Title: The effect of sensitisation to insulin with pioglitazone on fasting and postprandial lipid metabolism, lipoprotein modification by lipases, and lipid transfer activities in type 2 diabetic patients Al Majali K, Cooper MB, Staels B, Luc G, Taskinen MR, Betteridge DJ Ref: Diabetologia, 49:527, 2006 : PubMed
AIMS/HYPOTHESIS: Insulin resistance is thought to be central to the pathogenesis of diabetic dyslipidaemia. We hypothesised that improving insulin sensitivity would improve fasting and postprandial triglyceride metabolism in patients with type 2 diabetes. To this aim we studied fasting and postprandial lipaemia in type 2 diabetic patients before and after sensitisation to insulin with pioglitazone, compared with that observed in patients on an insulin-providing regime. METHODS: In a double-blind placebo-controlled protocol, 22 patients with type 2 diabetes were randomly allocated to receive either pioglitazone (45 mg/day) or glibenclamide (5 mg/day), for a 20-week period. Fasting and postprandial lipid metabolism were investigated at baseline and at the end of the treatment period. A group of non-diabetic subjects was also studied. RESULTS: Compared with glibenclamide treatment, pioglitazone treatment decreased fasting triglyceride, glucose and insulin levels and the homeostasis model assessment score of insulin resistance. Decreased fasting triglyceride after pioglitazone treatment was due to reduced VLDL triglyceride, particularly VLDL-2. Lipoprotein lipase activity was unchanged by pioglitazone treatment but hepatic lipase showed a significant decrease. Pioglitazone treatment lowered total postprandial triglyceride, as well as chylomicron- and chylomicron-remnant retinyl palmitate levels to normal. Glucose disposal improved but remained abnormal. CONCLUSIONS/INTERPRETATION: Insulin sensitisation with pioglitazone has major effects in restoring postprandial lipaemia to normal, while also correcting fasting hypertriglyceridaemia; both factors may have consequences for atherogenic risk in diabetes.
Title: Different VLDL apo B, and HDL apo AI and apo AII metabolism in two heterozygous carriers of unrelated mutations in the lipoprotein lipase gene Perez-Mendez O, Duhal N, Lacroix B, Bonte JP, Fruchart JC, Luc G Ref: Clinica Chimica Acta, 368:149, 2006 : PubMed
BACKGROUND: Lipoprotein lipase (LPL) deficiency has been suggested as a cause of low HDL-cholesterol (HDL-C) plasma levels, by a mechanism that involves an enhanced catabolism of HDL apolipoprotein (apo) AI. To verify the role of 2 different LPL gene mutations on HDL metabolism, we studied the in vivo turnover of the apo AI and apo AII in heterozygous carriers of LPL deficiency. METHODS: Apo AI and AII kinetics were studied by a 10-h primed constant infusion of 5,5,5-2H3-leucine approach in 2 carriers, 1 man (patient 1) and 1 woman (patient 2), and 5 control subjects. The rates of HDL apolipoproteins production (PR) and catabolism (FCR) were estimated using a one-compartment model-based analysis. RESULTS: Both carriers had low HDL-C plasma levels and only patient 1 was hypertriglyceridemic. VLDL apo B was 4-times slower in patient 1 as compared to patient 2. The FCRs of apo AI in both carriers was within the range of the controls (0.200, 0.221 and 0.211+/-0.051 day(-1), respectively). Apo AII FCR in patient 1 was about 20% lower than the mean of the control group whereas being normal in patient 2. Apo AI PR in patient 1 (9.20 mg kg(-1) day(-1)) was below the lowest value in controls (range, 10.52-13.24 mg kg(-1) day(-1)) whereas in patient 2 it was normal. Apo AII PR in both patients was similar to controls. CONCLUSION: The heterozygous carriers of 2 different mutations in the LPL gene had different VLDL apo B FCR, and from normal to slightly low HDL apolipoprotein FCR and PR. These results disagree with the putative enhanced apo AI FCR in LPL deficient patients and suggest the need to reconsider the effects of LPL activity on HDL metabolism.
Using polymerase chain reaction (PCR) based techniques, we have identified individuals in the ECTIM study of myocardial infarction survivors (cases) and healthy matched controls who are carriers for a mutation of the gene for lipoprotein lipase (LPL) which alters amino acid 9 from aspartic acid to asparagine (LPL-D9N). The frequency of carriers in the cases from Belfast and France (3 separate centres) was 2.5 and 3.7%, respectively (mean 3.3%, 95% CI 1.9-4.7) and in the controls 2.0 and 2.9%, respectively (mean 2.7%, 95% CI 1.6-3.8%), but this difference was not statistically significant. In the cases, carriers of the allele for LPL-N9 had higher levels of several plasma lipid traits including total triglycerides (TG) (30%), very low density lipoprotein (VLDL) cholesterol (19%), apo E (24%), apo C-III (17%), lipoprotein particles (Lp) containing both apo E and apo B (LpE:B) (32%), and particles containing both apo C-III and apo B (LpCIII:B) (39%), and this effect was consistent in cases both from Belfast and from the French centres combined. By contrast, in the controls there were no differences in any lipid trait between carriers and non-carriers of the mutation that was consistent between the French centres and Belfast. There were no significant differences in the levels of any measured factor between cases and controls that could explain the different effect on plasma lipid traits associated with the mutation. However, compared to the non-carriers, in both cases and controls who carried the mutation, plasma TG concentrations were higher in those whose body mass index (BMI) was above the mean of the sample (26.0 kg/m2), with statistically significant interaction seen between BMI and genotype and levels of apo C-III, and lipoprotein particles containing both apo C-III and apo B (P < 0.02). The data suggest that carriers for the LPL-N9 mutation have a mild genetic predisposition to developing hyperlipidaemia and an atherogenic lipid profile, but that this requires the presence of other genetic or environmental factors for full expression, one of which appears to be increasing obesity.
Several lipoprotein lipase (LPL) gene polymorphisms have been found associated with fasting lipid levels, but their impact on coronary heart disease (CHD) is less clearly established. We investigated associations of LPL polymorphisms (HindIII, PvuII, Ser447-->Ter) and the newly described mutation Asn291-->Ser with the risk of myocardial infarction (MI), severity of atherosclerosis, and fasting plasma lipoprotein concentrations in the ECTIM study (614 patients and 733 controls). The Ter447 allele had a lowering effect on triglycerides (P < 0.01), VLDL-cholesterol (P < 0.05), apoC-III (P < 0.001), LpE:B (P < 0.01), and LpCIII:B (P < 0.05), and a raising effect on apoA-I levels (P < 0.05). The H- allele of the HindIII polymorphism was associated with lower apoC-III (P < 0.01) and higher HDL-cholesterol (P < 0.05) levels. The PvuII and Asn291-->Ser polymorphisms did not exhibit any significant association with the biochemical traits examined. The HindIII genotype distributions differed between cases and controls, the odds ratios for MI associated with H+H+ and H+H- genotypes being 2.05 (P < 0.01) and 1.74 (P < 0.05) by reference to H-H-. The lack of association between Ser447-->Ter and MI suggested that this mutation was unlikely to be the cause of the association found with HindIII. In some cases, the severity of atherosclerosis assessed by coronarography increased with the presence of P+ allele (coronary scores: 1.41, 1.57, and 1.64 in P-P-, P-P+, and P+P+ individuals respectively, P < 0.05). A similar trend on the coronary score was observed with the presence of the Asn291-->Ser mutation (1.58 vs. 1.90, P = 0.06). Our results suggest that the LPL gene is involved in the determination of lipoprotein profiles, the predisposition to CHD, and the severity of atherosclerosis.
Title: Compound heterozygote for lipoprotein lipase deficiency: Ser----Thr244 and transition in 3' splice site of intron 2 (AG----AA) in the lipoprotein lipase gene Hata A, Emi M, Luc G, Basdevant A, Gambert P, Iverius PH, Lalouel JM Ref: American Journal of Human Genetics, 47:721, 1990 : PubMed
Cloning and sequencing of translated exons and intron-exon boundaries of the lipoprotein lipase gene in a patient of French descent who has the chylomicronemia syndrome revealed that he was a compound heterozygote for two nucleotide substitutions. One (TCC----ACC) leads to an amino acid substitution (Ser----Thr244), while the other alters the 3' splice site of intron 2 (AG----AA). The functional significance of the Thr244 amino acid substitution was established by in vitro expression in cultured mammalian cells.
