Ana M. Wägner

The inflammatory properties of electronegative low-density lipoprotein from type 1 diabetic patients are related to increased platelet-activating factor acetylhydrolase activity

Aims/hypothesisChemical and biological characteristics of LDL(−) from type 1 diabetic subjects were analysed. The diabetic patients were studied during poor and optimised glycaemic control.Materials and methodsTotal LDL was subfractionated into electropositive LDL(+) and electronegative LDL(−) by anion exchange chromatography and the lipid and protein composition of the two determined.ResultsLDL(−) differed from LDL(+) in that it had higher triglyceride, non-esterified fatty acids, apoE, apoC-III and platelet-activating factor acetylhydrolase (PAF-AH), as well as lower apoB relative content. No evidence of increased oxidation was observed in LDL(−). LDL(−) increased two-fold the release of interleukin 8 (IL-8) and monocyte chemotactic protein 1 (MCP-1) in endothelial cells, suggesting an inflammatory role. Optimisation of glycaemic control after insulin therapy decreased the proportion of LDL(−), but did not modify the composition of LDL subfractions, except for a decrease in PAF-AH activity in LDL(−). The possibility that LDL(−) could be generated by non-enzymatic glycosylation was studied. Fructosamine and glycated LDL content in LDL subfractions from type 1 diabetic patients was greater than in LDL subfractions isolated from normoglycaemic subjects, and decreased after glycaemic optimisation in both subfractions. However, no difference was observed between LDL(+) and LDL(−) before and after insulin therapy.Conclusions/interpretationThese results provide evidence that LDL(−) is not produced by glycosylation. Nevertheless, LDL(−) from diabetic patients displays inflammatory potential reflected by the induction of chemokine release in endothelial cells. This proatherogenic effect could be related to the high PAF-AH activity in LDL(−).

LDL-cholesterol/apolipoprotein B ratio is a good predictor of LDL phenotype B in type 2 diabetes

Abstract. LDL phenotype B is a component of diabetic dyslipidaemia, but its diagnosis is cumbersome. Our aim was to find easily available markers of phenotype B in a group of type 2 diabetic subjects. We studied 123 type 2 diabetic patients (67.5% male, aged 59.3±10.1 years, mean HbA1c 7.4%). Clinical features and fasting total cholesterol, triglyceride, HDL cholesterol, LDL cholesterol (LDLc, using Friedewalds equation and an alternative formula), apolipoprotein B (apoB), lipoprotein (a) and LDL particle size (on gradient polyacrylamide gel electrophoresis) were assessed. Patients with phenotypes A (predominant LDL size ≥25.5 nm) and B (<25.5 nm) were compared, and regression analysis was performed to find the best markers of LDL particle. Cut-off points were obtained and evaluated as predictors of phenotype B (kappa index). Patients with phenotype B (36%) showed higher total cholesterol, triglyceride and apolipoprotein B, and lower HDL cholesterol and LDLc/apoB ratio. Triglyceride was the best predictor of LDL particle size (r=−0.632, p<0.01), but an LDLc/apoB ratio below 1.297 mmol/g detected phenotype B best (sensitivity n65.9%, specificity 92.4%, kappa=0.611). Although triglyceride concentration is the best predictor of LDL size in type 2 diabetes, LDLcholesterol/apolipoproteinB ratio is the best tool to detect phenotype B.

Deleterious effects of glucocorticoid replacement on bone in women after long-term remission of Cushing's syndrome.

Endogenous hypercortisolism and high‐dose and long‐term glucocorticoid (GC) therapy reduce bone mass. Patients in remission after successful treatment of Cushings syndrome (CS) often present hypoadrenalism and require long‐term GC replacement. The aim of our study was to evaluate whether this GC “replacement” had any further effect on bone in women after long‐term remission of CS. Thirty‐seven women (mean age: 50 ± 14 yr; 27 of pituitary and 10 of adrenal origin) with cured CS (mean time of cure: 11 ± 6 yr), 14 with active CS, and 85 sex‐, body mass index (BMI)‐, and age‐matched controls were enrolled. BMD and BMC were measured by DXA scanning. Bone biochemical markers were also measured. Duration and dose of GC replacement and duration of endogenous hypercortisolism were calculated. Cured and active CS patients had less BMC, BMD, and osteocalcin than controls (p < 0.01). These differences were observed in estrogen‐sufficient women but not in those with estrogen deficiency. Duration of GC treatment (mean: 42 mo; range, 2–420 mo) and endogenous hypercortisolism (mean: 70 mo; range, 13–241 mo) negatively correlated with BMC and lumbar spine BMD. After regression analysis, the main predictor of abnormal BMC and BMD was the duration of GC replacement (p < 0.01). Patients treated for CS persistently have less bone mass despite long‐term cure. Both duration of endogenous hypercortisolism and mainly exogenous “replacement” therapy with GC negatively affect bone mass. Thus, the additional deleterious effect of GC for the treatment of adrenal axis suppression should be considered.

Electronegative low-density lipoprotein subfraction from type 2 diabetic subjects is proatherogenic and unrelated to glycemic control

The physicochemical and biological characteristics of electronegative low‐density lipoprotein (LDL) (LDL(−)) from type 2 diabetic patients (DM2), before and after insulin therapy, were studied.

Effect of improving glycemic control on low-density lipoprotein particle size in type 2 diabetes

The current study sought to assess the effect of improving glycemic control in type 2 diabetes on the components of diabetic dyslipidemia, especially low-density lipoprotein (LDL) size. A total of 33 type 2 diabetic patients (48.5% women, age 59.6 +/- 11.1 years, body mass index [BMI] 28.9 +/- 4.9, diabetes duration 6 [0 to 40] years, 40.7% on insulin) were seen at the hospital because of poor glycemic control (hemoglobin A(1c) [HbA(1c)] 10.33% +/- 1.89%). Triglyceride, LDL-cholesterol (LDLc, Friedewald/ ultracentrifugation), high-density lipoprotein HDL-cholesterol (HDLc, direct method), apolipoproteins AI (apoAI) and B (apoB) (immunoturbidimetry), and LDL size (gradient gel electrophoresis) were measured at baseline and after improvement in glycemic control (decrease >/= 1 percentage point in HbA(1c) and final HbA(1c) </= 8%). Improvement in glycemic control (HbA(1c) 7.01% +/- 0.63%, P <.0005 v baseline) after a follow-up of 3.5 (range, 1 to 13) months resulted in a significant reduction in LDLc (3.34 +/- 1.02 v 3.62 +/- 1.15 mmol/L, P <.05) and apoB (1.07 +/- 0.25 v 1.17 +/- 0.29 g/L, P <.01) and an increase in HDLc (1.21 +/- 0.32 v 1.13 +/- 0.34 mmol/L, P <.05) and apoAI (1.36 +/- 0.24 v 1.27 +/- 0.24 mmol/L, P < 0.01) in the whole group, and an increase in LDL particle size (25.61 +/- 0.53 v 25.10 +/- 0.31 nm, P <.005) in the 14 patients showing LDL phenotype B at baseline. No significant changes were seen in body weight or BMI. We conclude that improvement of glycemic control in type 2 diabetes improves most of the components of diabetic dyslipidemia, including a shift towards larger LDL particles in subjects with phenotype B.

Gender dimorphism in body composition abnormalities in acromegaly: males are more affected than females

BACKGROUNDnAcromegaly changes body composition (BC), but long-term gender differences have not been reported.nnnOBJECTIVEnTo evaluate BC in active and controlled acromegalic patients.nnnDESIGN AND METHODSnClinical and biochemical variables and BC (by dual-energy X-ray absorptiometry) were evaluated in 60 acromegalic patients (19 active, 41 controlled) and 105 controls, matched for age and gender.nnnRESULTSnAcromegalic males (n=24) had more total mass (89+/-13 vs 76.5+/-15.3 kg, P<0.001), lean body mass (LBM; 64.6+/-8.7 vs 56.4+/-5.8 kg, P<0.001), and bone mineral content (BMC; 2.9+/-0.5 vs 2.6+/-0.3 kg, P<0.05) than controls (n=33). Controlled male patients (n=14) had more total mass (89+/-14.7 vs 76.5+/-15.3 kg, P<0.05) and a trend to have more LBM (61.8+/-9.4 vs 56.4+/-5.8 kg, P=0.065) than controls. Only in active disease was a decrease in fat mass (FM) observed, compared with controlled patients and controls (males: 19.5+/-5.3 vs 27+/-6.2 and 25.9+/-4%, P<0.001; females: 30.3+/-6.7 vs 37.1+/-5.8 and 36.5+/-6.6%, P<0.01). In females, no further differences were observed. No differences in BMC were found between eugonadal and hypogonadal acromegalic patients, but in hypogonadal females, acromegaly appeared to prevent the BMC loss seen in hypogonadal postmenopausal controls. GH and IGF1 levels were negatively correlated with FM (males, P<0.05; females, P<0.001), but in the regression analysis GH was a predictor of FM only in women.nnnCONCLUSIONSnControl of acromegaly reverts decreased FM in both genders; only in males more total mass and a trend for more LBM persist. The anabolic effect of GH on bone reverted in cured males, but persisted in females and appeared to override the bone loss of menopause.

Effect of statin and fibrate treatment on inflammation in type 2 diabetes. A randomized, cross-over study

A randomized, crossover study compared the effects of atorvastatin, gemfibrozil and their combination on inflammatory markers in type 2 diabetes. C-reactive protein (CRP), lipoprotein-associated phospholipase A2 (Lp-PLA2), secretory phospholipase A2 (sPLA2), interleukin 8 (IL8), monocyte chemotactic protein 1 (MCP1) and tumor necrosis factor α (TNFα) were measured. Both lipid-lowering drugs had positive, complementary and additive effects on inflammatory markers, which were closely related to baseline inflammatory status.

The effect of VLDL particles on the accuracy of a direct LDL-cholesterol method in type 2 diabetic patients.

OBJECTIVEnTo assess the accuracy of the direct method LDL-c Plus, in type 2 diabetic patients.LDL-c Plus was measured in 64 consecutive samples of type 2 diabetic patients and compared with betaquantification (BQ), Friedewalds and an alternative formula.nnnMETHODSnLDL-c Plus was also measured in the VLDL (d<1.006 Kg/L) fraction of these samples and in total serum and the VLDL fraction of a phenotype III patient, before and after diluting it with saline or VLDL from normolipidemic subjects.nnnRESULTSnLDL-c Plus showed a significant, constant bias (-8.5 +/- 5.6%) against BQ which correlated with VLDL-cholesterol/total triglyceride ratio (r = 0.760, p < 0.0005); bias decreased to zero when the ratio increased. In the VLDL fraction of the diabetic patients and the phenotype III patient LDL-c Plus measured 20.7 +/- 11.6% and 56.2% of the cholesterol, respectively. Dilution with saline did not alter the latter percentage, whereas dilution with normolipidemic VLDL reduced it showing that LDL-c Plus recognized cholesterol-enriched particles in the d<1.006 Kg/L. Friedewalds formula also showed a significant, constant bias (-3.1 +/- 6.4%) against BQ, whereas the alternative formula did not (0.5 +/- 6.1%). Both calculations classified patients better than LDL-c Plus did at NCEP cut-off points.nnnCONCLUSIONSnIn type 2 diabetic patients, LDL-c Plus underestimates LDL-c but measures cholesterol associated to IDL particles in the d<1.006 Kg/L fraction. Although LDLc-Plus might be a better cardiovascular risk estimator when well standardized, at the moment, it does not seem to be superior to calculations.

Postprandial lipidemia is normal in non-obese type 2 diabetic patients with relatively preserved insulin secretion.

To assess postprandial lipidemia in normotriglyceridaemic type 2 diabetic patients treated with diet only, 12 non-obese patients (8 males, hemoglobin A(1c) [HbA(1c)] 6.80 +/- 0.67%) and 14 controls of similar age, body mass index (BMI), and fasting triglyceride (Tg) were given a test meal (58 g fat, 100,000 IU vitamin A). Fasting low-density lipoprotein (LDL) cholesterol (LDLc), high-density lipoprotein (HDL) cholesterol (HDLc), free fatty acids, and apolipoprotein B (apoB), and fasting and postprandial Tg, retinylpalmitate (RP), LDL size, glucose, and insulin were measured. The homeostasis assessment model (HOMA) index and lipoprotein (Lpl) and hepatic (HL) lipase activities were estimated. Patients showed lower fasting HDLc (1.12 +/- 0.26 v 1.40 +/- 0.28 mmol/L, P =.02) and a trend towards smaller LDL particles, which was significant 4 hours postprandially (25.86 +/- 0.40 v 26.16 +/- 0.30 nm, P =.04). The area under the curve of Tg (AUC-Tg) and RP, and Lpl were similar, but HL was higher in patients (156.63 +/- 23.89 v 118 +/- 43.27 U/L, P =.011). HL correlated inversely with LDL size and directly with the HOMA index. In conclusion, normotriglyceridemic type 2 diabetic patients with insulin resistance but relatively preserved insulin secretion show low fasting HDLc and increased HL, but normal postprandial lipidemia.

Apo(B)-dependent dyslipidemic phenotypes in type 1 diabetic patients

BACKGROUNDnThe prevalence of apo(B)-dependent dyslipidemic phenotypes, which are associated with cardiovascular disease, is increased in normocholesterolemic type 2 diabetic patients. Our aim was to determine the impact of including apo(B) in the evaluation of normocholesterolemic type 1 diabetic patients.nnnMETHODSnA total of 123 type 1 diabetic patients (47% male, age 36.6+/-12.5 years) were included. The apo(B) cut-off point (1.14 g/l) was obtained from a group of 53 normolipidemic control subjects of similar age and gender distribution; for low density lipoprotein cholesterol (LDLc), triglycerides, and high density lipoprotein cholesterol (HDLc), we used the cut-off points recommended by the National Cholesterol Education Program. LDLc was determined by ultracentrifugation or Friedewalds equation, depending on triglyceride concentrations, and apo(B) by immunoturbidimetry.nnnRESULTSnA total of 113 (92%) type 1 diabetic patients were normocholesterolemic, and 13% of these were dyslipidemic. The frequency of hyperapo(B) was similar in normocholesterolemic patients and controls (6.2 vs. 9.4%, respectively). Diabetic patients with hyperapo(B) had poorer glycemic control, higher total cholesterol, triglycerides, and LDLc, and a lower HDLc and LDLc/apo(B) ratio.nnnCONCLUSIONSnUnlike type 2 diabetes, type 1 diabetes is not associated with an increased prevalence of hyperapo(B)-dependent dyslipidemic phenotypes. Thus, only in patients with poor glycemic control who display other components of diabetic dyslipidemia, typical for type 2 diabetes, does determining apo(B) concentrations provide additional information in type 1 diabetes.