no significant differences in these ratios between non-diabetic and diabetic ESRD.
4. Discussion CMs are only generated in a post-absorptive state in the intestine, and once generated they are quickly hydrolyzed by the action of lipoprotein lipase circulating in the blood. For this reason, the serum apoB48 level in the fasting state is a reliable index of the number of CM remnant particles. The size and density of CM remnants are wide ranging: apoB48-containing particles are detectable from CM to LDL fraction. Campos et al. [23] reported that a half of apoB48 particles were found in the LDL density range in the fasting state. ApoB48 is measured semi-quantitatively by SDSpolyacrylamide gel electrophoresis (PAGE) with isolated TGRL fraction [24]. If apoB48 is present in LDL fraction, the SDS-PAGE method underestimates the total apoB48 concentration. The apoB level can now be measured directly by the ELISA method using specific monoclonal antibody against apoB48. The plasma apoB48 level in our control subjects, 3.7 g/ml, was comparable to the median level (3.9 g/ml) in 335 normolipidemic subjects reported by Sakai et al. [18]. Our findings on plasma apoB48 levels in the present study indicated an elevation in patients with type 2 diabetes and a further elevation in patients in the advanced stage of diabetic nephropathy. In fact, the apoB48 level in the latter patients
was about five-fold greater than those in controls. Given that CM is produced postprandially, the plasma CM remnant level in the fasting state is virtually regulated by its removal efficiency. Indeed, Weintraub et al. [25] found a severe defect in postprandial CM remnant catabolism labeled with retinyl palmitate in patients with ESRD. How is the catabolism of CM remnants impaired in ESRD? CM remnants are taken up by LDL-related protein (LRP) in the liver [11,15]. Kim and Vaziri [26] recently observed downregulation of the gene expression and protein of LRP in 5/6 nephrectomized rats with chronic renal failure. Our group previously reported a marked elevation of apoCIII levels in plasma or TGRL in patients with both diabetic and non-diabetic ESRD [10], and the results of our present study corroborate this finding. ApoCIII inhibits the catabolism of TGRLs by suppressing lipolysis with lipoprotein lipase and particle uptake by the liver. Thus, increases of apoCIII and decreases of LRP may be both associated with catabolic defects of CM remnant in ESRD. Hepatic lipase is downregulated in ESRD [27] and clears remnants by lipolytic and non-lipolytic processing [28]. Non-lipolytic processing (the bridging function) has been postulated to remove apoB48and apoB100-containing remnants by whole particle uptake [28]. Thus, decrease of hepatic lipase may also be responsible for the defect in CM remnant catabolism. We were interested to find that plasma apoB48 increased continuously with the progression of diabetic nephropathy and reached peak levels in diabetic ESRD, whereas the serum TG and RLP-C levels in diabetic ESRD were somewhat lower than those in proteinuric diabetics. In non-diabetic ESRD, meanwhile, we found no change in TG or RLP-C, whereas apoB48 was substantially elevated. These findings suggest that the rise in apoB48 is directly associated with ESRD regardless of the presence of diabetes or hypertriglyceridemia. According to the analysis by Campos et al. [29], RLP fraction in the fasting state consists of two-thirds apoB100 particles and one-third apoB48 particles. If RLPC is as imprecise a marker of CM remnant as this suggests, the dissociation of apoB48 and RLP-C sometimes found is unsurprising. The apoB48 level was about two times higher in diabetic ESRD than in non-diabetic ESRD. The increasing of plasma apoB48 level in diabetic nephropathy may be due to the association of diabetes and chronic renal failure, which additively reduces CM remnant clearance and/or increases CM production [30]. The plasma apoB48/TG ratio was substantially elevated in both diabetic and non-diabetic ESRD. The ratio
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of apoB48/total apoB also showed a specific elevation of apoB48 in ESRD. According to the data from Sakai et al. [18], the apoB48/TG ratio was about 0.04 in control subjects and over 0.1 in type III dyslipidemic subjects. This ratio exceeded 0.1 in our patients with ESRD, implying that a specific elevation of apoB48 in ESRD is equivalent to type III dyslipidemia with extremely high levels of remnants and a high prevalence of CHD. The data from clinical studies have yet to clarify whether apoB48 is actually a risk factor for CHD. Valero et al. [31] found no connection of apoB48 with the presence or severity of CHD. Karpe et al. [32], on the other hand, reported that the fasting apoB48 concentration in VLDL d < 1.006 g/ml was higher in patients with CHD than in controls. A large cohort study will be required to elucidate whether increased serum apoB48 becomes an independent risk factor for CHD in patients with ESRD.
[13]
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[19]
Acknowledgement The authors thank Fujirebio for apoB48 assay.
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