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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 8 4441-4445
Copyright © 2005 by The Endocrine Society

RAPID COMMUNICATION

Increased Transvascular Lipoprotein Transport in Diabetes: Association with Albuminuria and Systolic Hypertension

Jan Skov Jensen, Bo Feldt-Rasmussen, Knut Borch-Johnsen, Kurt Svarre Jensen and Børge Grønne Nordestgaard

Department of Nephrology and Endocrinology P (J.S.J., B.F.-R., K.S.J.), The National University Hospital, DK-2100 Copenhagen, Denmark; Steno Diabetes Center (K.B.-J.), DK-2820 Gentofte, Denmark; Department of Clinical Biochemistry (B.G.N.), Herlev University Hospital, DK-2730 Herlev, Denmark; and The Copenhagen City Heart Study (J.S.J., B.G.N.), Bispebjerg University Hospital, DK-2400 Copenhagen, Denmark

Address all correspondence and requests for reprints to: Jan Skov Jensen, M.D., Ph.D., D.M.Sc., Department of Cardiology P, Gentofte University Hospital, Niels Andersens Vej 65, DK-2900 Hellerup, Denmark. E-mail: jsje{at}c.dk.

Abstract

Context: Diabetes is associated with a highly increased risk of atherosclerosis, especially if hypertension or albuminuria is present.

Objective: We hypothesized that the increased transvascular lipoprotein transport in diabetes may be further accelerated if hypertension or albuminuria is present, possibly explaining increased intimal lipoprotein accumulation and thus atherosclerosis.

Design: The study was cross-sectional and was performed in 1999–2002.

Setting: The study took place in the referral center.

Patients: The patients included 60 with diabetes mellitus (27 with type 1 diabetes and 33 with type 2 diabetes) and 42 healthy controls. All were randomly recruited.

Main Outcome Measure: We used an in vivo method for measurement of transvascular transport of low-density lipoprotein (LDL). Autologous 131I-LDL was reinjected iv, and the 1-h fractional escape rate was taken as an index of transvascular transport.

Results: Transvascular LDL transport was 1.8 (1.6–2.0), 2.3 (2.0–2.6), and 2.6 (1.3–4.0)%/[h x (liter/m2)] in healthy controls, diabetic controls, and diabetes patients with systolic hypertension or albuminuria, respectively (P = 0.013; F = 4.5; df =2; ANOVA). These differences most likely were not caused by altered hepatic LDL receptor expression, glycosylation of LDL, small LDL size, or medicine use.

Conclusions: Transvascular LDL transport is increased in patients with diabetes mellitus, especially if systolic hypertension or albuminuria is present. Accordingly, lipoprotein flux into the arterial wall could be increased in these patients, possibly explaining accelerated development of atherosclerosis.

DIABETES MELLITUS IS the most serious risk factor of cardiovascular disease identified at the individual level (1). Follow-up studies of diabetes populations have indicated that patients with albuminuria are at particularly high risk (2, 3, 4, 5). Although albuminuria and hypertension are strongly correlated (6), the pathophysiological mechanism behind this association remains to be clarified. In a few studies of selected groups of diabetes patients, the fractional escape rate of albumin from the intravascular compartment (FERalb) was found to be elevated if microalbuminuria or macroalbuminuria was present (7, 8). Based on these observations, it was hypothesized that albuminuria may reflect a widespread vascular damage with transvascular leakage of macromolecules, including lipoproteins (9). This would potentially lead to increased lipoprotein accumulation in the vessel wall and thus progressed atherosclerosis (10, 11).

To test this hypothesis, we developed a clinical in vivo method to measure the human fractional escape rate from the intravascular compartment of low-density lipoprotein (FERLDL) using iv injection of radioactively labeled autologous LDL (12). By this method, we found elevated FERLDL in patients with insulin-dependent as well as noninsulin-dependent diabetes (12, 13).

In the present study, we measured FERLDL in a group of diabetes patients with or without albuminuria or systolic hypertension and compared it with that in healthy controls. We also measured LDL size and distribution volume of LDL, because this could affect FERLDL.

Subjects and Methods

Subjects

We studied a random sample of 60 patients with diabetes mellitus, 27 with type 1 diabetes and 33 with type 2 diabetes. The age range was 21–81 yr. All were recruited from the Steno Diabetes Center in Copenhagen. Any chronic disease (with possible influence on transvascular transport of macromolecules) other than diabetes or its related complications constituted exclusion criteria. Among these 60 patients, 11 had microalbuminuria (first morning void urine albumin/creatinine concentration ratio above 3 mg/mmol), and three had albuminuria (first morning void urine albumin/creatinine concentration ratio above 25 mg/mmol) according to the definitions by Mogensen et al. (14), whereas six had systolic hypertension (systolic blood pressure above 160 mm Hg). Five had a history of acute coronary occlusion, four suffered from intermittent claudication, and 16 suffered from retinopathy. They used insulin (n = 47), peroral antidiabetic agents (n = 6), angiotensin converting enzyme inhibitors (n = 12), angiotensin II antagonists (n = 4), ß-adrenoceptor blockers (n = 7), calcium channel blockers (n = 11), diuretics (n = 22), acetyl salicylic acid (n = 22), and statins (n = 8). For comparison, we studied 42 clinically healthy individuals with similar age and sex distribution as the diabetes patients. They were recruited from the Copenhagen City Heart Study, a major epidemiological study of cardiovascular disease (15). All participants gave written informed consent. The study was in accordance with the Declaration of Helsinki and was approved by the Copenhagen and Frederiksberg Ethics Committee (file number 01-302/97). The study was surveyed by the National Department of Isotope Pharmacy, who permitted investigation of two subjects per week maximally.

Methods

FERLDL and FERalb were measured by means of plasma decay curves during 1 h after iv injection of autologous 131I-LDL and commercially available 125I-human serum albumin (125I-albumin), respectively.

LDL was isolated from 100 ml of blood by sequential ultracentrifugation at 4 C in solvent densities of 1.019 and 1.050 g/ml, respectively, at 50,000 rpm for 20 h in a Beckman Instruments (Fullerton, CA) 50.4 Ti rotor. 131-iodination of LDL was done with 18.5 MBq 131-iodine using iodine monochloride (16). The iodination efficiency was 25 ± 5% (n = 54), which corresponds to 52 ± 13 cpm/ng LDL protein. In the labeled preparations, 98.6 ± 0.4% of the 131I radioactivity was precipitable with 15% (vol/vol) trichloroacetic acid (TCA), and 5.6 ± 0.5% of the 131I radioactivity was lipid soluble, i.e. extractable into chloroform-methanol (1:1, vol/vol). In fixed-density ultracentrifugation analysis of labeled LDL in the presence of added carrier plasma, 96% or more of the total radioactivity was in the LDL density range of 1.019–1.063 g/ml. No evidence of fragmentation of the labeled LDL was detected using a 3–8% Tris-acetate Gradient Gel, followed by autoradiography. In all labeled preparations, test for sterility was negative, and less than 5 pg of pyrogenes was detectable per milliliter sample.

The participants met at 0800 h after an 8-h fast and tobacco abstinence. A 17-gauge Teflon cannula was inserted in an antecubital vein in both arms, one for blood sampling and one for injection. After a 30-min rest at recumbency, the preparation containing 131I-LDL (700 kBq) and 125I-albumin [500 kBq; code IFE-IT.23S or IFE-IT.20S; Isopharma AS, Kjeller, Norway (free 125I radioactivity < 1.5 ± 0.2%)] was injected iv. Venous blood samples of 10 ml were drawn without stasis in heparinized tubes before and at 10, 20, 30, 40, 50, and 60 min after injection. Proteins in plasma (3 ml) and doses (0.1 ml with 2.9 ml unlabeled plasma added) were precipitated at 4 C with TCA at a final concentration of 15% (vol/vol). After mixing and centrifugation, total radioactivity as well as radioactivity in the supernatant was counted for 20 min in a double-channel gamma counter (1282 Compugamma; LKB Wallac, Turku, Finland). For both tracers, the TCA-precipitable radioactivity at each time point was plotted vs. time after logarithmic transformation. FERLDL and FERalb (in percent per hour) were then calculated on the basis of the slopes (ß) of the best linear curves fitted by the least-squares method using the following formula: (1 – 60eß) x 100%, thus assuming that radioactivities declined monoexponentially with time (one-compartment system). Distribution volumes of LDL (DVLDL) and albumin (DValb = plasma volume) were calculated from the amounts of injected radioactivities divided by the plasma radioactivities at time zero, as derived from the intercepts of the fitted lines for the two tracers, respectively. The obtained DV values were corrected for body surface area (in square meters) by the following formula: 0.007184 x weight0.425 x height0.725.

The contribution of receptor-mediated elimination of LDL from the intravascular compartment to FERLDL during the 1 h blood sampling period was elucidated by comparing FERLDL with FERGly-LDL in three humans without diabetes mellitus (12). Glycosylated LDL is not recognized by LDL receptors (17, 18), and thus the difference between FERLDL and FERGly-LDL represents receptor elimination. Glycosylation of LDL was performed as described previously (17, 19, 20). Autologous 131I-LDL (700 kBq) and autologous 125I-Gly-LDL (500 kBq) was reinjected under similar conditions as described above. Venous blood samples of 10 ml were drawn without stasis in heparinized tubes before and at 10, 20, 30, 40, 50, and 60 min after reinjection. Eleven additional blood samples were obtained during the subsequent 6 d. Plasma was precipitated with TCA and counted for radioactivity as described above. For both tracers, the logarithmically transformed TCA-precipitable radioactivity was plotted vs. time, and FERLDL and FERGly-LDL were calculated as described previously. Mean FERLDL was about 1%/h higher than mean FERGly-LDL (3.6 ± 1.1 vs. 2.6 ± 1.1%/h). Moreover, fractional catabolic rates, FCRLDL and FCRGly-LDL (in percent per hour), were calculated according to Matthews (21) using the following formula: (C1/ß1 + C2/ß2)–1, where ß1 and ß2 are slopes, and C1 and C2 are intercepts of the late and initial linear curve fits, respectively. Mean FCRLDL was about two times higher than mean FCRGly-LDL (P < 0.01), documenting that Gly-LDL was indeed glycosylated.

The use of a one-compartment system for calculation of FERLDL was validated by comparing FERLDL with transvascular LDL permeability as described by Matthews (21), which takes into account an extravascular protein compartment, receptor-mediated metabolism, and excretion. In eight subjects without diabetes, blood samples were collected every 10th minute during the first hour and subsequently once a day during the next week during reinjection of autologous 131I-LDL. Transvascular LDL permeability using the multicompartment model was calculated by the following formula: C1C2(b2 – b1)2/(C1b2 + C2b1) (21). There was a positive correlation between FERLDL using one-compartment kinetics and transvascular LDL permeability using multicompartment kinetics (R2 = 0.41; n = 8; one-sided P < 0.05) (our unpublished observations). The equation for the linear correlation was one-compartment FERLDL = 0.43 x multicompartment FERLDL + 2.8 (all in percent per hour). The overestimation of FERLDL by one-compartment kinetics was most pronounced in the lower range. Finally, we correlated FERLDL to FCRLDL in 27 subjects, in which FCRLDL was calculated by multicompartmental analysis using the SAAM II software (SAAM Institute, Seattle, WA) (22). Because there was no correlation between FERLDL and FCRLDL (R < 0.01; P = 0.99), it is unlikely that metabolism, i.e. receptor mediated elimination of LDL, contributes to FERLDL to any significant degree.

Other measurements

Urine concentration of albumin was measured by a micro ELISA method (23), and urine concentration of creatinine was measured by a photometric method (Vitros Crea Slide; Johnson & Johnson, Rochester, NY). Plasma concentration of insulin was measured by a two-site fluoroimmunometric assay (AutoDELFIA Insulin; Wallac Oy, Turku, Finland). Plasma concentrations of total, LDL, and high-density lipoprotein cholesterol, triglycerides, and creatinine were all measured by commercially available assays (Roche Diagnostics, Mannheim, Germany) using an Hitachi analyzer. Plasma concentration of C-reactive protein was measured by a high-sensitivity nephelometric method (Behring Diagnostica, Marburg, Germany). LDL particle size was measured by nondenaturing pore gradient gel electrophoresis as described previously (12, 24). All blood samples were drawn after an 8 h fast and tobacco abstinence. Systolic and diastolic blood pressures were measured by auscultation using a manometer and an appropriately sized cuff. Body mass index (kilograms per square meter) was calculated as weight/height2.

Statistics

Comparisons between groups were performed by Student’s t test, ANOVA, or the {chi}2 test. Associations were explored by linear regression analyses. Urine albumin/creatinine, and plasma triglycerides, insulin, C-reactive protein, and creatinine were log transformed before the analyses because of non-normal distribution. P values < 0.05 were significant.

Results

Characteristics of diabetes patients with or without systolic hypertension or albuminuria and nondiabetic controls are shown in Table 1Go.


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  		TABLE 1. Characteristics of diabetes patients with systolic hypertension or albuminuria, diabetic controls, and healthy nondiabetic controls

 
FERLDL was higher in diabetes patients than in nondiabetic controls, whereas FERalb only tended to be higher in diabetes patients than in nondiabetic controls (Table 2Go). However, when corrections were made for the smaller distribution volumes of LDL and albumin in diabetes patients, the difference in both FERLDL/DVLDL and FERalb/DValb between diabetes patients and nondiabetic controls was more pronounced (Table 2Go).


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  		TABLE 2. FERs and DVs of LDL and albumin, and LDL size in diabetes patients with systolic hypertension or albuminuria, diabetic controls, and healthy nondiabetic controls

 
There was a significant variation in FERLDL/DVLDL between healthy controls, diabetic controls, and diabetes patients with systolic hypertension or albuminuria. The figures were 1.8 (1.6–2.0), 2.3 (2.0–2.6), and 2.6 (1.3–4.0) %/[h x (liter/m2)], respectively (P = 0.013; F = 4.5; df = 2; ANOVA) (Table 2Go and Fig. 1Go). According to Table 1Go, diabetes patients with systolic hypertension or albuminuria were characterized by higher frequencies of men and smokers and higher plasma creatinine and urine albumin/creatinine ratio than diabetes patients without systolic hypertension or albuminuria (Table 1Go). However, neither male sex, smoking, plasma creatinine, urine albumin/creatinine ratio, or urine albumin/creatinine ratio more than 3 mg/mmol were associated with FERLDL/DVLDL in linear regression analyses. It is therefore unlikely that these four variables confound the association between systolic hypertension or albuminuria and FERLDL/DVLDL in diabetes patients.



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  		FIG. 1. FERLDL/DVLDL in diabetes patients with systolic hypertension (systolic blood pressure > 160 mm Hg) or albuminuria (urine albumin/creatinine > 25 mg/mmol), diabetes controls, and nondiabetic controls. Means ± SE are shown. P = 0.013; F = 4.5; df = 2; ANOVA.

 
Besides diabetes, the only variable associated with FERLDL/DVLDL was FERalb/DValb (R2 = 0.62; P < 0.001). None of the variables listed in Table 1Go were associated with FERLDL/DVLDL. There was also no association between LDL diameter or distribution volume, medicine use, coronary heart disease, intermittent claudication, or retinopathy and FERLDL/DVLDL.

Discussion

In the present study, we measured the FERLDL by an in vivo isotope technique in a group of diabetes patients and a group of age- and sex-matched healthy controls. Based on the so-called "Steno hypothesis," diabetes patients with albuminuria may have a systemic vascular damage, including transvascular leakage of albumin and lipoproteins (7, 8, 9). In support of this, we found that diabetes patients had elevated FERLDL compared with nondiabetic controls, especially if systolic hypertension, i.e. systolic blood pressure above 160 mm Hg, or albuminuria, i.e. urine albumin/creatinine concentration ratio above 25 mg/mmol in a morning urine sample, was present. If elevated FERLDL reflects increased intimal influx and deposition of lipoproteins in vessel walls (10, 11), our finding may at least in part explain the increased risk of cardiovascular disease in these patients (2, 3, 4, 5).

Another obvious possibility apart from the above mentioned considerations is that FERLDL reflects metabolism of LDL rather than transvascular transport. However, there was no relationship between FERLDL and FCRLDL as calculated by the SAAM II method (22). This would have been the case if FERLDL was influenced by metabolism.

Glycosylation of LDL could also influence the disappearance of LDL from the intravascular compartment. Thus, glycosylated LDL is not recognized by LDL receptors (17, 18), as confirmed by the significantly lower FCRGly-LDL than FCRLDL in our validation experiments. We therefore studied the contribution of receptor elimination to FERLDL by measuring FERGly-LDL and FERLDL simultaneously. FERGly-LDL was about 1%/h lower than FERLDL in nondiabetic humans, indicating that receptor elimination contributes to FERLDL only by approximately 1%/h (corresponding to about one third of FERLDL). This is in accordance with the overestimation of FERLDL by 1–3%/h when our one-compartment model is used compared with a multicompartment model that subtracts the contribution of metabolism (21). It is also in accordance with the slightly bigger distribution volume of LDL than albumin. However, in diabetes patients, especially patients with hypertension or albuminuria (25), glycosylation of LDL particles may be increased due to the hyperglycemic milieu. This may lead to an underestimation of the true difference in FERLDL between diabetes patients and controls and between diabetes patients with and without systolic hypertension or albuminuria.

Because FERLDL also was independent of LDL size and endothelial surface area as reflected by the plasma volume, we suggest the elevated FERLDL in diabetes patients, especially those with systolic hypertension or albuminuria, to result mainly from higher hydraulic pressure or increased transvascular permeability. This latter could be a consequence of endothelial cell death or damage (26, 27, 28) due to, for example, hyperinsulinemia (29, 30, 31) or to circulating advanced glycation end products inducing transvascular hyperpermeability (32, 33, 34, 35). However, other authors have observed increased intimal LDL accumulation before the formation of advanced glycation end products and suggest a direct effect of hyperglycemia on the vessel wall (36).

Aggregation of LDL at the endothelial surface is not a likely explanation of the increased FERLDL observed in diabetes patients with systolic hypertension or albuminuria. This is because FERalb was also increased in these patients and because FERalb is unlikely affected by aggregation of LDL at the endothelial surface.

There was no association between FERLDL and diabetic retinopathy. This is in accordance with another recent Danish study in which type 2 diabetic patients with retinopathy had similar FERalb as patients without retinopathy (37).

The main proportion of transvascular LDL transport probably takes place in the capillaries. However, there exists indirect evidence for similar transport of albumin and lipoproteins in capillaries and arteries (38). Furthermore, the tight positive correlation between FERLDL and FERalb observed in this study is analogous with the correlation between the transport of LDL and albumin across the arterial wall in rabbits (39). The lower FERLDL than FERalb is in accordance with the three times larger size of LDL particles than of albumin.

Other limitations should be taken into account in the interpretations of the results obtained in this study. Whereas classification of albuminuria is usually based on the albumin excretion rate in three urine samples (14), we measured albumin/creatinine concentration ratio in one urine sample only. This may have caused some misclassification leading to underestimation of the true difference in FERLDL between diabetes patients with or without albuminuria. Similarly, blood pressure was only measured once. Blood pressure could be determined more precisely by using 24-h ambulatory blood pressure measurements. To obtain sufficient statistical power, we pooled patients with type 1 diabetes and type 2 diabetes, and patients with systolic hypertension and albuminuria. Despite this, only eight patients in this sample had systolic hypertension or albuminuria. They received more drugs than others, which may have affected FERLDL, although no relationship was observed between medicine use and FERLDL or FERalb (data not shown).

In conclusion, this human in vivo study has shown elevated fractional escape of LDL particles from the intravascular compartment among patients with diabetes mellitus, especially if systolic hypertension or albuminuria is present. We suggest that this difference is not caused by altered LDL receptor expression in the liver, glycosylation of LDL, or small LDL size. Rather, this is likely due to increased transvascular leakage of LDL, potentially leading to increased LDL accumulation in the vessel wall and thus progressed atherosclerosis.

Footnotes

This work was supported by the following: the Danish Heart Foundation; the Danish Diabetes Association; the Novo Nordisk Foundation; the Copenhagen University Hospitals (H:S) Research Foundation; the Danish Medical Association Research Fund; the A. P. Møller Foundation for the Advancement of Medical Science; Bayer A/S; the Eli Lilly Diabetological Research Foundation; the Danish Foundation of Fight Against Circulatory Diseases; the Boserup Foundation; the Aage and Johanne Louis-Hansen Foundation; the Karl G. Andersen Foundation; the Kathrine and Vigo Skovgaard Foundation; the Jacob Madsen Foundation; the Lauritz Peter Christensen Foundation; the P. A. Messerschmidt Foundation; the König-Petersen Foundation; and the Björnow Foundation.

First Published Online May 17, 2005

Abbreviations: alb, Albumin; DV, distribution volume; FCR, fractional catabolic rate; FER, fractional escape rate from the intravascular compartment; LDL, low-density lipoprotein; TCA, trichloroacetic acid.

Received December 9, 2004.

Accepted May 10, 2005.

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J. Sendra, V. Llorente-Cortes, P. Costales, C. Huesca-Gomez, and L. Badimon
Angiotensin II upregulates LDL receptor-related protein (LRP1) expression in the vascular wall: a new pro-atherogenic mechanism of hypertension
Cardiovasc Res, March 14, 2008; (2008) cvn043v2.
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