Effect of telmisartan on selected adipokines, insulin sensitivity, and substrate utilization during insulin-stimulated conditions in patients with metabolic syndrome and impaired fasting glucose.

OBJECTIVE: Telmisartan improves glucose and lipid metabolism in rodents. This study evaluated the effect of telmisartan on insulin sensitivity, substrate utilization, selected plasma adipokines and their expressions in subcutaneous adipose tissue (SAT) in metabolic syndrome. DESIGN AND METHODS: Twelve patients with impaired fasting glucose completed the double-blind, randomized, crossover trial. Patients received telmisartan (160 mg/day) or placebo for 3 weeks and vice versa with a 2-week washout period. At the end of each period, a hyperinsulinemic euglycemic clamp (HEC) combined with indirect calorimetry was performed. During HEC (0, 30, and 120 min), plasma levels of adipokines were measured and a needle biopsy (0 and 30 min) of SAT was performed. RESULTS: Fasting plasma glucose was lower after telmisartan compared with placebo (P<0.05). There were no differences in insulin sensitivity and substrate utilization. We found no differences in basal plasma adiponectin, resistin and tumour necrosis factor α (TNFα), but an increase was found in basal leptin, after telmisartan treatment. Insulin-stimulated plasma adiponectin (P<0.05), leptin and resistin (P<0.001) were increased, whereas TNFα was decreased (P<0.05) after telmisartan treatment. Expression of resistin, but not adiponectin, TNFα and leptin was increased after telmisartan treatment. CONCLUSIONS: Despite the decrease in fasting plasma glucose, telmisartan does not improve insulin sensitivity and substrate utilization. Telmisartan increases plasma leptin as well as insulin-stimulated plasma adiponectin, leptin and resistin, and decreases plasma TNFα during HEC. Changes in plasma adipokines cannot be explained by their expressions in SAT. The changes in plasma adipokines might be involved in the metabolic effects of telmisartan in metabolic syndrome.

Novel APC mutations in Czech and Slovak FAP families: clinical and genetic aspects.

BACKGROUND: Germline mutations in the adenomatous polyposis gene (APC) result in familial adenomatous polyposis (FAP). FAP is an autosomal dominantly inherited disorder predisposing to colorectal cancer. Typical FAP is characterized by hundreds to thousands of colorectal adenomatous polyps and by several extracolonic manifestations. An attenuated form of polyposis (AFAP) is characterized by less than 100 adenomas and later onset of the disease. METHODS: Here, we analyzed the APC gene for germline mutations in 59 Czech and 15 Slovak FAP patients. In addition, 50 apparently APC mutation negative Czech probands and 3 probands of Slovak origin were screened for large deletions encompassing the APC gene. Mutation screening was performed using denaturing gradient gel electrophoresis and/or protein truncation test. DNA fragments showing an aberrant electrophoretic banding pattern were sequenced. Screening for large deletions was performed by multiplex ligation dependent probe amplification. The extent of deletions was analyzed using following microsatellite markers: D5S299, D5S82, D5S134 and D5S346. RESULTS: In the set of Czech and Slovak patients, we identified 46 germline mutations among 74 unrelated probands. Total mutation capture is 62,2% including large deletions. Thirty seven mutations were detected in 49 patients presenting a classical FAP phenotype (75,5%) and 9 mutations in 25 patients with attenuated FAP (36%). We report 20 novel germline APC mutations and 3 large deletions (6%) encompassing the whole-gene deletions and/or exon 14 deletion. In the patients with novel mutations, correlations of the mutation localization are discussed in context of the classical and/or attenuated phenotype of the disease. CONCLUSION: The results of the molecular genetic testing are used both in the establishment of the predictive diagnosis and in the clinical management of patients. In some cases this study has also shown the difficulty to classify clinically between the classical and the attenuated form of FAP according to the established criteria. Interfamilial and/or intrafamilial phenotype variability was also confirmed in some cases which did not fit well with predicted genotype-phenotype correlation. All these findings have to be taken into consideration both in the genetic counselling and in the patient care.

Variability in apo(a) gene regulatory sequences, compound genotypes, and association with Lp(a) plasma levels.

OBJECTIVES: Lipoprotein(a) is an independent risk factor of atherosclerosis. DESIGN AND METHODS: We assigned frequencies of six polymorphic sites from apo(a) gene transcription control regions, linkage disequilibrium, and 5-polymorphic compound genotypes association with Lp(a) levels. RESULTS: Significant linkage disequilibrium between polymorphic sites was detected. Compound genotypes were significantly associated with Lp(a) levels (P<0.0001). Major 5-polymorphic genotypes were distributed in a broad range of concentrations. CONCLUSIONS: Major 5-polymorphic compound genotypes are not associated with restricted range of Lp(a) levels.

Detection of variability in apo(a) gene transcription regulatory sequences using the DGGE method.

BACKGROUND: Increased lipoprotein(a), Lp(a), concentration is an independent risk factor for premature atherosclerosis. Apolipoprotein(a), apo(a), determines properties of the lipoprotein and its production rate is the limiting step in Lp(a) particle formation. METHODS: Subjects covering the whole range of Lp(a) concentration were separated into quintiles. A randomly chosen sample from each quintile was derived, there being a total number of 713 individuals. The DGGE method was used to scan the known transcription regulatory regions of apo(a) gene (promoter; DHII and DHIII enhancers) for variability and its distribution across quintiles. RESULTS: Besides 5 previously reported nucleotide substitutions (+121 G>A; +93 C>T; -1712 G>T; -1617 C>A; -1230 A>G) 16 unreported rare sequence variants were detected. All polymorphic variants were distributed throughout the quintiles with several significant differences. The novel +62 C variant was found only among individuals with Lp(a) levels over 16 mg/dl. CONCLUSION: The apo(a) gene transcription regulatory regions were not revealed to be extremely polymorphic. However, we should consider a combined effect of all polymorphic sites from the whole apo(a) gene locus, including the apo(a) gene length polymorphism, when dealing with high population variability of Lp(a) levels.