Influence of endogenous hyperinsulinism on high density lipoprotein2 level in type 2 (non-insulin-dependent) diabetes mellitus and impaired glucose tolerance

We determined the insulin response to an oral glucose ingestion and levels of serum lipoproteins in 25 untreated patients with type 2 diabetes mellitus, in 26 subjects with impaired glucose tolerance (IGT), and in 35 non-diabetic control subjects. The three groups had similar compositions with respect to age and sex distribution. The levels of VLDL triglycende in the subjects with type 2 diabetes or IGT were higher than those in controls. Serum HDL- and HDL₂ cholesterol were significantly decreased in type 2 diabetics, and the subjects with IGT showed a similar tendency. Serum apolipoprotein A-II levels were lower in the male subjects with type 2 diabetes or IGT than in controls. Insulin reponse, i.e., sum of immunoreactive insulin (IRI) levels at basal, 30, 60, 90 and 120 min after a 75-g oral glucose load, negatively correlated to HDL and HDL₂ cholesterol levels (r = −0.396, P < 0.05; r = −0.482, P < 0.001, respectively), and positively correlated to VLDL triglyceride values (r = 0.485, P < 0.001) in the male subjects with type 2 diabetes or IGT. In the female subjects, fasting plasma IRI values significantly correlated to HDL cholesterol (r = −0.496, P < 0.05). There was a significant negative correlation between the concentrations of HDL₂ cholesterol and VLDL trgglyceride. These data show that lipoprotein metabolism, not only in type 2 diabetics, but also in IGT tends to show changes such as decreased HDL₂ cholesterol and increased VLDL triglyceride levels, and which might be related to the hypersecretion of endogenous insulin.     

The effect of bezafibrate on very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and low density lipoprotein (LDL) composition in type 1 diabetes associated with hypercholesterolaemia or combined hyperlipidaemia.

Lipoprotein composition was examined in type 1 diabetic subjects with hypercholesterolaemia +/- hypertriglyceridaemia during a 3-month double-blind placebo controlled assessment of bezafibrate therapy. The predominant effect was on lipoprotein lipid content. In those with hypercholesterolaemia alone, bezafibrate significantly reduced the cholesterol (particularly esterified cholesterol) and triglyceride content of large very low density lipoprotein (VLDL) (Svedberg flotation units (Sf) 60-400) in comparison to the placebo group (P less than 0.05), and a trend towards a reduction in free and esterified cholesterol within the intermediate density lipoprotein fraction (IDL) (Sf 12-20) was noted. Low density lipoprotein (LDL) composition was unaltered and in general phospholipid and protein concentrations and cholesteryl ester/protein ratios within the lipoprotein fractions were unaffected. Large VLDL cholesterol and triglyceride concentrations in those with combined hyperlipidaemia were significantly decreased following bezafibrate therapy, both in comparison to placebo-treated subjects and to baseline concentrations (P less than 0.05). An additional significant reduction in small VLDL (Sf 20-60) free cholesterol was recorded (P less than 0.05). Average reductions of large and small VLDL protein of 50-56% were not significant because of wide variation in responses. Bezafibrate had no effect on the abnormal composition of IDL and LDL, characteristic of Type 1 diabetes, regardless of whether or not hypertriglyceridaemia was associated with hypercholesterolaemia. Its major action was to lower VLDL lipid concentrations, but it may also reduce the lipid content of intermediate density lipoprotein in Type 1 diabetes.     

Unique character and metabolism of high density lipoprotein (HDL) in fetus

Lipid and lipoprotein profiles, and enzymes for the lipid metabolism were compared between cord and adult blood. Consistent with previous reports, the major lipoprotein in cord blood was high-density lipoprotein (HDL), and that in adult blood was low-density lipoprotein (LDL). The level of apolipoprotein E (apo E) in cord blood was almost equivalent to that in adult blood, while other apolipoproteins and lipids were all lower than the adult level. In cord blood, apo E-rich HDL cholesterol represented more than 30% of total HDL cholesterol (around 11% in adult), and the concentration was about twice of that in adult blood. This apo E-rich HDL cholesterol was poorly esterified (E/T 56%) compared with that in adults (93%). The lecithin:cholesterol acyltransferase (LCAT) activity in cord blood was extremely low, while the activity and mass of cholesteryl ester transfer protein (CETP) were higher than those in adult blood. The apo E genotype did not show influences on total cholesterol, LDL cholesterol, total HDL cholesterol, and apo E rich HDL cholesterol levels in cord blood, as opposed to those in adult blood. The association of D442G mutation of the CETP gene with the increased HDL cholesterol in adult blood was not seen in cord blood. Rather, the mutation was associated with low total cholesterol and LDL cholesterol levels in cord blood. These results indicate that, in fetus, the character and metabolism of HDL, especially of apo E-rich HDL cholesterol, are distinct from those in adults.     

Low density lipoprotein (LDL) modification: basic concepts and relationship to atherosclerosis.

A large number of clinical studies support the hypothesis that the risk for atherosclerosis is associated with the proportion of different LDL subfractions in blood. Electronegatively modified forms of LDL (LDL(-)) isolated using different chromatographic techniques are characterised by significant differences in the protein and lipid content as compared to the native LDL subfraction. LDL(-) composition appears to influence its atherogenic properties as well as its high susceptibility to oxidation and impaired metabolism. Increased LDL(-) levels are found in subjects with coronary artery disease, particularly in diabetics and patients undergoing haemodialysis (HD). Whether elevated LDL(-) levels are due to the LDL oxidation in blood remains disputed despite the oxidative character of LDL(-) modification. Plausible means for LDL(-) formation in blood include glycation and protein-radical interactions with ApoB 100. The latter can prevail during HD as observed in in vitro studies using a model HD system. The rapid and progressive formation of LDL(-) during standard HD can be significantly reduced employing haemolipodialysis (HLD), which provides local delivery of specific antioxidants (vitamin E and C) to blood at concentrations above normal physiologic levels. This procedure appears to be more effective than oral supplementation with antioxidants and may be a promising approach to reducing the rapid progression of atherosclerosis in HD patients.     

Insulin‐secretion capacity in normal glucose tolerance,impaired glucose tolerance,and diabetes in obese and non‐obese Japanese patients

Aims/Introduction: Pronounced reduction of insulin secretion in response to a rise in glucose level has been reported in Japanese patients compared with Caucasian patients, but the mean body mass index (BMI) is also lower in Japanese patients. As BMI is a determinant of insulin secretion, we examined insulin‐secretion capacity in obese and non‐obese Japanese patients. Materials and Methods: Using the oral glucose tolerance test (OGTT), we estimated the insulin‐secreting capacity in obese (BMI ≥ 25) and non‐obese (BMI < 25) Japanese patients, including 1848 patients with normal glucose tolerance (NGT), 321 patients with impaired glucose tolerance (IGT) and 69 diabetes (DM) patients. Results: The insulinogenic index (I.I.), calculated by dividing the increment in serum insulin by the increment in plasma glucose from 0 to 30 min during OGTT, decreased from NGT to IGT and to DM in patients with and without obesity. In patients with NGT, IGT and DM, the I.I. values of obese patients were higher than those of the non‐obese patients. The peak of insulin concentration in OGTT appeared at 60 min in NGT and at 120 min in IGT in both obese and non‐obese patients, but in DM it was observed at 120 min in obese patients and at 60 min in non‐obese patients. Conclusions: These results show that early‐phase insulin secretion in obese Japanese patients is higher than in non‐obese patients in all stages of glucose tolerance, and delayed insulin‐secretion capacity is also conserved in obese Japanese patients, even in IGT and DM, which is similar to Caucasian patients. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00180.x , 2011)     

Association of low density lipoprotein receptor related protein-associated protein (LRPAP1) gene insertion/deletion polymorphism with gallstone disease

BACKGROUND AND AIM: Gallstones are byproducts of cholesterol supersaturated bile. Various studies have indicated that there might be a genetic predisposition to the disease. Receptor-associated protein (RAP) is a molecular chaperone for low density lipoprotein receptor-related protein (LRP), which plays a key role in cholesterol metabolism. Intron 5 insertion/deletion polymorphism of RAP gene (LRPAP1) has been implicated in other diseases sharing etiology with gallstone disease (GSD). METHODS: To analyze the association of insertion/deletion polymorphism in GSD, 130 gallstone patients and 202 healthy subjects took part in the present study. For genotyping, polymerase chain reaction was followed by 2% agarose gel electrophoresis. RESULTS: The results showed that frequencies of D and I allele were 65.77% and 34.23% in patients, 76.24% and 23.76% in controls, respectively. Frequency of I allele was significantly higher in the patient group than in the control group (P = 0.003). CONCLUSION: In the present study I (insertion) allele was found to be associated with GSD.     

Low density lipoprotein cholesterol, lipoprotein(a), and apo(a) isoforms in the elderly: relationship to fasting insulin. Associazione Medica Sabin

BACKGROUND AND AIM: Insulin resistance/hyperinsulinemia are often associated with aging and could play an important role in the development of glucose intolerance and dyslipidemia in the elderly. We investigated the relationship between plasma fasting insulin with total cholesterol (TC) and low density lipoprotein LDL cholesterol (LDL-C), triglycerides (TG), lipoprotein(a) [Lp(a)] levels apolipoprotein (a) [apo (a)] isoforms in 100 free-living "healthy" octo-nonagenarians. METHODS AND RESULTS: Fasting insulin was positively correlated with TG, whereas a negative relation was found with TC and LDL-C (r = -0.29 and r = -0.28 respectively; p < 0.01), LDL-C/apo B, HDL-C and apo A-I levels. Fasting insulin was also inversely correlated with Lp(a) levels (r = -0.22; p < 0.03), whereas the latter were significantly related with TC and LDL-C (r = 0.30 and r = 0.31; p < 0.005), TG (r = 0.21; p < 0.05) and apo B (r = 0.26; p < 0.02). There was a negative relation between Lp(a) levels and apo(a) isoforms: the greater the apo(a) molecular weight, the lower the Lp(a) level (p < 0.0001). Fasting insulin increased with apo(a) size, though the difference in insulin levels among apo(a) isoforms was not significant (p = 0.4). Multiple regression analysis showed that fasting insulin was the best predictor of LDL-C (R2 = 0.14; p = 0.002) irrespective of age, gender, BMI, waist circumference and TG, while apo(a) isoform size, BMI and waist circumference were related with Lp(a) irrespective of TC and LDL-C, TG and apo B (R2 = 0.35 to 0.37; p < 0.0001). CONCLUSIONS: These results suggest that fasting insulin levels significantly influence LDL-C metabolism in old age. Lp(a) levels seem to be very strongly related to genetic background, although an indirect relation with insulin through adiposity and/or other associated lipid abnormalities cannot be ruled out.     

Antibodies to apolipoprotein A‐I,high‐density lipoprotein,and C‐reactive protein are associated with disease activity in patients with systemic lupus erythematosus

Objective

Inflammatory disease activity in patients with systemic lupus erythematosus (SLE) may affect the development of atherosclerosis, contributing to their increased risk of cardiovascular disease (CVD). This process may be mediated by anti–apolipoprotein A‐I (anti–Apo A‐I), anti–high‐density lipoprotein (anti‐HDL), and anti–C‐reactive protein (anti‐CRP) autoantibodies. We undertook this study to examine whether levels of these antibodies rise in association with increased SLE disease activity.

Methods

IgG anti–Apo A‐I, anti‐HDL, and anti‐CRP levels were measured in serum from the following groups: 39 patients with persistently high disease activity (British Isles Lupus Assessment Group [BILAG] A or B score) over the previous 2 years, 42 patients with persistently low disease activity (no BILAG A or B scores) over the previous 2 years, 34 healthy controls, 25 individual patients from whom paired samples (at time of disease flare and quiescence) were obtained and compared, 16 patients with newly diagnosed lupus nephritis from whom multiple samples were obtained and who were followed up prospectively for up to 2 years, and 24 patients with SLE who had experienced CVD events.

Results

Serum levels of IgG anti–Apo A‐I, anti‐HDL, and anti‐CRP were higher in patients with SLE than in controls. Anti–Apo A‐I and anti‐HDL levels, but not anti‐CRP levels, were higher in patients with persistently high disease activity than in those with low disease activity. Mean levels of the 3 autoantibodies in patients who had experienced CVD events lay between the mean levels in the high and low disease activity groups. Only levels of anti–Apo A‐I were significantly higher in samples obtained from individual patients during disease flares than in samples obtained during disease quiescence. In the lupus nephritis patients, anti–Apo A‐I and anti‐HDL levels correlated with serum levels of high avidity IgG anti–double‐stranded DNA.

Conclusion

Persistent disease activity is associated with a significant increase in IgG anti–Apo A‐I and anti‐HDL in patients with SLE.