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Lipoprotein abnormalities may well contribute to the increased risk of coronary heart disease, cerebrovascular disease and peripheral vascular disease observed in type 1 (insulin-dependent) diabetes mellitus. The spectrum of diabetes-associated changes in lipoprotein metabolism is discussed. The plasma levels of lipoprotein cholesterol and triglycerides are largely influenced by the degree of glycaemic control. With poor metabolic control, plasma cholesterol and triglycerides are frequently elevated. In contrast, in well-regulated patients without micro- and macrovascular complications lipid levels are generally normal or even favourable, although lipoprotein composition abnormalities can persist despite intensified insulin treatment. With the development of diabetic nephropathy the cardiovascular risk increases markedly and this complication is associated with increased concentrations of cholesterol and of the atherogenic lipoprotein species, lipoprotein(a), and low levels of high-density lipoprotein cholesterol. The rationale for treatment of lipid disorders in diabetes mellitus is based upon results of trials conducted primarily in non-diabetic populations. It is hoped that with increased recognition of dyslipidaemia and aggressive therapeutic measures the overkill in diabetes mellitus from macrovascular diseases will be reduced.

Common polymorphisms of the Cholestryl Ester Transfer Protein (CETP) gene may predict lower risk of cognitive decline. We investigated the association of cognitive function with CETP genotype in a population-based cohort of 4135 persons aged 35-82 years. Cognitive function was measured with the Ruff Figural Fluency Test (RFFT; worst score, 0 points; best score, 175 points) and CETP I405V and Taq1B genotypes were determined by polymerase chain reaction. RFFT score was not associated with I405V genotype in persons aged 35-64 years. Remarkably, beyond age 65, homozygous valine carriers had higher RFFT scores than heterozygous carriers and noncarriers: RFFT (SD), 52 (21), 49 (18), and 47 (17) points, respectively (p = 0.005). There also was a statistically significant interaction between I405V genotype and age. Beyond age 65, the difference between homozygous valine carriers and noncarriers increased by 0.11 point per year (p = 0.005). RFFT score was not associated with Taq1B genotype. In conclusion, CETP I405V valine homozygosity was associated with better cognitive function in persons aged 65 years or older. (C) 2012 Elsevier Inc. All rights reserved.

The mechanism responsible for the atherogenic lipoprotein changes associated with cigarette smoking are largely unknown. Lecithin: cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) are key factors in the esterification of plasma cholesterol and the transfer of cholesteryl ester from high-density lipoproteins (HDLs) toward very-low- and low-density lipoproteins (VLDLs+LDLs). Another transfer factor, phospholipid transfer protein (PLTP), recently has been shown to be involved in the interconversion of HDL particles in vitro, but its physiological function is not yet clear. We measured the activities of LCAT, CETP (as cholesteryl ester exchange activity), and PLTP using exogenous substrate assays as well as lipoprotein profiles in the plasma of 21 normolipidemic cigarette-smoking men (total plasma cholesterol below 6.5 mmol/L and triglyceride below 2.5 mmol/L) and 21 individually matched nonsmoking control subjects. HDL cholesterol, HDL cholesteryl ester, and plasma apolipoprotein A-I levels were lower in the smokers than in the control subjects (P < or = .05 for all parameters). Median plasma CETP activity was 18% higher (P < .02) and median plasma PLTP activity was 8% higher (P < .05) in the smokers compared with the nonsmokers. LCAT activity was not different between the groups. HDL cholesteryl ester concentration was positively related to LCAT activity in control subjects but not in smokers. By contrast, there was an inverse relation of CETP activity with HDL cholesteryl ester in smokers but not in nonsmokers. Multiple regression analysis demonstrated that the lowering effect of smoking on HDL cholesteryl ester could be explained by its influence on CETP activity.(ABSTRACT TRUNCATED AT 250 WORDS)

POEMS syndrome is a multisystem disorder associated with plasma cell dyscrasias. This report describes a patient with POEMS-associated renal disease and reviews the literature on biopsy-proven renal involvement in POEMS syndrome. Our patient had glomerulonephritis with membranoproliferative features on light-microscopy without characteristic findings on immunofluorescence, and with ultrastructural evidence of glomerular microangiopathy. Ultrastructural evidence of microangiopathy was also found in vasa nervorum. In 20 other cases of POEMS-associated renal disease, 16 had glomerular disease. Light-microscopy showed membranoproliferative-like glomerulopathy in 14 patients and glomerular microangiopathy in two. Ultrastructural evidence of microangiopathy was present in all 15 patients in whom electron-microscopy was done. Thus, in most patients with POEMS-associated glomerular disease a characteristic lesion is present with evidence of endothelial injury. As endothelial damage is also found in endoneural vessels, generalized endothelial injury may play a role in non-renal manifestations of POEMS syndrome. In previous reviews manifestations of the POEMS syndrome were similar for patients with or without myeloma. Among patients with biopsy-proven glomerular disease, however, myeloma patients are underrepresented. Whether this represents a sampling error or has true pathophysiological significance remains to be established.

Elevated serum levels of the atherogenic and thrombogenic lipoprotein (a) (Lp(a)) have been recognized as a feature of the nephrotic syndrome associated hyperlipidaemia. To examine a possible relationship between serum Lp(a) concentration and proteinuria, serum albumin, or blood pressure, we studied nine patients with nephrotic-range proteinuria both at baseline and after various forms of antihypertensive and antiproteinuric treatment. In fixed order, patients received conventional antihypertensive treatment (either alpha-methyldopa or clonidine), subsequently ACE-inhibition therapy (lisinopril), ACE inhibition combined with an NSAID (indomethacin), and finally NSAID plus conventional antihypertensive therapy. Measurements were performed at the end of each 2-month study period. When compared to controls (n = 29), proteinuric patients before treatment showed increased levels of total cholesterol, very-low and low-density lipoprotein (VLDL+LDL) cholesterol, triglycerides and apolipoprotein B (apoB), while high-density lipoprotein (HDL) HDL cholesterol was lower. Lp(a) was significantly higher in patients (107 (95% CI: 55-208) mg/l) as compared to controls (25 (13-49) mg/l, P < 0.01). Conventional antihypertensive treatment did not reduce proteinuria, while Lp(a) remained unaffected. ACE-inhibitor treatment lowered proteinuria, raised serum albumin, while La(a) tended to fall (-11 +/- 8%). Addition of an NSAID induced a further fall in proteinuria and a rise in serum albumin. Lp(a) now fell by 40 +/- 5% from baseline values (P < 0.01). Both serum total, HDL and VLDL+LDL cholesterol fell significantly. Finally, during subsequent single therapy with NSAID most parameters, including proteinuria and Lp(a), returned towards values obtained during single therapy with ACE inhibiton.(ABSTRACT TRUNCATED AT 250 WORDS)

The stimulatory effects of growth hormone (GH) and glucagon on renal function are well known, but it is uncertain whether these hormones are involved in the increase in renal function, characteristic of type 1 (insulin-dependent) diabetes mellitus. Therefore, the circulatory levels of GH and glucagon were measured in 10 type 1 diabetic patients with an elevated glomerular filtration rate (GFR130 ml min-1 1.73 m-2) and in 20 age and sex matched normofiltering patients (GFR ranging from 90-130 ml min-1 1.73 m-2). In the patients, fasting glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined using 125I-iothalamate and 131I-hippuran, respectively, during near-normoglycaemia. On a separate day, the levels of glucagon and GH were determined in the fasting basal state and after exercise. Multiple regression analysis disclosed that GFR was positively correlated with HbA1 (r2 = 0.18, p0.01), glucagon (r2 = 0.14, p0.03) as well as exercise-stimulated GH (r2 = 0.10, p0.05). ERPF was independently associated with HbA1 (r2 = 0.24, p0.005) and glucagon (r2 = 0.18, p0.01), whereas renal vascular resistance (RVR) was negatively correlated with stimulated GH (r2 = 0.18, p0.02). Kidney volume was positively correlated with HbA1 (r2 = 0.26, p0.001) and inversely with RVR (r2 = 0.16, p0.01), but not with glucagon or stimulated GH. The present study suggests that circulatory GH and glucagon play a contributory role in the renal haemodynamic changes in type 1 diabetes mellitus.

Role of elevated lecithin: Cholesterol acyltransferase and cholesteryl ester transfer protein activities in abnormal lipoproteins from proteinuric patients. Lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) are key factors in the esterification of free cholesterol, and the distribution of cholesteryl ester among lipoproteins in plasma. Alterations in these processes may play a role in the lipoprotein abnormalities associated with glomerular proteinuria. The activities of LCAT and CETP were measured using excess exogenous substrate assays in nine patients with nephrotic-range proteinuria and in 18 matched controls. The proteinuria-lowering effect of four weeks of angiotensin converting enzyme (ACE) inhibition with enalapril was also studied. Plasma very low lipoprotein and low density lipoprotein (VLDL and LDL) cholesterol, triacylglycerol and apolipoprotein B levels were significantly elevated in the patients compared with controls. High density lipoprotein (HDL) total cholesterol, free cholesterol, cholesteryl ester and the free cholesterol/cholesteryl ester ratio in HDL were lower. Total plasma apolipoprotein A1 was normal. Plasma LCAT and CETP activities were elevated in the patients by 30% (P < 0.01) and by 39% (P < 0.01), respectively, and were both inversely related to serum albumin. VLDL and LDL cholesterol levels were positively related to LCAT and CETP activities, whereas the HDL free cholesterol content was inversely related to LCAT activity. ACE inhibition resulted in a 40% reduction of proteinuria, a partial normalization of LCAT activity, and a decrease in VLDL and LDL cholesterol. In conclusion, elevated activities of LCAT and CETP may provide a mechanism that contributes to the low proportion of cholesterol in HDL relative to that in VLDL and LDL, as well as to the compositional changes of HDL seen in glomerular proteinuria. Such abnormalities could contribute to accelerated development of atherosclerosis in proteinuric states.

We conducted a 2-year prospective randomised study to investigate the effects of a linoleic-acid-enriched diet on albuminuria and lipid levels in Type 1 (insulin-dependent) diabetic patients with elevated urinary albumin excretion (overnight urinary albumin excretion rate between 10 and 200 μg/min). Thirty-eight patients were randomly assigned to increase dietary polyunsaturated: saturated fatty acids ratio to 1.0 by replacement of saturated fat with linoleic-acid-rich products (n=18, two dropouts, analysis was performed in n=16) or to continue their usual diet (n=20). The total fat and protein content of the diet was unaltered. Clinical characteristics, albuminuria, blood pressure, glomerular filtration rate, metabolic control and dietary composition were similar in the two groups at baseline. In the high linoleic acid diet group, linoleic intake rose from 7±4 to 11±2 energy % and polyunsaturated: saturated fatty acids ratio rose from 0.60±0.28 to 0.96±0.16 (p

Context The importance of the cholesteryl ester transfer protein (CETP) pathway in coronary disease is uncertain. Study of CETP genotypes can help better understand the relevance of this pathway to lipid metabolism and disease risk. Objective To assess associations of CETP genotypes with CETP phenotypes, lipid levels, and coronary risk. Data Sources Studies published between January 1970 and January 2008 were identified through computer-based and manual searches using MEDLINE, EMBASE, BIOSIS, Science Citation Index, and the Chinese National Knowledge Infrastructure Database. Previously unreported studies were sought through correspondence with investigators. Study Selection Relevant studies related principally to 3 common (TaqIB [rs708272], I405V [rs5882], and −629C>A [rs1800775]) and 3 uncommon (D442G [rs2303790], −631C>A [rs1800776], and R451Q [rs1800777]) CETP polymorphisms. Data Extraction Information on CETP genotypes, CETP phenotypes, lipid levels, coronary disease, and study characteristics was abstracted from publications, supplied by investigators, or both. Results Ninety-two studies had data on CETP phenotypes, lipid levels, or both in 113 833 healthy participants, and 46 studies had data on 27 196 coronary cases and 55 338 controls. For each A allele inherited, individuals with the TaqIB polymorphism had lower mean CETP mass (−9.7%; 95% confidence interval [CI], −11.7% to −7.8%), lower mean CETP activity (−8.6%; 95% CI, −13.0% to −4.1%), higher mean high-density lipoprotein cholesterol (HDL-C) concentrations (4.5%; 95% CI, 3.8%-5.2%), and higher mean apolipoprotein A-I concentrations (2.4%; 95% CI, 1.6%-3.2%). The pattern of findings was very similar with the I405V and −629C>A polymorphisms. The combined per-allele odds ratios (ORs) for coronary disease were 0.95 (95% CI, 0.92-0.99) for TaqIB, 0.94 (95% CI, 0.89-1.00) for I405V, and 0.95 (95% CI, 0.91-1.00) for −629C>A. Conclusions Three CETP genotypes that are associated with moderate inhibition of CETP activity (and, therefore, modestly higher HDL-C levels) show weakly inverse associations with coronary risk. The ORs for coronary disease were compatible with the expected reductions in risk for equivalent increases in HDL-C concentration in available prospective studies.

The activity of cholesteryl ester transfer protein is instrumental in the distribution of cholesteryl ester between lipoproteins in plasma. We measured the activity of cholesteryl ester transfer protein in plasma, designated cholesteryl ester transfer activity, as the rate of cholesteryl ester transfer between exogenous radiolabelled low-density and high-density lipoproteins. The effect of hypothyroidism on cholesteryl ester transfer activity was investigated in 13 athyreotic patients who were studied in the hypothyroid condition and in the euthyroid state, after they had received triiodothyronine supplementation for 33 to 67 days. During hypothyroidism plasma total cholesterol, very-low- plus low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, plasma triacylglycerol, apolipoprotein A1 and B were significantly higher than in the euthyroid state. Cholesteryl ester transfer activity was 15% lower during hypothyroidism (P less than 0.02), and an effect of treatment duration was observed. The changes in high-density lipoprotein total cholesterol (P less than 0.02), free cholesterol (P less than 0.001), triacylglycerol (P less than 0.05) and the free cholesterol/cholesteryl ester molar ratio in high-density lipoproteins (P less than 0.01) were inversely-related to the changes in cholesteryl ester transfer activity. We concluded that thyroid hormone is involved in the regulation of cholesteryl ester transfer protein activity, and that cholesteryl ester transfer protein activity may play a role in the alterations in high-density lipoprotein lipids observed in hypothyroidism.

A.V. Bergh, G.V. Berg, M. Schoorl, W. Sluiter, A.V. Vliet, E. Hoving, B. Szabo, J. Langendijk, B. Wolffenbuttel, R. Dullaart Radiation Oncology, University Medical Center Groningen, Groningen, Netherlands, Endocrinology, University Medical Center Groningen, Groningen, Netherlands, Radiology, University Medical Center Groningen, Groningen, Netherlands, Neurosurgery, University Medical Center Groningen, Groningen, Netherlands

Background: Despite advances in revascularisation techniques, limb salvage and relief of ischaemic pain cannot be achieved in many patients with diffuse peripheral disease. This is especially true in diabetic patients where occlusions show a predilection for distal vessels. Earlier findings suggest that IM delivery of a plasmid encoding VEGF can promote the development of blood vessels in ischaemic limbs. Our objective was to determine the effect of IM administration of phVEGF165 (VEGF gene containing plasmid; 2 mg on day 1 and 28) on CLI, compared to placebo (0.9 % NaCl).

Alimentary lipemia stimulates the transfer of cholesteryl ester between lipoproteins in vitro and may alter lipoprotein cholesteryl ester distribution in vivo. The effect of a single, large oral fat load on lipoprotein cholesteryl ester redistribution and the activity of cholesteryl ester transfer protein was investigated in six normolipidemic men (Group A), six combined hyperlipidemic men (Group B), and six hypercholesterolemic men (Group C). Fasting triglyceride-rich lipoprotein cholesteryl ester was high in Group B, low in Group A, and intermediate in Group C (A less than C less than B, p less than 0.05). After an oral fat load, total plasma cholesteryl ester was unchanged in all groups. In Group A, cholesteryl ester increased in smaller triglyceride-rich lipoproteins and remained so at 24 hours. Conversely, low density and high density lipoprotein cholesteryl ester decreased and returned to fasting values at 24 hours. In Group B, cholesteryl ester increased in large triglyceride-rich lipoproteins. Low density and high density lipoprotein cholesteryl ester (expressed as percentage of plasma cholesteryl ester) decreased. By contrast, in Group C, triglyceride-rich lipoprotein and low density lipoprotein cholesteryl ester remained unaltered, and only high density lipoprotein cholesteryl ester decreased. The activity of cholesteryl ester transfer protein increased in all groups and returned to fasting values at 24 hours. No differences in response were observed among the three groups. It is concluded that an oral fat load can induce a shift in lipoprotein cholesteryl ester distribution from high and low density lipoproteins to triglyceride-rich lipoproteins without affecting total plasma cholesteryl ester.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: We sought to determine whether concurrently high levels of HDL cholesterol and CRP predict initial cardiovascular events in women, and to assess additional risk involving two genes encoding proteins involved in reverse cholesterol transport.Methods: A graphical approach identified high-risk subgroups in a population-based female cohort. Polymorphism-associated risk was assessed for CETP (TaqIB [rs708272]) and LPL (D9N [rs1801177]) using multivariable analysis adjusted for clinical parameters and biomarkers.Results: A high HDL-C/high CRP high-risk subgroup was identified. Multivariable modeling revealed D9N as predicting subgroup cardiovascular disease risk directly (minor allele-carriers versus major allele homozygotes: HR 5.16, 95% CI 1.43-18.54, p = 0.012) and through interaction with TaqIB (highest risk in minor allele carriers of both polymorphisms).Conclusions: In women with high HDL-C and high CRP levels, an LPL polymorphism associated with risk and interacted with a CETP polymorphism such that the highest risk occurred in subjects with presumably decreased activities of both proteins. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

In Type 1 (insulin-dependent) diabetes mellitus, macrovascular complications and the increased risk for cardiovascular disease in patients with microvascular complications may be related to alterations in plasma cholesterylester transfer. The activity of cholesterylester transfer protein, which mediates cholesterylester transfer between lipoproteins and lipoprotein lipid levels, was assessed in 7 normolipidaemic control subjects, 7 Type 1 diabetic control subjects without complications, 11 Type 1 diabetic patients with microvascular complications (retinopathy, incipient nephropathy) and in 7 Type 1 diabetic patients with macrovascular atherosclerotic lesions. The cholesterylester transfer activity was 30% higher in the diabetic groups with macrovascular and microvascular lesions than in the 2 control groups. Very low + low density lipoprotein cholesterol was higher in the 3 diabetic groups than in the non-diabetic control group. High density lipoprotein cholesterol was not different. The cholesterylester transfer activity was correlated positively with HbA1, urinary albumin excretion rate, serum cholesterol, very low + low density lipoprotein cholesterol and apolipoprotein B. The high density lipoprotein over very low + low density lipoprotein cholesterylester molar ratio was lower in the diabetic groups with micro- and macrovascular complications. A role for cholesterylester transfer activity in the lipoprotein abnormalities found in complicated Type 1 diabetes is suggested. A high cholesterylester transfer activity might be indicative of mechanisms which promote atherogenesis.

The process of cholesterylester (CE) transfer is supposed to be a regulatory factor in the distribution of CE between lipoproteins. In addition to the activity of CE transfer protein, this process may be affected by acceptor lipoprotein characteristics. In this study the effect of the composition of different very low density lipoproteins (VLDL) and low density lipoproteins (LDL) on the ability to accept CE from HDL in vitro was investigated. [3H]-CE high density lipoprotein (HDL) (100 nmol CE) from one batch was incubated with VLDL (75 nmol CE), isolated from fifteen subjects for 4 h and separately with LDL (250 nmol CE), isolated from thirteen subjects for 16 h, both in the presence of lipoprotein-free plasma providing a source of cholesterylester transfer protein. The CE transfer rate of VLDL (range 1.34-2.84% [3H]-CE transferred h-1) was correlated to the triacylglycerol (TG):CE molar ratio (r: 0.63, P less than 0.05), to the phospholipid (PL):CE molar ratio (r: 0.75, P less than 0.01), to the protein (Pr):CE ratio (expressed in g nmol-1) (r: 0.72, P less than 0.01) and to the free cholesterol (FC):CE molar ratio (r: 0.69, P less than 0.01), but not to the FC:PL molar ratio (r: -0.08, NS). The CE transfer rate to LDL (range 1.18-3.59 nmol CE h-1) was correlated to the Pr:CE ratio (r: 0.72, P less than 0.01) and inversely to the FRC:PL molar ratio (r: -0.88, P less than 0.001), but not to the TG:CE molar ratio (r: 0.40, NS), nor to the FC:CE molar ratio (r: -0.37, NS).(ABSTRACT TRUNCATED AT 250 WORDS)

The relationships between serum lipid, apolipoprotein levels and urinary albumin excretion were investigated in 20 male Type 1 (insulin-dependent) diabetic patients with microalbuminuria (overnight urinary albumin excretion between 10 and 200 micrograms/min), in 18 male Type 1 diabetic patients without microalbuminuria and in 18 male control subjects. In the microalbuminuric patients low density lipoprotein cholesterol was higher than in the control subjects (p less than 0.05); the high density lipoprotein/low density lipoprotein cholesterol ratio was lower than in the normalbuminuric diabetic patients (p less than 0.05), and in the control subjects (p less than 0.01); apolipo-protein B was higher than in the normalbuminuric patients (p less than 0.05); the apolipoprotein A1/B ratio was lower than in the normoalbuminuric diabetic patients (p less than 0.05). Serum triglyceride was higher in the microalbuminuric diabetic patients and in the control subjects than in the normalbuminuric diabetic patients (p less than 0.05, for both), but was not different between the microalbuminuric diabetic patients and the control subjects. No significant differnces between the 3 groups were present with respect to serum cholesterol, high density lipo-protein cholesterol and apolipoprotein A1. In the 2 combined Type 1 diabetic groups there were significant correlations between urinary albumin excretion and the high density lipoprotein/low density lipoprotein cholesterol ratio (R -0.40, p less than 0.02), apolipoprotein B (R 0.35, p less than 0.05) and the apolipoprotein A1/B ratio (R -0.44, p les than 0.01). These results indicate microalbuminuria related differences in lipid and apolipoprotein levels in male Type 1 diabetic patients, which may contribute to an increased risk of cardiovascular disease.

Background The plasma renin activity (PRA) assay measures the ability of renin to generate angiotensin I (AngI) from angiotensinogen. It is used to monitor mineralocorticoid therapy and to screen hypertensive individuals for primary aldosteronism (PA). Methods Samples were incubated in the presence of protease inhibitors for 6.5 and 24 h. The reaction was stopped by the addition of 2% ammonium hydroxide. AngI was then quantified by liquid chromatography tandem mass spectrometry using online solid-phase extraction (XLC-MS/MS). Results This method requires a sample volume of 50 μL and has an inter-assay precision 2 = 0.98), but a 37% negative bias. We also found that renin is stable in whole blood for up to 24 h at room temperature. In contrast, storage at 4°C should be avoided as prorenin cryoactivation can affect the PRA result in some patient groups. Conclusions We have developed and fully validated a semi-automated XLC-MS/MS method for the measurement of PRA. In addition, a reference range specific to this assay has been defined. We have also demonstrated that renin is stable for up to 24 h at room temperature. This will enable this assay to be extended to samples taken in primary care, potentially increasing the number of hypertensive patients who can be screened for PA.