Serum aspirin esterase is strongly associated with glucose and lipids in healthy subjects: different association patterns in subjects with type 2 diabetes mellitus

<p>Abstract</p> <p>Background</p> <p>Aspirin esterase (AE) activity can account for part of aspirin pharmacokinetics in the circulation, possibly being associated with the impairment of aspirin effectiveness as an inhibitor of platelet aggregation.</p> <p>Aims</p> <p>The study was aimed at investigating the correlations of serum AE activity with cholinesterase (ChE) and metabolic variables in healthy subjects in comparison to subjects with type 2 diabetes mellitus (T2DM).</p> <p>Methods</p> <p>In cardiovascular disease-free T2DM subjects and healthy controls, the AE activity levels and/or the correlation patterns between AE and the other variables were analyzed.</p> <p>Results</p> <p>Neither AE nor ChE activities were higher in the subjects with T2DM. Serum AE activity strongly correlated with ChE as well as glucose/lipids variables such as total cholesterol and triglyceride in healthy subjects, while the correlations between AE and glucose/lipids variables were not present in T2DM subjects.</p> <p>Conclusions</p> <p>These data may reflect the pathophysiological changes between healthy and T2DM subjects. Our data may thus provide the basis for future studies to unravel the mechanisms.</p

Intracellular apoprotein B degradation is suppressed by decreased albumin concentration in Hep G2 cells

Intracellular apoprotein B degradation is suppressed by decreased albumin concentration in Hep G2 cells. It is generally accepted that hepatic secretion of apoprotein (apo) B-containing lipoproteins is substantially increased in nephrosis. To elucidate the mechanisms for the oversecretion of apo B, we investigated the effect of a various concentration of albumin on apo B kinetics in the absence or presence of oleate in Hep G2 cells. Hep G2 cells were labeled with [3H]-leucine in leucine-free medium containing 0, 1.5, 3.0 or 4.5% BSA for 180 minutes, and the secreted radiolabeled apo B, apo Al and albumin were isolated by immunoprecipitation and counted. The secretions of apo B and albumin were suppressed by BSA (bovine serum albumin) in a dose-dependent manner, but the secretion of apo Al was not suppressed significantly. Oleate (0.4mM) increased the rate of apo B secretion by 2.5-fold when oleate was bound to 1.5% BSA, but at higher concentrations of BSA (3.0 or 4.5%), apo B secretion was less responsive to oleate. A pulse-chase study indicated that early apo B degradation was significantly suppressed in cells incubated with lower concentrations of BSA (0 or 1.5% BSA), thereby rapidly stimulating apo B secretion. Oleate (0.4mM) potently inhibited apo B degradation when oleate was bound to 1.5% BSA, whereas the inhibition was not observed when oleate was bound to 4.5% BSA. Intracellular albumin synthesis was stimulated in BSA-free medium, but intracellular decay of albumin was essentially unaffected by concentration of BSA. Similar to BSA, a higher concentration of dextran (3.0 or 4.5%) reduced apo B secretion, and this was the result of increased early apo B degradation in the cells. These results indicate that reduced albumin suppresses intracellular apo B degradation, and the inhibition of apo B degradation by oleate is manifested only at a low concentration of albumin. Therefore, the present study suggests that free fatty acids bound to low concentration of albumin in the circulating plasma play an important role on hepatic oversecretion of apo B-containing lipoprotein in hypoalbuminemic state, such as nephrotic syndrome

Egyptian glycogen storage disease type III – identification of six novel AGL mutations, including a large 1.5 kb deletion and a missense mutation p.L620P with subtype IIId

Background: Glycogen storage disease type III (GSD III) is caused by mutations in AGL which encodes for a single protein with two enzyme activities: oligo-1, 4-1, 4-glucantransferase (transferase) and amylo-1, 6-glucosidase. Activity of both enzymes is lost in most patients with GSD III, but in the very rare subtype IIId, transferase activity is deficient. Since the spectrum of AGL mutations is dependent on the ethnic group, we investigated the clinical and molecular characteristics in Egyptian patients with GSD III. Methods: Clinical features were examined in five Egyptian patients. AGL was sequenced and AGL haplotypes were determined. Results: Six novel AGL mutations were identified: a large deletion (c.3481–3588+1417del1525 bp), two insertions (c.1389insG and c.2368insA), two small deletions (c.2223–2224delGT and c.4041delT), and a missense mutation (p.L620P). p.L620P was found in a patient with IIId. Each mutation was located on a different AGL haplotype. Conclusions: Our results suggest that there is allelic and phenotypic heterogeneity of GSD III in Egypt. This is the second description of a large deletion in AGL. p.L620P is the second mutation found in GSD IIId. Clin Chem Lab Med 2009;47:1233–8.Peer Reviewe

VLDL Triglyceride Kinetics in Wistar Fatty Rats, An Animal Model of NIDDM: Effects of Dietary Fructose Alone or in Combination With Pioglitazone

The effects of dietary fructose alone or in combination with a new oral agent, pioglitazone, on VLDL-triglyceride (TG) turnover were studied in genetically obese Wistar fatty rats characterized by hyperinsulinemia (7,488 ± 954 pmol/l), hyperglycemia (22.5 ± 1.4 mmol/l), and hypertriglyceridemia (4.39 ± 0.54 mmol/l). They had an increased hepatic TG production (16.2 ± 0.1 μmol/min; lean rats, 5.4 ± 0.3 μmol/min) as well as a longer half-life of VLDL-TG from lean donors (8.8 ± 1.4 min, lean recipients; 2.3 ± 0.9 min). In addition, in lean recipients, the half-life of VLDL-TG from fatty donors was longer than that from lean donors (4.80 ± 0.56 vs. 3.14 ± 0.23 min). Although feeding fructose into fatty rats did not change plasma glucose and insulin levels, it produced a twofold increase in TG levels (8.74 ± 1.15 mmol/l). This was associated with a 1.7-fold increase in TG production to 27.5 ± 1.2 μmol/min, while no significant change was found in the half-life of lean VLDL-TG in fructose-fed fatty recipients (10.9 ± 2.4 min) or in that of VLDL-TG from fructose-fed fatty donors in lean recipients (4.46 ± 0.76 min). Daily administration of pioglitazone (3 mg/kg body weight) in fructose-fed fatty rats ameliorated glycemia and triglyceridemia to the level of lean rats (8.1 ± 0.7 and 1.18 ± 0.05 mmol/l, respectively) and insulinemia to a lesser extent (2,712 ± 78 pmol/l). A fall in TG levels was associated with improvement of an impairment in the ability of fructose-fed fatty rats to remove lean VLDL-TG (half-life: 2.6 ± 0.6 min). Pioglitazone, however, produced no change in TG production (25.9 ± 2.7 μmol/min), the half-life of VLDL-TG from fructose-fed fatty donors in lean recipients (4.17 ± 0.38 min), or the activity of lipoprotein lipase and hepatic lipase in postheparin plasma. We conclude that in Wistar fatty rats 1) hypertriglyceridemia is attributed to TG overproduction and impaired TG catabolism, and the latter is due to changes in both VLDL, such that they are less able to be removed, and changes in the nature of Wistar fatty rats, such that they are less able to remove VLDL-TG; 2) fructose further increases hepatic TG production with a resultant deterioration in hypertriglyceridemia; 3) pioglitazone normalizes TG levels by altering the physiology of the Wistar fatty rats in a manner that increases their ability to remove VLDL-TG from the circulation.</jats:p

Molecular features of 23 patients with glycogen storage disease type III in Turkey: a novel mutation p.R1147G associated with isolated glucosidase deficiency, along with 9 AGL mutations.

Glycogen storage disease type III (GSD III) is an autosomal recessive disorder caused by deficiency in the glycogen debranching enzyme (gene symbol: AGL) with two enzyme activities: transferase and glucosidase. A missense mutation causing isolated glucosidase deficiency has never been reported. In this study, we examined 23 patients of Turkish ancestry and identified a novel missense mutation p.R1147G with isolated glucosidase deficiency, along with nine AGL mutations: six nonsense mutations (p.W373X, p.R595X, p.Q667X, p.Q1205X, p.W1327X and p.Q1376X), one deletion (c.1019delA) and two splicing mutation (c.293+2T > G and c.958+1G > A). As p.R1147G impaired glucosidase activity, but maintained transferase activity in vitro, a 12-year-old girl homozygous for p.R1147G was diagnosed with having isolated glucosidase deficiency. Of nine other mutations, p.W1327X and c.1019delA were recurrent, whereas seven mutations were novel. Six patients with p.W1327X were all from two nearby cities on the East Black Sea and shared the same AGL haplotype, indicating a founder effect in Turkish patients. Patients with the same mutations had identical haplotypes. Our results provide the first comprehensive overview of clinical and molecular features of Turkish GSD III patients and the first description of the missense mutation associated with isolated glucosidase deficiency. Journal of Human Genetics (2009) 54, 681-686; doi:10.1038/jhg.2009.100; published online 16 October 200