Biomedical subjects

O Pedersen

Publications and source records attributed to O Pedersen.

At least 73 records · Page 4Linked to original sources

PubMed2001

Double-blind, randomised study of the effect of combined treatment with vitamin C and E on albuminuria in Type 2 diabetic patients.

AIMS: Elevated levels of urinary albumin excretion rate (AER) predict high risk for progressing to end-stage renal disease. In streptozotocin-induced diabetes, supplementation with vitamin C or E reduces albuminuria and glomerular hypertrophy. We tested the hypothesis that supplementation of both vitamin C and E in pharmacological doses lowers AER in Type 2 diabetic patients with persistent micro/macroalbuminuria. METHODS: Thirty Type 2 diabetic patients with AER 30-300 mg/24 h were included in a double-blind randomised, cross-over trial. Patients received vitamin C (1250 mg) and vitamin E (680 IU) per day or matching placebo for 4 weeks with a 3-week wash-out period between treatment periods in random order. RESULTS: Combined treatment with vitamin C and E reduced AER by 19% (95% CI 6-34%) (p = 0.04), geometric mean 197 mg/24 h (95% CI 114-341 mg/24 h) vs. 243 mg/24 h (146-404 mg/24 h). No changes were seen in serum creatinine, haemoglobin A1C or blood pressure. Fasting plasma concentrations of vitamin C and E increased in all patients during active treatment (mean vitamin C 79.4 micromol/L (SD 27.8) vs. 41.9 micromol/L (18.4) and vitamin E 47.0 micromol/L (19.8) vs. 29.5 micromol/L (15.3), P < 0.000001). Except for two patients that started additional blood pressure lowering treatment during the run-in period, no changes in medication, food and exercise habits or in the number of smokers occurred during the study. CONCLUSION: Short-term treatment with vitamin C and E in pharmacological doses lowers AER in Type 2 diabetic patients with micro/macroalbuminuria. Further long-term, large-scale studies of this albuminuria reducing treatment modality are warranted.

Albuminuria↗

PubMed2001

Rosiglitazone treatment of patients with extreme insulin resistance and diabetes mellitus due to insulin receptor mutations has no effects on glucose and lipid metabolism.

BACKGROUND: Rosiglitazone, a thiazolidinedione (TZD), increases insulin sensitivity by reducing levels of plasma NEFA, triglycerides (TG), glucose and serum insulin. Rosiglitazone treatment decreases insulin resistance in type 2 diabetic patients, but no data exist concerning rosiglitazone treatment of patients with syndromes of extreme insulin resistance. OBJECTIVES: To evaluate whether hyperglycaemia in two lean patients with primary severe insulin resistance due to insulin receptor (IR) mutations and diabetes mellitus could be reduced by supplement of rosiglitazone for 180 days and secondary, to evaluate the effects on plasma NEFA, TG, Apo B, PAI-1 and serum insulin. SUBJECTS: Both patients (brothers) have known mutations in the IR gene localized to the tyrosine kinase domain and a deletion of exon 17 in part of their IR mRNA. Prior to the study the HbA1c values were higher than 10% in both patients for more than 12 months during treatment with insulin and metformin. RESULTS: After 180 days of rosiglitazone supplement (8 mg day(-1)), no changes were observed in fasting plasma glucose and HbA1c. Incremental plasma glucose areas under the curves during a 75-g oral glucose tolerance test (OGTT) were unchanged. Likewise, no improvements were seen in either first or second phase insulin secretion during a 0.3 g kg(-1) intravenous glucose tolerance test (IVGTT). Fasting plasma VLDL and HDL cholesterol, TG and Apo B levels were unchanged, whereas a small increase was seen in total and LDL cholesterol levels. Fasting plasma NEFA increased by 51% in KC after 90 days of treatment, and after 180 days plasma NEFA was still 26% higher, when compared with pretreatment levels. In BC an initial 16% decrease was seen in plasma NEFA after 90 days of treatment. Plasma NEFA was increased 14% after 180 days of treatment, when compared with pretreatment levels, but 35% when compared with day 90. Plasma PAI-1 decreased in both patients after 45 and 90 days of treatment but the decrease was only maintained in KC (47%). CONCLUSIONS: Rosiglitazone treatment, in combination with insulin and metformin, of patients with severe primary insulin resistance due to IR mutations and diabetes mellitus, had no impact on the measured estimates of glucose and lipid metabolism. These findings may suggest that the effect of rosiglitazone on glucose and lipid metabolism are dependent on the presence of intact IR protein.

Adolescent↗

PubMed2001

Limited impact of lifestyle education in patients with Type 2 diabetes mellitus and microalbuminuria: results from a randomized intervention study.

AIMS: To assess the effect of intensified education on lifestyle (diet, exercise and smoking) as part of an intensified multifactorial intervention over a 4-year period in patients with Type 2 diabetes mellitus with microalbuminuria. METHODS: Patients, aged 45-65 years, were randomly assigned either to an intensive group focusing on change of behaviour as well as polypharmacological treatment (n = 80) or to a control group receiving conventional treatment (n = 80). Diet intervention focused on dietary fat and carbohydrate. Food intake was estimated by dietary history interviews and nutrients were calculated from food tables. Exercise and smoking habits were evaluated by interviews. RESULTS: Mean follow-up was 3.8 (SD 0.3) years. The decrease in total fat intake (% of energy intake) was larger in the intensive group as compared to the control group (41.2 (6.2) to 34.2 (6.0) vs. 41.9 (6.5) to 38.3 (6.4)%, P = 0,0001). The decrease in saturated fatty acids (% of total fat intake) was from 47 (4) to 44 (6)% with intensive therapy vs. 45 (5) to 46 (5)%, P = 0.001 and the increase in polyunsaturated fatty acids was from 14 (4) to 18 (6) vs. 16 (5) to 14 (4)%, P < 0.0001. Also the increase in carbohydrate was larger with intensive therapy. However, changes in exercise and smoking habits did not differ between groups. CONCLUSION: Despite the many resources invested in behaviour modification in this study, only modest changes were obtained in nutrient intake. Further studies are required to determine the best method of inducing long-lasting changes in behaviour in Type 2 diabetic patients.

Aged↗

PubMed2001

Pooling analysis of genetic data: the association of leptin receptor (LEPR) polymorphisms with variables related to human adiposity.

Analysis of raw pooled data from distinct studies of a single question generates a single statistical conclusion with greater power and precision than conventional metaanalysis based on within-study estimates. However, conducting analyses with pooled genetic data, in particular, is a daunting task that raises important statistical issues. In the process of analyzing data pooled from nine studies on the human leptin receptor (LEPR) gene for the association of three alleles (K109R, Q223R, and K656N) of LEPR with body mass index (BMI; kilograms divided by the square of the height in meters) and waist circumference (WC), we encountered the following methodological challenges: data on relatives, missing data, multivariate analysis, multiallele analysis at multiple loci, heterogeneity, and epistasis. We propose herein statistical methods and procedures to deal with such issues. With a total of 3263 related and unrelated subjects from diverse ethnic backgrounds such as African-American, Caucasian, Danish, Finnish, French-Canadian, and Nigerian, we tested effects of individual alleles; joint effects of alleles at multiple loci; epistatic effects among alleles at different loci; effect modification by age, sex, diabetes, and ethnicity; and pleiotropic genotype effects on BMI and WC. The statistical methodologies were applied, before and after multiple imputation of missing observations, to pooled data as well as to individual data sets for estimates from each study, the latter leading to a metaanalysis. The results from the metaanalysis and the pooling analysis showed that none of the effects were significant at the 0.05 level of significance. Heterogeneity tests showed that the variations of the nonsignificant effects are within the range of sampling variation. Although certain genotypic effects could be population specific, there was no statistically compelling evidence that any of the three LEPR alleles is associated with BMI or waist circumference in the general population.

Adipose Tissue↗

PubMed2001

Elevated levels of plasma von Willebrand factor and the risk of macro- and microvascular disease in type 2 diabetic patients with microalbuminuria.

BACKGROUND: The purpose of this study was to examine the concept suggesting that microalbuminuria in combination with high levels of plasma von Willebrand factor is a stronger predictor for cardiovascular disease and microvascular complications than microalbuminuria alone in type 2 diabetic patients. METHODS: One hundred and sixty patients with type 2 diabetes mellitus and persistent microalbuminuria were followed for an average of 3.8 (SD 0.3) years. 70% of the patients were treated with angiotensin converting enzyme (ACE)-inhibitors. Patients in this subanalysis were divided into two groups according to baseline plasma von Willebrand factor levels below or above the median. The main outcome was cardiovascular disease (cardiovascular mortality, non-fatal stroke, non-fatal myocardial infarction, coronary artery bypass graft and revascularization or amputation of legs), progression to diabetic nephropathy or progression in diabetic retinopathy. RESULTS: At baseline the two groups were comparable for HbA(1c), fasting levels of s-total-cholesterol, s-HDL-cholesterol and s-triglycerides, systolic and diastolic blood pressure, gender, known diabetes duration, smoking habits, previous cardiovascular disease and antihypertensive therapy as well as retinopathy. Odds ratio for cardiovascular disease was 1.11 (95% CI 0.45-2.73, P=0.82) (multiple logistic regression), odds ratio for progression to nephropathy was 1.08 (0.41-2.85, P=0.87) and odds ratio for progression in retinopathy was 0.96 (0.46-2.00, P=0.92), all with plasma von Willebrand factor levels above the median. CONCLUSIONS: Our results do not support the suggestion that the combination of high plasma levels of von Willebrand factor and microalbuminuria is a stronger predictor for cardiovascular disease, progression to diabetic nephropathy or progression in diabetic retinopathy than microalbuminuria alone in patients with type 2 diabetes and persistent microalbuminuria.

Adult↗

PubMed2001

Diabetic microvascular complications are not associated with two polymorphisms in the GLUT-1 and PC-1 genes regulating glucose metabolism in Caucasian type 1 diabetic patients.

BACKGROUND: An XbaI polymorphism in the gene encoding the glucose transporter, GLUT-1, is associated with development of diabetic nephropathy in Chinese type 2 diabetic patients. In addition, an amino acid variant (K121Q) in the gene encoding the glycoprotein plasma cell differentiating antigen (PC-1), a specific inhibitor of insulin receptor signalling, has been reported to predict a faster progression of nephropathy in Italian and British type 1 diabetic patients. METHODS: The XbaI and K121Q polymorphisms were determined by PCR-RFLP in Danish type 1 diabetic patients with nephropathy (122 men/77 women, age 40.9+/-9.6 years, diabetes duration 27+/-8 years) and type 1 diabetic patients with persistent normoalbuminuria (118 men/74 women, age 42.7+/-10.2 years, diabetes duration 26+/-9 years). Proliferative retinopathy was present in 156 patients (40%), while 67 patients (17%) had no diabetic retinopathy. RESULTS: There were no differences in the frequency of GLUT-1 XbaI genotypes between type 1 diabetic patients with diabetic nephropathy and type 1 diabetic patients with normoalbuminuria: 72 (41%)/87 (50%)/16 (9%) vs 94 (49%)/74 (39%)/24 (13%) had GLUT-1 XbaI +/+, +/- or -/- genotype respectively (NS). The frequency of PC-1 KK, KQ and QQ genotypes were 141 (71%)/52 (26%)/6 (3%) vs 138 (73%)/45 (24%)/7 (4%) in patients respectively with and without nephropathy (NS). Neither were associations between the investigated polymorphisms and simplex or proliferative retinopathy revealed. CONCLUSIONS: Neither the PC-1 K121Q nor the GLUT-1 XbaI polymorphism contribute to the genetic susceptibility of diabetic microvascular complications in Danish type 1 diabetic patients.

Adolescent↗

PubMed2001

A prevalent polymorphism in the promoter of the UCP3 gene and its relationship to body mass index and long term body weight change in the Danish population.

Variability of the uncoupling protein 3 (UCP3) promoter has been associated with increased body mass index (BMI) and altered lipid profiles. Here we tested the hypothesis that variation of the UCP3 promoter is associated with either juvenile or maturity-onset obesity or body weight change over a 26-yr follow-up among Danish subjects. Mutation screening of approximately 1 kb 5' upstream of the UCP3 gene revealed one previously described -55 C-->T variant. The frequency of the polymorphism was evaluated by restriction fragment length polymorphism analysis in four groups of subjects: 1) a group of 744 obese Danish men who at the draft board examinations had a body mass index (BMI) of at least 31 kg/m(2), 2) a randomly selected control group consisting of 857 draftees, 3) 258 middle-aged subjects, and 4) 409 60-yr-old subjects. The frequency of the T allele was 26.0% (95% confidence interval, 23.8-28.2%) among the obese draftees and 26.9% (24.8-29.0%) in the control group (P = 0.6). The variant was not associated with BMI at a young age or with weight gain after a 26-yr follow-up. The frequency of the T allele was 29.5% (25.6-33.4%) in the middle-aged group and 25.8% (22.8-28.8%) among the 60-yr-old subjects. The polymorphism was not associated with increased BMI or percent body fat in these 2 groups. It is concluded that this variant does not play a major role in the development of common obesity among Danish subjects.

Adult↗

PubMed2001

Studies of genetic variability of the glucose transporter 2 promoter in patients with type 2 diabetes mellitus.

This study was performed to test the hypothesis that genetic variation in the promoter of the glucose transporter 2 (GLUT2) might predispose to prediabetic phenotypes or type 2 diabetes. A total of 1611 bp comprising the minimal promoter region of the GLUT2 gene were examined by combined single-strand conformational polymorphism and heteroduplex analysis followed by direct sequencing of identified variants on genomic DNA from 96 randomly recruited Danish type 2 diabetic patients. We identified 4 nucleotide variants, -447g-->a, -149c-->a, -122t-->c, and -44g-->a. None of the variants were positioned in known or presumed transcription factor binding sites, TATA-box, or transcriptional start site. Association studies of the -149c-->a, -122t-->c, and -44g-->a variants revealed that the variants were as prevalent in 320 type 2 diabetic patients [11.0% (95% confidence interval, 8.4-13.6), 9.8% (7.4-12.2), and 29.0% (24.4-33.6), respectively] as in 241 age-matched glucose-tolerant subjects [13.1% (9.8-16.4), 11.2% (8.3-14.1), and 33.4% (28.8-38.0), respectively]. The -447g-->a mutation was only identified in a single diabetic patient and did not show cosegregation with diabetes in the family of the proband. The three common variants showed in a primary genotype-phenotype study comprising 241 glucose-tolerant middle-aged subjects association to increased plasma glucose levels during an oral glucose tolerance test. However, this result could not be replicated in a second sample of 298 60-yr-old glucose-tolerant subjects. In conclusion, we found no evidence supporting the hypothesis that genetic variability in the minimal promoter of the GLUT2 is associated with type 2 diabetes or prediabetic phenotypes in the Danish population.

Adult↗

PubMed2001

Chronic treatment with 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside increases insulin-stimulated glucose uptake and GLUT4 translocation in rat skeletal muscles in a fiber type-specific manner.

Recent studies have demonstrated that chronic administration of AICAR (5-aminoimidazole-4-carboxamide- 1-beta-D-ribofuranoside), an activator of the AMP-activated protein kinase, increases hexokinase activity and the contents of total GLUT4 and glycogen in rat skeletal muscles. To explore whether AICAR also affects insulin-stimulated glucose transport and GLUT4 cell surface content, Wistar rats were subcutaneously injected with AICAR for 5 days in succession (1 mg/g body wt). Maximally insulin-stimulated (60 nmol/l) glucose uptake was markedly increased in epitrochlearis (EPI) muscle (average 63%, P < 0.001, n = 18-19) and in extensor digitorum longus muscle (average 26%, P < 0.001, n = 26-30). In contrast, administration of AICAR did not maximally influence insulin-stimulated glucose transport in soleus muscle. Studies of EPI muscle with the 4,4'-O-[2-[2-[2-[2-[2-[6-(biotinylamino)hexanoyl]amino]ethoxy]ethoxy] ethoxy]-4-(1-azi-2,2,2,-trifluoroethyl)benzoyl]amino-1,3-propanediyl]bis-D-mannose photolabeling technique showed a concomitant increase (average 68%, P < 0.02) in cell surface GLUT4 content after insulin exposure in AICAR-injected rats when compared with controls. In conclusion, 5 days of AICAR administration induces a pronounced fiber type-specific increase in insulin-stimulated glucose uptake and GLUT4 cell surface content in rat skeletal muscle with the greatest effect observed on white fast-twitch glycolytic muscles (EPI). These results are comparable with the effects of chronic exercise training, and it brings the AMP-activated protein kinase into focus as a new interesting target for future pharmacological intervention in insulin-resistant conditions.

Aminoimidazole Carboxamide↗

PubMed2001

In vitro and in vivo studies of a naturally occurring variant of the human p85alpha regulatory subunit of the phosphoinositide 3-kinase: inhibition of protein kinase B and relationships with type 2 diabetes, insulin secretion, glucose disappearance constant, and insulin sensitivity.

In humans, the Met326Ile missense variant of the p85alpha regulatory subunit of the phosphoinositide 3-kinase (PI3K) has been associated with either significant reductions in glucose effectiveness and intravenous glucose tolerance in Caucasians or a significantly higher insulin secretory response in Pima Indians. In the present study, we genotyped 1,190 Caucasian males to evaluate the impact in vivo of the Met326Ile variant of the p85alpha subunit of PI3K on the acute insulin response, intravenous glucose tolerance, insulin-mediated glucose uptake, and the prevalence of type 2 diabetes after 20 years of follow-up. We also expressed the variant in vitro to evaluate the impact on insulin-stimulated activation of protein kinase B (PKB). The Met326Ile variant of p85alpha was not associated with type 2 diabetes or with alterations in insulin secretion, insulin sensitivity, or intravenous glucose tolerance in vivo. Expressed in vitro, the Ile326 and the Met326 variant acted equally as a dominant-negative and prevented (60-70% inhibition) insulin-mediated activation of PKB by inhibiting the phosphorylation of PKB at Thr308. We conclude that the Met326Ile variant of the p85alpha regulatory subunit of PI3K is likely to be as functionally normal in vivo as in vitro.

Aged↗

PubMed2001

Serum leptin levels in pregnant women with type 1 diabetes mellitus.

BACKGROUND: Leptin is an important weight regulator and during pregnancy leptin is not only synthesized in adipose tissue but also in the placenta. AIM: To examine changes in serum leptin levels in women with type 1 diabetes mellitus during pregnancy and post delivery in relation to concomitant changes in maternal body weight, birth weight, glycemic control, and blood pressure. METHODS: Non-fasting serum leptin from 45 women with type 1 diabetes mellitus were studied consecutively throughout pregnancy and 3 months post partum. RESULTS: Serum leptin was positively associated with HbA1c in week 18, 22 and 30 (r=0.38, 0.41, and 0.54, respectively, p<0.05, adjusted for body weight). Moreover, serum leptin correlated positively with maternal body weight and BMI (0.45 25 kg/m2), the changes during pregnancy and the level of serum leptin were significantly greater compared to lean women (p<0.05). The women with low ambulatory blood pressure (lower tertile, mean arterial blood pressure <83.4 mmHg) showed the lowest level of serum leptin throughout pregnancy and it changed significantly differently from the women with higher blood pressure (p<0.05). CONCLUSION: Changes in serum leptin levels of pregnant women with type 1 diabetes mellitus were associated with parallel changes in maternal body weight and glycemic control. Women with low blood pressure had the lowest serum leptin levels throughout pregnancy.

Adult↗

PubMed2000

Volume control in sickle cells is facilitated by the novel anion conductance inhibitor NS1652.

A low cation conductance and a high anion conductance are characteristic of normal erythrocytes. In sickle cell anemia, the polymerization of hemoglobin S (HbS) under conditions of low oxygen tension is preceded by an increase in cation conductance. This increase in conductance is mediated in part through Ca(++)-activated K(+) channels. A net efflux of potassium chloride (KCl) leads to a decrease in intracellular volume, which in turn increases the rate of HbS polymerization. Treatments minimizing the passive transport of ions and solvent to prevent such volume depletion might include inhibitors targeting either the Ca(++)-activated K(+) channel or the anion conductance. NS1652 is an anion conductance inhibitor that has recently been developed. In vitro application of this compound lowers the net KCl loss from deoxygenated sickle cells from about 12 mmol/L cells/h to about 4 mmol/L cells/h, a value similar to that observed in oxygenated cells. Experiments performed in mice demonstrate that NS1652 is well tolerated and decreases red cell anion conductance in vivo. (Blood. 2000;95:1842-1848)

Anemia, Sickle Cell↗

PubMed2000

Adenovirus-mediated expression of a naturally occurring Asp905Tyr variant of the glycogen-associated regulatory subunit of protein phosphatase-1 in L6 myotubes.

AIMS/HYPOTHESIS: The glycogen-associated protein phosphatase-1 (PP1G) is thought to play an important part in the regulation of skeletal muscle glycogen content. We have previously identified an Asp905Tyr polymorphism of the glycogen-associated regulatory subunit of the protein phosphatase 1 (PPP1R3) gene which among healthy subjects was associated with decreased insulin stimulated non-oxidative glucose metabolism, i.e. primary glycogen synthesis. In this study, the functional effect of the polymorphism was examined in vitro. METHODS: Wild type (PPP1R3-Asp905) and mutant (PPP1R3-Tyr905) PPP1R3 were expressed in L6 myotubes using adenovirus-mediated gene transfer. Basal and insulin-stimulated glucose uptake and glycogen synthesis were measured. Furthermore, the sensitivity of glycogen synthesis to a cyclic AMP agonist was measured. RESULTS: Compared with green fluorescent protein-transduced myotubes and non-transduced myotubes, overexpression of PPP1R3-Asp905 and PPP1R3-Tyr905 increased both basal and insulin-stimulated glycogen synthesis approximately twofold. Treatment of both non-transduced and PPP1R3-transduced L6 myotubes with a cAMP agonist decreased both basal and insulin-stimulated glycogen synthesis by about 40%. Overexpression of PPP1R3 did not affect either basal or insulin-stimulated 2-deoxy-D-glucose uptake compared with green fluorescent protein-transduced cells. CONCLUSION/INTERPRETATION: Results obtained from L6 myotubes transduced with PPP1R3-Asp905 or PPP1R3-Tyr905 showed no statistically significant difference. Therefore, the Asp905Tyr variant alone is unlikely to account for the decreased insulin stimulated non-oxidative glucose metabolism observed in the human study reported previously.

Adenoviridae↗

PubMed2000

Missense mutations in the human insulin promoter factor-1 gene and their relation to maturity-onset diabetes of the young and late-onset type 2 diabetes mellitus in caucasians.

Increasing evidence suggests that defects in genes encoding transcription factors that are expressed in the pancreatic beta-cells may be important contributors to the genetic basis of type 2 diabetes mellitus. Maturity-onset diabetes of the young (MODY) now exists in five subtypes (MODY1-5), four of which are caused by mutations in transcription factors hepatocyte nuclear factor-4alpha (HNF-4alpha), HNF-1alpha, insulin promoter factor-1 (IPF-1), and HNF-1beta (MODY1, -3, -4, and -5). Recent evidence from the British population even suggested that IPF-1 may be a predisposing gene for type 2 diabetes. Thus, highlighting the potential role of this transcription factor in the genetic basis of Danish and Italian MODY as well as in Danish patients with late-onset type 2 diabetes mellitus, we have examined the human IPF-1 gene for mutations by single strand conformation polymorphism and heteroduplex analysis in 200 Danish patients with late-onset type 2 diabetes and in 44 Danish and Italian MODY patients. In the patients with late-onset type 2 diabetes we identified a noncoding G insertion/deletion polymorphism at nucleotide -108, a silent G54G, and a rare missense D76N variant. Moreover, a Danish MODY patient was carrier of an A140T variant. Neither the D76N nor the A140T segregated with diabetes, and their transcriptional activation of the human insulin promoter expressed in vitro was indistinguishable from that of the wild type (115 +/- 21% and 84 +/- 12% vs. 100%). We conclude that variants in IPF-1 are not a common cause of MODY or late-onset type 2 diabetes in the Caucasian population, and that in terms of insulin transcription both the N76 and the T140 mutations are likely to represent functionally normal IPF-1 variants with no direct role in the pathogenesis of MODY or late-onset type 2 diabetes mellitus.

3T3 Cells↗

PubMed2000

Studies of the variability of the genes encoding the insulin-like growth factor I receptor and its ligand in relation to type 2 diabetes mellitus.

Insulin-like growth factor I (IGF-I) is an important regulator of many aspects of growth, differentiation, and development, and as low birth weight has been associated with impaired glucose tolerance and overt type 2 diabetes in adult life, we considered the genes encoding the IGF-I and the IGF-I receptor (IGF-IR) as candidates for low birth weight, insulin resistance, and type 2 diabetes. Here we report the mutational analysis of the coding regions of the IGF-I and IGF-IR performed on genomic DNA from probands of 82 Danish type 2 diabetic families. No mutations predicting changes in the amino acid sequences of the IGF-I or IGF-IR genes were detected, but several silent and intronic polymorphisms were found. The impact of the most prevalent polymorphism, GAG1013GAA of the IGF-IR, was evaluated in a population-based sample of 349 young healthy subjects, where the variant had an allele frequency of 0.44 (95% confidence interval, 0.40-0.48). No significant relationships between this variant and birth weight, birth length, or insulin sensitivity index were detected. In addition, we did not observe any significant differences in allelic frequencies of the codon 1013 variant between 395 type 2 diabetic patients (allele frequency, 0.52; 95% confidence interval, 0.49-0.55) and 238 matched glucose-tolerant control subjects (allelic frequency, 0.47; 95% confidence interval, 0.43-0.50). In conclusion, variability in the coding regions of IGF-I and the IGF-IR does not associate with reduced birth weight, insulin sensitivity index, or type 2 diabetes in the Danish population.

Adult↗

PubMed2000

The -238 and -308 G-->A polymorphisms of the tumor necrosis factor alpha gene promoter are not associated with features of the insulin resistance syndrome or altered birth weight in Danish Caucasians.

Recently, two G-->A polymorphisms at positions -308 and -238, in the promoter of the tumor necrosis factor alpha (TNF-alpha) gene, have been identified. These variants have, in different ethnic groups, been linked to estimates of insulin resistance and obesity. The objective of the present study was to investigate whether these genetic variants of TNF-alpha were associated with features of the insulin resistance syndrome or alterations in birth weight in two Danish study populations comprising 380 unrelated young healthy subjects and 249 glucose-tolerant relatives of type 2 diabetic patients, respectively. All study participants underwent an iv glucose tolerance test with the addition of tolbutamide after 20 min. In addition, a number of biochemical and anthropometric measures were performed on each subject. The subjects were genotyped for the polymorphisms by applying PCR restriction fragment length polymorphism. Neither of the variants was related to altered insulin sensitivity index or other features of the insulin resistance syndrome (body mass index, waist to hip ratio, fat mass, fasting serum lipids or fasting serum insulin or C-peptide). Birth weight and the ponderal index were also not associated with the polymorphisms. In conclusion, although the study was carried out on sufficiently large study samples, the study does not support a major role of the -308 or -238 substitutions of the TNF-alpha gene in the pathogenesis of insulin resistance or altered birth weight among Danish Caucasian subjects.

Adolescent↗

PubMed2000

Variability of the insulin receptor substrate-1, hepatocyte nuclear factor-1alpha (HNF-1alpha), HNF-4alpha, and HNF-6 genes and size at birth in a population-based sample of young Danish subjects.

Reduced size at birth has been proposed to be a risk factor for insulin resistance and type 2 diabetes. It is, however, not known whether this association is explained by unfavorable intrauterine environment or by specific susceptibility genotypes predisposing for both reduced fetal growth and insulin resistance and type 2 diabetes. The present study was performed to evaluate whether previously identified amino acid polymorphisms of genes that from animal models have been suggested to play important roles during fetal development are associated with alterations in size at birth. The study population comprised 380 subjects randomly recruited from a population of young Danish Caucasian individuals, aged 18-32 yr. The original data of birth length and weight for 331 of 380 subjects were obtained from the midwife records. The Gly/Arg972 of insulin receptor substrate-1 (IRS-1), the Thr/Ile130 of the hepatocyte nuclear factor-4alpha (HNF-4alpha), the Pro/Ala75 of HNF-6, and the Ile/Leu27, Ala/Val93, and Ser/Asn4s7 polymorphisms of the HNF-lalpha gene were examined for association with birth weight and length and the ponderal index. Using a generalized linear model, including gender and the genotype as fixed variables, and applying Bonferroni correction for multiple testing, we could not demonstrate any significant differences in these estimates among wild-type, heterozygous, and homozygous carriers with respect to any of the gene variants. In conclusion, common variability in the genes encoding the IRS-1, HNF-lalpha, HNF-4alpha, and HNF-6 proteins can be excluded as major factors influencing size at birth among Danish Caucasian subjects.

Adolescent↗

PubMed2000

Studies of the synergistic effect of the Trp/Arg64 polymorphism of the beta3-adrenergic receptor gene and the -3826 A-->G variant of the uncoupling protein-1 gene on features of obesity and insulin resistance in a population-based sample of 379 young Danish subjects.

This study examined whether the simultaneous presence of the previously identified Trp/Arg64 polymorphism of the beta3-adrenergic receptor (BAR) gene and the -3826 A-->G nucleotide variant of the uncoupling protein-1 (UCP1) gene are associated with obesity, insulin resistance, or alterations in size at birth in a Danish study population comprising 379 unrelated young Caucasian subjects. All study participants underwent an iv glucose tolerance test with addition of tolbutamide after 20 min. In addition, a number of biochemical and anthropometric measures were performed on each subject. The subjects were genotyped for the 2 polymorphisms by applying PCR-restriction fragment length polymorphism. The subjects were divided into 4 groups according to their BAR and UCP1 genotype: wild-type carriers (n = 184), only Trp/Arg64 carriers (n = 29), only A-->G UCP1 carriers (n = 146), and carriers of both genetic variants (n = 20). There were no differences across the genotype groups with respect to body mass index, fat mass, waist to hip ratio, birth weight or length, ponderal index, or weight gain during childhood or adolescence, nor was the combined genotype related to alterations in fasting serum levels of lipids, insulin, or C peptide or the insulin sensitivity index. In conclusion, the present study failed to demonstrate an additive or synergistic effect of the Trp/Arg64 variant of the BAR gene and the -3826 A-->G variant of the UCP1 gene on the development of obesity and insulin resistance among randomly recruited Danish Caucasian subjects.

Adolescent↗