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Biomedical subjects

P Poulsen

Publications and source records attributed to P Poulsen.

At least 19 recordsLinked to original sources
PubMed2006

Metabolic aspects of insulin resistance in individuals born small for gestational age.

Numerous studies have shown an association between low weight at birth and being born small for gestational age (SGA) on the one hand and risk of developing insulin resistance and type 2 diabetes on the other. Our studies in twins have indicated a non-genetic age-dependent origin of insulin resistance and type 2 diabetes associated with being born SGA. In order to gain insight into the molecular metabolic defects and mechanisms linking SGA with insulin resistance and type 2 diabetes, we performed a series of experiments in young and elderly twins, and, in particular, in young men (aged 19-23 years) with a weight at birth at term in the lowest 10th percentile with no family history of diabetes. The control group included age-matched men with birth weights at term in the upper normal range. While body mass index and waist-to-hip ratios were similar in the individuals born SGA and controls, dual-energy X-ray absorptiometry studies documented a higher degree of abdominal obesity in the men who had a low weight at birth. Using the gold standard hyperinsulinaemic-euglycaemic clamp technique combined with glucose tracers and studies of forearm glucose uptake, we found an impairment of insulin-stimulated glycolytic flux and reduced forearm (muscle) glucose uptake in the face of normal whole-body glucose uptake. In addition, we found a significantly decreased insulin secretion rate during oral glucose ingestion after correction for insulin action (disposition index), a paradoxical enhanced insulin suppression of hepatic glucose production and lower fasting plasma glycerol levels, suggesting impaired lipolysis. Finally, analysis of skeletal muscle biopsies showed reduced muscle expression of several key proteins involved in insulin signalling and glucose transport, including protein kinase C-zeta, the two subunits of phosphoinositol 3-kinase (i.e., p85alpha and p110beta) and the insulin-sensitive glucose transporter, Glut-4, in individuals of low birth weight. In conclusion, being born SGA and of low birth weight is associated with type 2 diabetes in a non-genetic manner, and programming of muscle insulin action and signalling represents an early mechanism responsible for this association.

Adipose Tissue↗
PubMed2006

Energy expenditure, body composition and insulin response to glucose in male twins discordant for the Trp64Arg polymorphism of the beta3-adrenergic receptor gene.

AIM: The tryptophan to arginine change in position 64 (Trp64Arg) polymorphism of the beta3-adrenergic receptor (beta3AR) gene has been associated with an increased prevalence of obesity, insulin resistance and type 2 diabetes. In this, decreased rates of energy expenditure and impaired insulin secretion could play a role. METHODS: In 10 male twin pairs discordant for the Trp64Arg polymorphism, we examined insulin response to glucose by an oral glucose tolerance test (OGTT), a frequently sampled intravenous glucose tolerance test (FSIGT), body composition by the bioimpedance method, dual-energy X-ray absorptiometry scanning and energy expenditure by indirect and direct calorimetry. RESULTS: Twins heterozygous for the Trp64Arg polymorphism showed significantly lower fat mass independent of the method used, and significantly lower fasting insulin and glucose concentrations compared with their homozygous wild-type co-twins. Correspondingly, insulin resistance and insulin secretion determined by homeostasis model assessment were significantly lower in twins carrying the Trp64Arg polymorphism. However, there were no significant differences in adiponectin levels, insulinogenic index assessed by OGTT, or insulin sensitivity, acute insulin response to glucose, glucose effectiveness or insulin disposition index assessed by minimal modelling of the FSIGT. Furthermore, there were no differences in sleeping, resting or post-prandial energy expenditure. CONCLUSIONS: In male twins with a high similarity in genetic and environmental background, the Trp64Arg polymorphism of the beta3AR gene is associated with lower fat mass, fasting insulin levels and an appropriate insulin response to glucose. Thus, heterozygosity for the Trp64Arg variant is unlikely to increase the risk of obesity, insulin resistance or type 2 diabetes.

Blood Glucose↗
PubMed2005

Plasma cytokine levels in young and elderly twins: genes versus environment and relation to in vivo insulin action.

AIMS/HYPOTHESIS: We studied the impact of genetic versus pre- and postnatal environmental factors on the plasma levels of IL6, TNF and the soluble TNF receptor superfamily, member 1A (TNFRSF1A, previously known as TNF receptor type1 [TNFR1]). MATERIALS AND METHODS: Using the hyperinsulinaemic-euglycaemic clamp, we assessed the association between cytokine levels and both peripheral insulin sensitivity and hepatic glucose production. Fasting plasma IL6, TNF and soluble TNFRSF1A levels were measured using ELISA in 55 young and 43 elderly twin pairs. RESULTS: Plasma IL6 and TNF were influenced by genetic factors in young and elderly twins respectively, while no significant impact of genetics was found for soluble TNFRSF1A. Significant intra-twin pair correlations between birthweight and both IL6 and soluble TNFRSF1A levels were found. In addition to the effect of birthweight on IL6, age and fat % also significantly influenced IL6 levels, whereas soluble TNFRSF1A levels were significantly influenced by zygosity, age, fat % and sex. Plasma soluble TNFRSF1A was associated with higher plasma NEFA and to some extent with reduced insulin sensitivity. Plasma IL6 was associated positively with basal NEFA. TNF level was not associated with in vivo glucose or fat metabolism after correction for known confounders. CONCLUSIONS/INTERPRETATION: Plasma IL6 and soluble TNFRSF1A are influenced by the intrauterine environment. We found some evidence of a genetic component for TNF and IL6 in young and elderly twins respectively. Plasma IL6 may influence basal lipolysis, but neither plasma TNF nor IL6 levels are independently associated with hepatic or peripheral insulin action. Nevertheless, plasma soluble TNFRSF1A may play some role in the control of insulin action.

Adult↗
PubMed2005

Amino acid sensing by Ssy1.

Saccharomyces cerevisiae senses extracellular amino acids using two members of the family of amino acid transporters, Gap1 or Ssy1; aspects of the latter are reviewed here. Despite resemblance with bona fide transporters, Ssy1 appears unable to facilitate transport. Exposure of yeast to amino acids results in Ssy1-dependent transcriptional induction of several genes, in particular some encoding amino acid transporters. Amino acids differ strongly in their potency, leucine being the most potent one known. Using a selection system in which potassium uptake was made dependent on amino acid signalling, our laboratory has obtained and described gain-of-function mutations in SSY1. Some alleles conferred inducer-independent signalling; others increased apparent affinity for inducers. These results revealed that amino acid transport is not required for signalling and support the notion that sensing by Ssy1 occurs via its direct interaction with extracellular amino acids. Current work includes development of quantitative assays of sensing. We use the finding by Per Ljungdahl's laboratory that the signal transduction from Ssy1 involves proteolytic removal of an inhibitory part of the transcriptional activator Stp1. Protein-A Z-domain fused to the C-terminus of Stp1 and Western analysis using antibody against horseradish peroxidase allow quantification of sensing.

Amino Acids↗
PubMed2005

Novel polymorphisms in the GCKR gene and their influence on glucose and insulin levels in a Danish twin population.

AIM: The glucokinase regulatory protein gene is a candidate gene for Type 2 diabetes. This study reveals three new polymorphisms and examines the impact of one new and one known polymorphism on insulin secretion and parameters associated with the insulin resistance syndrome in Danish twins with different degrees of glucose tolerance. METHODS: Single nucleotide polymorphism detection was performed in 20 healthy subjects and in 20 subjects with Type 2 diabetes. The effect of the polymorphisms on lipid, glucose and insulin measures was studied in 566 same-sex twins aged 55-74 years. RESULTS: The new nucleotide (nt) 363 polymorphism was found only in subjects with impaired glucose tolerance and Type 2 diabetes. The nt 11216 polymorphism influenced insulin measured at 120 min during an oral glucose tolerance test (OGTT). Subjects with genotype C11216C/T11216C had 21% higher insulin values (P<0.05) than subjects with genotype T11216T. In twins discordant for this genotype, the C-allele was associated with significantly higher plasma insulin levels at all time points during the OGTT, higher beta-cell function and lower plasma glucose levels during the OGTT. CONCLUSION: The C-allele of nt 11216 polymorphism was associated with increased insulin secretion, and may therefore exert a potentially protective effect against Type 2 diabetes. This remains to be shown in a larger study population.

Aged↗
PubMed2003

The impact of genes and pre- and postnatal environment on the metabolic syndrome. Evidence from twin studies.

Our population-based Danish twin study demonstrated a genetic influence on several of the components included in the metabolic syndrome, i.e. glucose intolerance, overall obesity, systolic and diastolic blood pressure and low levels of HDL-cholesterol. Abdominal obesity, insulin resistance and hypertriglyceridaemia had, on the other hand, a relatively higher environmental aetiological component. Furthermore we demonstrated a difference in aetiology among male and female twins indicating an influence of sex on several of the components in the metabolic syndrome. Studies have demonstrated an impact of the intrauterine environment (i.e. low birth weight) for the development of the components in the metabolic syndrome. The validity of conclusions drawn from classical twin studies has therefore been questioned due to the different prenatal circumstances characterising monozygotic (MZ) and dizygotic (DZ) pregnancies. Due to a potentially more adverse intrauterine environment among MZ compared to DZ twins, MZ twins may be more prone to develop various metabolic abnormalities. Our findings of a higher glucose and insulin profiles after oral glucose ingestion, and recently lower insulin-stimulated glucose uptake--indicating glucose intolerance and insulin resistance--together with higher levels of total-cholesterol and triglycerides among MZ compared to DZ twins demonstrate an effect of zygosity (i.e. intrauterine environment) on these metabolic variables and therefore question the assumption of equal pre- and postnatal environment in MZ and DZ twins. Our studies provide further evidence for a prenatal component in the aetiology of the components included in the syndrome and question the validity of classical twin studies on phenotypes with a known prenatal aetiological component. However, our present knowledge is currently far too insufficient to discard the results from classical twin studies concerning the relative role of genes versus environment for the development of the metabolic and haemodynamic components included in the metabolic syndrome.

Diseases in Twins↗
PubMed2003

Retention of glassionomer sealant in primary teeth in young children.

AIM: The purpose of the study was to determine the retention of glassionomer sealants in primary teeth of preschool children. METHODS: Fissure sealants (Fuji II LC) were placed on primary molars, without conditioner, by two experienced dentists under good clinical conditions in well equipped clinics and with the assistance of a chair side dental assistant. Sealants were scored as "fully retained", "partly retained", or "completely lost" after two years. RESULTS: There were 65 children included, out of which 29 had all primary molars. Mean age at the time of sealing was slightly less than 41/2 years. Mean follow-up time was two years. About 75% of the sealants placed in second primary molars were fully or partly retained after 12 months, compared with less that 50% of the sealants placed in first primary molars. New carious lesions were too few to allow for an assessment of whether the sealants were effective in preventing caries. CONCLUSION: Retention rates for glass ionomer fissure sealants were satisfactory. However, high quality randomised clinical trials to estimate the caries preventive effect are still needed.

Cariostatic Agents↗
PubMed2002

Age-dependent impact of zygosity and birth weight on insulin secretion and insulin action in twins.

AIMS/HYPOTHESIS: Study the influence of age, zygosity and birth weight on insulin action and insulin secretion in twins. METHODS: In vivo insulin action and insulin secretion were measured using the euglycaemic, hyperinsulinaemic clamp technique and intravenous glucose tolerance test, respectively. We examined 104 monozygotic (MZ) twins and 88 dizygotic (DZ) twins in two age groups (25-34 and 57-66 years). RESULTS: There were no differences in birth weight, body mass index, waist to hip ratio or lean body mass between monozygotic and dizygotic twins. Younger monozygotic twins had a slightly higher insulin-stimulated glucose uptake (M) than younger dizygotic twins. In contrast, elderly monozygotic twins had a lower insulin-stimulated glucose uptake value compared with elderly dizygotic twins. Elderly monozygotic twins had a reduced insulin secretion relative to insulin resistance compared to dizygotic twins during oral glucose tolerance test (OGTT). Birth weight per se was not associated with insulin secretion or action in the twins. However, correcting for the genetic influence on birth weight using intrapair differences among monozygotic twin pairs, low birth weight was associated with insulin resistance and low insulin secretion after both oral and intravenous glucose administration in elderly MZ twins. CONCLUSION/INTERPRETATION: Zygosity status has a major age (or time) dependent impact on in vivo insulin secretion and insulin action in twins independent of birth weight and adult antropometry. An additional non-genetic impact of low birth weight on insulin secretion and insulin action was found in elderly monozygotic twins. Ageing could play an important role by unmasking the influence of an adverse intrauterine environment on insulin resistance and low insulin secretion in twins.

Adult↗
PubMed2002

The influence of the polymorphism in apolipoprotein B codon 2488 on insulin and lipid levels in a Danish twin population.

AIMS: The apolipoprotein B codon 2488 polymorphism has been associated with the metabolism of lipoproteins in subjects with Type 2 diabetes. However, no data are available on the influence of the polymorphism on insulin or glucose metabolism. This study examines the impact of the polymorphism on parameters associated with the insulin resistance syndrome in Danish twins. METHODS: The effect of the polymorphism on lipid, glucose and insulin measures was studied in 548 same sex twins aged 55-74 years. RESULTS: The codon 2488 polymorphism influenced fasting triglyceride levels, as well as insulin, as measured at 120 min in an oral glucose tolerance test. Subjects with the genotype T2488T had 14% higher triglyceride levels (P = 0.02) and 31% higher insulin levels (P = 0.004) than subjects with genotype C2488C. In twins discordant for genotype, the T-allele was associated with higher levels of triglyceride (P = 0.04) and insulin (P = 0.02) and lower levels of HDL-cholesterol (P = 0.04). CONCLUSION: The T-allele of the codon 2488 polymorphism influenced parameters related to the insulin resistance syndrome, i.e. increased levels of insulin, increased levels of triglyceride and decreased levels of HDL. As the polymorphism is silent, these effects must be mediated through linkage to other polymorphisms in apolipoprotein B or other genes on chromosome 2.

Aged↗
PubMed2002

Antimicrobial susceptibility of Neisseria gonorrhoeae strains isolated in Nuuk, Greenland during 1998-1999.

Sixty-one gonococcal strains isolated in Greenland during 1998-1999 were tested locally for susceptibility to penicillin and ciprofloxacin by a disc diffusion method (Rosco) and at the reference laboratory in Copenhagen by the agar dilution method and the E-test, showed that more than 60% of the strains were less susceptible or resistant to penicillin (minimum inhibitory concentration [MIC] > or = 0.25 mg/L), indicating that penicillin should not be used as a first line drug for the treatment of gonorrhoea in Greenland. The Rosco disc diffusion method only identified 8% of strains as less susceptible to penicillin. Ciprofloxacin can still be used as a first line drug for treatment of gonorrhoea in Greenland since decreased susceptibility was only seen in one imported strain. However, the decreased susceptibility in this strain was not identified by the Rosco disc diffusion test, therefore the future local surveillance of antibiotic resistance in Neisseria gonorrhoeae will be based on MIC determinations.

Adolescent↗
PubMed2001

Crystallization and preliminary X-ray analysis of maltose O-acetyltransferase.

Maltose O-acetyltransferase (Mac) is a member of the hexapeptide-repeat family of enzymes, which contains proteins with left-handed parallel beta-helix architecture forming homotrimers. Diffraction data for four well diffracting crystal forms were collected. Crystal form I diffracted beyond 1.53 A resolution but was perfectly merohedrally twinned with an apparent space group P622. Crystal forms II and III (space groups R3 and C2, respectively) could be obtained under very similar conditions by adjusting the buffer pH differently. Crystal forms II and III had several monomers in the asymmetric unit and were difficult to derivatize. However, during soaking with trimethyl lead acetate, the form III crystals dissolved and crystals with a different habit and space group grew in their place (form IV). In three of the crystal forms, a ladder of peaks was visible in the native Patterson maps along the c axis. These peaks were interpreted as corresponding to the vectors between the beta-strands in the turns of the beta-helix. Crystal form IV is suitable for structure determination of Mac exploiting the anomalous scattering of lead.

Acetyltransferases↗
PubMed2001

Genetic versus environmental aetiology of the metabolic syndrome among male and female twins.

AIMS/HYPOTHESIS: The aetiology of the metabolic syndrome including hyperinsulinaemia, glucose intolerance, dyslipidaemia, hypertension and obesity is not known. We studied the relative impact of genetic versus environmental factors for the development of the components in the syndrome among male and female twins. METHODS: A total of 303 elderly twin pairs participated in the study. We report concordances and heritability estimates of the components by classic twin analysis to assess the proportion of variation attributed to genetic factors. RESULTS: All components correlated significantly. The concordance rates for glucose intolerance, overall obesity and low HDL-cholesterol were significantly higher among monozygotic than dizygotic twins indicating a genetic influence on the development of these phenotypes. The heritability estimates for glucose concentration, BMI and HDL-cholesterol among monozygotic twins confirmed these findings. The heritability estimates for waist-to-hip ratio, fasting insulin and triglycerides, however, were low, indicating a major environmental influence. We found a higher genetic influence on glucose intolerance and systolic blood pressure and a lower genetic influence on low HDL-cholesterol and diastolic blood pressure among male twins compared to female twins. CONCLUSION/INTERPRETATION: Based on the correlations between the components in the syndrome, we propose a core complex including hyperinsulinaemia, obesity, hypertriglyceridaemia and low HDL-cholesterol with only weak associations to glucose concentrations and blood pressure levels. The study confirms the notion of a multifactorial aetiology of the components including genetic and non-genetic factors. The differences in aetiology between male and female twins indicate an influence of sex on several of the components in the metabolic syndrome.

Aged↗
PubMed2001

Glucose and insulin metabolism in twins: influence of zygosity and birth weight.

Several epidemiological and metabolic studies have demonstrated an impact of the intrauterine environment on the development of disease in adult life, including Type 2 diabetes and glucose intolerance. Our finding of lower birth weights among monozygotic diabetic twins compared to their non-diabetic genetically identical co-twins confirms this association and, furthermore, eliminates the possibility that the association could be explained solely by common genes leading to both impaired intrauterine growth and increased risk of Type 2 diabetes. Due to an often shared placenta monozygotic twins may experience a more adverse intrauterine environment compared to dizygotic twins and may therefore be more prone to develop various metabolic abnormalities. Our findings of a higher glucose and insulin profile after oral glucose ingestion, and recently lower insulin-stimulated glucose uptake--indicating glucose intolerance and insulin resistance--among monozygotic compared to dizygotic twins may to some extent question the validity of classical twin studies in diabetes research where equal environmental influences in monozygotic and dizygotic twins is assumed. The potential role of an adverse intrauterine environment in causing Type 2 diabetes in humans, may to some degree alter our conception of the twin model in diabetes research including the interpretation of aetiological conclusions reached in previous classical twin studies of diabetes. However, our present knowledge is far too insufficient to discard the results from classical twin studies concerning the relative role of genes versus environment for the development of diabetes and its metabolic effects.

Birth Weight↗
PubMed2000

Dose-related efficacy and tolerability of fluticasone propionate nasal drops 400 microg once daily and twice daily in the treatment of bilateral nasal polyposis: a placebo-controlled randomized study in adult patients.

BACKGROUND: Topical corticosteroids are the accepted medical adjunct to surgery in patients suffering from nasal polyposis. Fluticasone propionate (FP) is a potent, topically active corticosteroid which has been formulated as nasal drops specifically for the treatment of polyposis. OBJECTIVES: To evaluate dose-related efficacy and tolerability of FP nasal drops (FPND) in the treatment of mild to moderate bilateral polyposis; in a double-blind, placebo-controlled, multicentre international study. METHODS: Adult patients (n = 142) with bilateral nasal polyps were randomized to receive either FPND 400 microg once daily (o.d.), FPND 400 microg twice daily (b.i.d.) or placebo for 12 weeks. The majority then entered a further 12 week open period during which all patients received FPND 400 microg o.d. The primary efficacy endpoint was the physicians' visual assessment of polyp size. Secondary clinical endpoints were nasal blockage and overall rhinitis (0-3 scores), peak nasal inspiratory flow (PNIF), olfactory function tests, and requirement for polypectomy. The patients also kept twice daily records of symptom scores, peak nasal inspiratory flow (PNIF) and use of rescue medication. RESULTS: At the end of the 12 week randomized treatment period, polyp size was reduced significantly by FPND 400 microg b.i.d. as compared with placebo (P = 0.006). Clinical assessments of nasal blockage and overall rhinitis showed significant improvements at several stages of treatment with both doses of FPND. Clinic PNIF was also improved significantly by both doses of FPND in comparison with placebo, and FPND 400 microg b.i.d. was significantly more effective than 400 microg o.d. (P = 0.045). Patient diary card scores supported the clinical assessments. Two patients on placebo required polypectomy and all treatments were well tolerated with a similar incidence of adverse events. CONCLUSION: FPND 400 microg once or twice daily is an effective and well-tolerated treatment for bilateral nasal polyposis.

Administration, Intranasal↗
PubMed2000

Characterization and crystallization of an active N-terminally truncated form of the Escherichia coli glycogen branching enzyme.

The prokaryotic glycogen branching enzymes (GBE) can be divided into two groups on the basis of their primary structures: the first group of enzymes, which includes GBE from Escherichia coli, is characterized by a long N-terminal extension that is absent in the enzymes of the second group. The extension consists of approximately 100 amino-acid residues with unknown function. In order to characterize the function of this region, the 728 amino-acid residue, full-length E. coli GBE, and a truncated form (nGBE) missing the first 107 amino-acid residues were overexpressed in E. coli. Both enzymes were purified to homogeneity by a simple purification procedure involving ammonium sulphate precipitation, ion-exchange chromatography, and a second ammonium sulphate precipitation. Purified full-length enzyme was poorly soluble and formed aggregates, which were inactive, at concentrations above 1 mg.mL-1. In contrast, the truncated form could be concentrated to 6 mg.mL-1 without any visible signs of aggregation or loss of activity on concentration. The ability to overexpress nGBE in a highly soluble form has allowed us to produce diffracting crystals of a branching enzyme for the first time. A comparison of the specific activities of purified GBE and nGBE in assays where amylose was used as substrate demonstrated that nGBE retained approximately half of the branching activity of full-length GBE and is therefore a suitable model for the study of the enzymes' catalytic mechanism.

1,4-alpha-Glucan Branching Enzyme↗
PubMed2000

Impact of the Xba1-polymorphism of the human muscle glycogen synthase gene on parameters of the insulin resistance syndrome in a Danish twin population.

AIMS: To establish the impact on the insulin resistance syndrome of the intron 14 Xba1-polymorphism in human muscle glycogen synthase (GYS1). METHODS: Parameters related to the insulin resistance syndrome were measured in 244 monozygotic twins and 322 dizygotic twins with or without impaired glucose tolerance. In addition a standard oral glucose tolerance test (OGTT) was performed. The twins were genotyped for Xba1-polymorphism in GYS1 intron 14. RESULTS: The allele frequency of Xba1 non-cutters (A1) was 0.95 and of cutters (A2) was 0.05. Of the 566 twins examined, 90.0% had the genotype A1A1 and the remainder had the genotype A1A2. No A2A2-genotypes were detected. In 11 genotypic discordant dizygotic twin pairs the insulin resistance was significantly increased in the twins carrying the A1A2 genotype regardless of sex (HOMA index 1.81 (A1A1) vs. 2.57 (A1A2), P < 0.05). Diastolic blood pressure was increased in female carriers of the A2-allele with impaired glucose tolerance or Type 2 diabetes mellitus (79 +/- 1 vs. 94 +/- 4 mmHg, P < 0.01). Apart from a marginal increased waist-to-hip ratio, no other elements of the insulin resistance syndrome were associated with the polymorphism. CONCLUSIONS: The Xba1-polymorphism of the human muscle glycogen synthase gene is correlated to insulin resistance and to diastolic blood pressure. The polymorphism does not involve any known transcription factor or any structural change in GYS1, and these correlations are therefore most probably caused by linkage to other functional polymorphisms in GYS1 or other gene polymorphisms on chromosome 19.

Aged↗