Biomedical subjects

Oluf Pedersen

Publications and source records attributed to Oluf Pedersen.

At least 19 recordsLinked to original sources

PubMed2007

The functional Pro129Thr variant of the FAAH gene is not associated with various fat accumulation phenotypes in a population-based cohort of 5,801 whites.

Food intake and weight gain are influenced by endocannabinoids whose actions are regulated by the fatty acid amide hydrolase (FAAH) enzyme. The homozygous Thr/Thr genotype of the functional Pro129Thr variant (rs324420) in the gene encoding FAAH was recently reported to associate with overweight and obesity in white and black populations. We investigated the Pro129Thr variant in relation to overweight and obesity in a relatively large population-based study sample of Danish whites (n=5,801). In case-control studies of obesity, a borderline association with the major Pro allele was identified; however, after correction for multiple testing, no association was found. Furthermore, a possible association between the major Pro allele and obesity was not supported by studies of obesity-related quantitative traits. In conclusion, in a large study sample, we were unable to find robust evidence of an association of the Pro129Thr FAAH variant with overweight, obesity, and any related quantitative traits among the examined whites.

Adult↗

PubMed2007

Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution.

We recently described an association between risk of type 2diabetes and variants in the transcription factor 7-like 2 gene (TCF7L2; formerly TCF4), with a population attributable risk (PAR) of 17%-28% in three populations of European ancestry. Here, we refine the definition of the TCF7L2 type 2diabetes risk variant, HapB(T2D), to the ancestral T allele of a SNP, rs7903146, through replication in West African and Danish type 2 diabetes case-control studies and an expanded Icelandic study. We also identify another variant of the same gene, HapA, that shows evidence of positive selection in East Asian, European and West African populations. Notably, HapA shows a suggestive association with body mass index and altered concentrations of the hunger-satiety hormones ghrelin and leptin in males, indicating that the selective advantage of HapA may have been mediated through effects on energy metabolism.

Asian People↗

PubMed2006

Relationships between the functional PPARalpha Leu162Val polymorphism and obesity, type 2 diabetes, dyslipidaemia, and related quantitative traits in studies of 5799 middle-aged white people.

Peroxisome proliferator-activated receptor-alpha (PPARalpha) is a nuclear receptor capable of regulating the expression of genes involved in peroxisomal and mitochondrial beta-oxidation pathways. The common Leu162Val polymorphism in the gene encoding PPARalpha has inconsistently shown association with quantitative traits related to obesity, type 2 diabetes, and dyslipidaemia. We genotyped the Leu162Val polymorphism in 1383 patients with type 2 diabetes and 4401 control subjects with normal glucose tolerance (NGT) without showing any association between diabetes and genotype. In addition, the Leu162Val polymorphism was not associated with WHO-defined obesity or dyslipidaemia in case-control settings involving 961 obese and 2563 lean subjects and 1399 dyslipidaemic and 4399 normolipidaemic subjects, respectively. Quantitative trait studies of metabolic variables were carried out in 5799 middle-aged, treatment-naïve subjects showing a difference in fasting serum triglyceride concentrations among homozygous Val-carriers (Leu/Leu+Leu/Val, n=5782, 1.33+/-1.35 mmol/l vs. Val/Val, n=17, 2.22+/-2.4 mmol/l, p=0.007). Similarly, Val/Val was associated with increased fasting serum total cholesterol concentrations (p=0.01). In conclusion, in a relative large-scale study of middle-aged whites we found no evidence of association between the PPARalpha Leu162Val polymorphism and obesity or type 2 diabetes. If replicated, the Val162Val variant may, however, confer an increase in fasting levels of serum lipids.

Aged↗

PubMed2006

Genotype-by-nutrient interactions assessed in European obese women. A case-only study.

BACKGROUND: The development of obesity is influenced by both genetic and environmental risk factors. Whereas changes in the environment appear to be responsible for the increasing prevalence of obesity, genetic factors interacting with environmental factors would contribute to explain obesity onset and severity. AIM: To explore epidemiologic genotype-by-nutrient interactions in obesity. METHODS: A total of 42 polymorphisms of 26 candidate genes for obesity were genotyped in 549 adult obese women recruited from eight European centres in a case-only study. The nutritional variables assessed in this study were the dietary fibre intake (grams per day), the ratio of dietary polyunsaturated fat to saturated fat (P:S ratio) and the percentage of energy derived from fat in the diet as calculated from a weighed three-day food record (%E). Under the assumption of genotype-nutrient independence in the population, the odds ratio calculated in a sample of obese women would indicate the existence of genotype-by-nutrient interactions, measured as deviations from the multiplicative effects of the genetic and the nutrient factors separately. RESULTS: No new but confirmaty evidences for genotype-by-nutrient interactions in obesity were detected in this case-only study. The test of interaction between fibre intake and the -514 C > T polymorphism of the hepatic lipase gene (LIPC) yielded P-values of 0.01 across different statistical models. Likewise, the -11377G > C polymorphism of the adiponectin gene (ADIPOQ) and the -681 C > G polymorphism of the PPARG3 gene might interact with the percentage of energy derived from fat in the diet for the development of obesity (P-values in the range of 0.01-0.05 across different statistical models). The P-values were not adjusted for multiple testing, so these results should be considered with caution. CONCLUSIONS: Although the use of obese-only samples is theoretically a useful approach to detect interactions, few genotype-by-nutrient interactions have been suggested in obese European women after the analysis of candidate polymorphisms and the selected nutrient variables. The most remarkable multiplicative interaction found in this study refers to the combination of the hepatic lipase gene polymorphism -514 C > T and fibre intake.

Adiponectin↗

PubMed2006

Studies of the common DIO2 Thr92Ala polymorphism and metabolic phenotypes in 7342 Danish white subjects.

CONTEXT: The type 2 iodothyronine deiodinase (D2) catalyzes the conversion of T(4) to the active form of thyroid hormone, which is a critical regulator of thermogenesis and glucose metabolism. A Thr92Ala polymorphism in the gene encoding D2 (DIO2) has been reported to associate with insulin resistance. OBJECTIVE: The aim of the present study was to assess the impact of the DIO2 Thr92Ala variant on type 2 diabetes (T2D), obesity, and related quantitative metabolic traits including measures of insulin resistance. Because DIO2 is activated through a beta-adrenergic receptor-dependent pathway, we further hypothesized that variation in the ADRB genes interacts with DIO2 Thr92Ala variant to influence metabolic traits. DESIGN AND PATIENTS: The DIO2 polymorphism was genotyped in a total of 7342 white subjects including 1405 T2D patients. RESULTS: We detected no significant association of the DIO2 Thr92Ala polymorphism with T2D or obesity. We observed nominal significant associations of genotype with increased area under the serum insulin curve during an oral glucose tolerance test (P = 0.03) and elevated fasting plasma glucose (P = 0.02) in homozygous Ala92 allele carriers, the latter strengthened by epistasis with the ADRB2 Gly16Arg variant in a double recessive model (P = 0.004). However, after permutation procedure, performed to correct for multiple hypothesis testing, the associations did not reach study-wide significance. CONCLUSIONS: The DIO2 Thr92Ala variant does not confer an increased risk of T2D, obesity, or insulin resistance.

Adult↗

PubMed2006

Association between neuromedin U gene variants and overweight and obesity.

BACKGROUND: Neuromedin U (NMU) is an anorexic neuropeptide expressed in the hypothalamus. Mice lacking the NmU gene are hyperphagic and obese, whereas mice overexpressing Nmu are hypophagic and lean. OBJECTIVE: Our objective was to investigate whether variants in NMU are associated with human obesity. DESIGN: The coding region of NMU was analyzed for variants in obese Czech children and obese Danish adults. Identified missense variants were investigated for cosegregation with obesity in families or association with obesity in the general population. SETTING: The study was performed at Steno Diabetes Center, Denmark, and Department of Pediatrics, Charles University, Czech Republic. SUBJECTS AND METHODS: A total of 289 Czech children and adolescents with early-onset obesity and 84 Danish obese adults were analyzed for variants in NMU. A NMU Ala19Glu polymorphism was genotyped in 5851 Danish subjects of the Inter99 cohort, and a rare NMU Arg165Trp mutation was sequenced in the proband family and in 53 lean and unrelated Czech subjects. RESULTS: The rare NMU Arg165Trp variant cosegregated with childhood obesity in a Czech family. Homozygous carriers of the Glu allele of the NMU Ala19Glu polymorphism were more common in the overweight and obese subjects; the Glu/Glu frequency was 0.4 (95% confidence interval, 0.2-0.6) among 2586 lean subjects (BMI < 25 kg/m2) and 0.9 (95% confidence interval, 0.7-1.1) among 3265 overweight and obese subjects (body mass index >or= 25 kg/m2) [odds ratio, 2.5 (1.2-5.3); P = 0.01]. CONCLUSION: Amino acid variants in NMU associate with overweight and obesity, suggesting that NMU is involved in energy regulation in humans.

Adolescent↗

PubMed2006

Variation in CAPN10 in relation to type 2 diabetes, obesity and quantitative metabolic traits: studies in 6018 whites.

The first type 2 diabetes (T2D) gene to be identified in a genome wide scan followed by positional cloning was CAPN10 encoding the cysteine protease calpain-10. Subsequently, a large number of studies have investigated variation in CAPN10 in relation to T2D. Two CAPN10 single nucleotide polymorphisms (SNPs), the SNP43 (rs3792267) and the SNP44 (rs2975760), have been associated with T2D in some, but not all studies conducted in a wide range of ethnicities. We investigated the two SNPs for association with T2D in a relatively large, homogenous population of Danish whites (n = 1359 T2D cases, n = 4659 normoglycemic and glucose-tolerant control subjects), however, no significant associations of the SNP43 or the SNP44 variant with T2D were found. Neither were the two variants associated with obesity, and no association of either variant with diabetes-related quantitative traits was found in a study involving a population-based sample of 5698 middle-aged subjects. Meta-analyses, however, of the present and previously published studies involving 15,368 (SNP43) or 13,628 (SNP44) subjects yielded odds ratios of 1.09 (95% CI 1.02-1.16, p = 0.007) and 1.15 (1.07-1.23, p = 0.0002), respectively, for association with T2D. In conclusion, in a relatively large study sample of whites we found no consistent evidence of association of the CAPN10 SNP43 or SNP44 with T2D, obesity, or related quantitative traits, although meta-analyses of these two CAPN10 SNPs demonstrated an association with T2D.

Blood Glucose↗

PubMed2006

Association of the calpain-10 gene with type 2 diabetes in Europeans: results of pooled and meta-analyses.

We conducted pooled and meta-analyses of the association of the calpain-10 gene (CAPN10) polymorphisms SNP-43, Indel-19 and SNP-63 individually and as haplotypes with type 2 diabetes (T2D) in 3237 patients and 2935 controls of European ancestry. In the pooled analyses, the common SNP-43*G allele was associated with modest but statistically significant increased risk of T2D (odds ratio (OR)=1.11 (95% confidence interval (CI), 1.02-1.20), P=0.01). Two haplotype combinations were associated with increased risk of T2D (1-2-1/1-2-1, OR=1.20 (1.03-1.41), P=0.02; and 1-1-2/1-2-1, OR=1.26 (1.01-1.59), P=0.04) and one with decreased risk (1-1-1/2-2-1, OR=0.86 (0.75-0.99), P=0.03). The meta-analysis also showed a significant effect of the 1-2-1/1-2-1 haplogenotype on risk (OR=1.25 (1.05-1.50), P=0.01). However, there was evidence for heterogeneity with respect to this effect (P=0.06). The heterogeneity appeared to be due to data sets in which the cases were selected from samples used in linkage studies of T2D. Using only the population-based case-control samples removed the heterogeneity (P=0.89) and strengthened the evidence for association with T2D in both the pooled (SNP-43*G, OR=1.19 (1.07-1.32), P=0.001; 1-2-1/1-2-1 haplogenotype, OR=1.46 (1.19-1.78), P=0.0003; 1-1-2/1-2-1 haplogenotype, OR=1.52 (1.12-2.06), P=0.007; and 1-1-1/2-2-1 haplogenotype, OR=0.83 (0.70-0.99), P=0.03) and the meta-analysis (SNP-43*G, OR=1.18 (1.05-1.32), P=0.005; 1-2-1/1-2-1 haplogenotype, OR=1.68 (1.33-2.11), P=0.00001). The pooled and meta-analyses as well as the linkage disequilibrium and haplotype diversity studies suggest a role for genetic variation in CAPN10 affecting risk of T2D in Europeans.

Calpain↗

PubMed2006

Genetic polymorphisms and weight loss in obesity: a randomised trial of hypo-energetic high- versus low-fat diets.

OBJECTIVES: To study if genes with common single nucleotide polymorphisms (SNPs) associated with obesity-related phenotypes influence weight loss (WL) in obese individuals treated by a hypo-energetic low-fat or high-fat diet. DESIGN: Randomised, parallel, two-arm, open-label multi-centre trial. SETTING: Eight clinical centres in seven European countries. PARTICIPANTS: 771 obese adult individuals. INTERVENTIONS: 10-wk dietary intervention to hypo-energetic (-600 kcal/d) diets with a targeted fat energy of 20%-25% or 40%-45%, completed in 648 participants. OUTCOME MEASURES: WL during the 10 wk in relation to genotypes of 42 SNPs in 26 candidate genes, probably associated with hypothalamic regulation of appetite, efficiency of energy expenditure, regulation of adipocyte differentiation and function, lipid and glucose metabolism, or production of adipocytokines, determined in 642 participants. RESULTS: Compared with the noncarriers of each of the SNPs, and after adjusting for gender, age, baseline weight and centre, heterozygotes showed WL differences that ranged from -0.6 to 0.8 kg, and homozygotes, from -0.7 to 3.1 kg. Genotype-dependent additional WL on low-fat diet ranged from 1.9 to -1.6 kg in heterozygotes, and from 3.8 kg to -2.1 kg in homozygotes relative to the noncarriers. Considering the multiple testing conducted, none of the associations was statistically significant. CONCLUSIONS: Polymorphisms in a panel of obesity-related candidate genes play a minor role, if any, in modulating weight changes induced by a moderate hypo-energetic low-fat or high-fat diet.

Journal Article↗

PubMed2006

PROactive study.

Explore the source record for details and available documents.

Blood Pressure↗

PubMed2006

Lens fluorescence in relation to glucose tolerance and genetic predisposition to type 2 diabetes mellitus in a population-based study.

PURPOSE: The fluorescence of the lens has the characteristics of a life-long cumulative index of glycemia, and it is elevated in patients with diabetes in proportion to the duration of diabetes and the level of glycemia. Consequently, lens fluorometry should be capable of providing an estimate of prediagnostic disease duration when patients are diagnosed with type 2 diabetes. Among euglycemic subjects, first-degree relatives of patients with type 2 diabetes tend to have higher glycemia levels than subjects who are unrelated to diabetes patients. They should therefore also have the higher lens fluorescence values. METHODS: The study comprised 218 Caucasian subjects in self-reported good health aged 30-88 years who were recruited from population-based studies to represent approximately equal proportions of different type 2 diabetes family history characteristics: no diabetic relative, first-degree offspring, second-degree offspring, not first-degree offspring but possibly second-degree offspring, or uncertain family history. Characterization of subjects included oral glucose tolerance testing and lens fluorometry. RESULTS: Type 2 diabetes was diagnosed in 10 subjects (4.6% of the population) and impaired glucose tolerance in 12 subjects (5.5%). Regression analysis indicated a prediagnostic duration of type 2 diabetes of 2.7 years versus 0.1 years for impaired glucose tolerance. Neither group demonstrated significantly increased lens fluorescence compared with euglycemic subjects. Being a first-degree relative of a patient with type 2 diabetes was associated with higher lens fluorescence than having no relative with diabetes (p = 0.02). CONCLUSIONS: Population screening by fasting blood glucose measurement can advance the diagnosis and initiation of treatment of type 2 diabetes mellitus by nearly a decade, compared with previous studies of patients diagnosed in routine clinical practice. In addition to higher than normal glycemia, euglycemic subjects who are offspring of patients with type 2 diabetes also have both elevated lens fluorescence and elevated glycemia. Fasting blood glucose measurement remains the method of choice for type 2 diabetes screening.

Adult↗

PubMed2006

A novel -192c/g mutation in the proximal P2 promoter of the hepatocyte nuclear factor-4 alpha gene (HNF4A) associates with late-onset diabetes.

Recently, it has been shown that mutations in the P2 promoter of the hepatocyte nuclear factor (HNF)-4 alpha gene (HNF4A) cause maturity-onset diabetes of the young (MODY), while single nucleotide polymorphisms in this locus are associated with type 2 diabetes. In this study, we examined 1,189 bp of the P2 promoter and the associated exon 1D of HNF4A for variations associated with diabetes in 114 patients with type 2 diabetes, 72 MODYX probands, and 85 women with previous gestational diabetes mellitus. A -192c/g mutation was found in five patients. We screened 1,587 diabetic subjects and 4,812 glucose-tolerant subjects for the -192c/g mutation and identified 5 diabetic and 1 glucose-tolerant mutation carriers (P=0.004). Examination of the families showed that carriers of the -192c/g mutation had a significantly impaired glucose-stimulated insulin release and lower levels of serum total cholesterol compared with matched control subjects. Furthermore, the mutation disrupted the binding of an unidentified sequence-specific DNA binding complex present in human islet extracts. Also, two novel linked polymorphisms in the P2 promoter at positions -1107g/t and -858c/t were identified. These variants were not significantly associated with type 2 diabetes or any pre-diabetic traits. In conclusion, a rare, novel mutation that disrupts a protein binding site in the pancreatic HNF4A promoter associates with late-onset diabetes.

Adult↗

PubMed2006

The HADHSC gene encoding short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) and type 2 diabetes susceptibility: the DAMAGE study.

The short-chain l-3-hydroxyacyl-CoA dehydrogenase (SCHAD) protein is involved in the penultimate step of mitochondrial fatty acid oxidation. Previously, it has been shown that mutations in the corresponding gene (HADHSC) are associated with hyperinsulinism in infancy. The presumed function of the SCHAD enzyme in glucose-stimulated insulin secretion led us to the hypothesis that common variants in HADHSC on chromosome 4q22-26 might be associated with development of type 2 diabetes. In this study, we have performed a large-scale association study in four different cohorts from the Netherlands and Denmark (n = 7,365). Direct sequencing of HADHSC cDNA and databank analysis identified four tagging single nucleotide polymorphisms (SNPs) including one missense variant (P86L). Neither the SNPs nor haplotypes investigated were associated with the disease, enzyme function, or any relevant quantitative measure (all P > 0.1). The present study provides no evidence that the specific HADHSC variants or haplotypes examined do influence susceptibility to develop type 2 diabetes. We conclude that it is unlikely that variation in HADHSC plays a major role in the pathogenesis of type 2 diabetes in the examined cohorts.

3-Hydroxyacyl CoA Dehydrogenases↗

PubMed2006

IL6 gene promoter polymorphisms and type 2 diabetes: joint analysis of individual participants' data from 21 studies.

Several lines of evidence indicate a causal role of the cytokine interleukin (IL)-6 in the development of type 2 diabetes in humans. Two common polymorphisms in the promoter of the IL-6 encoding gene IL6, -174G>C (rs1800795) and -573G>C (rs1800796), have been investigated for association with type 2 diabetes in numerous studies but with results that have been largely equivocal. To clarify the relationship between the two IL6 variants and type 2 diabetes, we analyzed individual data on >20,000 participants from 21 published and unpublished studies. Collected data represent eight different countries, making this the largest association analysis for type 2 diabetes reported to date. The GC and CC genotypes of IL6 -174G>C were associated with a decreased risk of type 2 diabetes (odds ratio 0.91, P = 0.037), corresponding to a risk modification of nearly 9%. No evidence for association was found between IL6 -573G>C and type 2 diabetes. The observed association of the IL6 -174 C-allele with a reduced risk of type 2 diabetes provides further evidence for the hypothesis that immune mediators are causally related to type 2 diabetes; however, because the association is borderline significant, additional data are still needed to confirm this finding.

Case-Control Studies↗

PubMed2006

EIF4A2 is a positional candidate gene at the 3q27 locus linked to type 2 diabetes in French families.

One of the most replicated loci influencing type 2 diabetes-related quantitative traits (quantitative trait loci [QTL]) is on chromosome 3q27 and modulates both type 2 diabetes-and metabolic syndrome-associated phenotypes. A QTL for type 2 diabetes age of onset (logarithm of odds [LOD] score = 3.01 at D3S3686, P = 0.0001) was identified in a set of French families. To assess genetic variation underlying both age-of-onset QTL and our previous type 2 diabetes linkage in a 3.87-Mb interval, we explored 36 single nucleotide polymorphisms (SNPs) in two biologically relevant candidate genes for glucose homeostasis, kininogen (KNG1), and eukaryotic translation initiation factor 4alpha2 (EIF4A2). Analysis of 148 families showed significant association of a frequent SNP, rs266714, located 2.47 kb upstream of EIF4A2, with familial type 2 diabetes (family-based association test, P = 0.0008) and early age of onset (P = 0.0008). This SNP also contributes to both age-of-onset QTL (1.13 LOD score decrease P = 0.02) and type 2 diabetes linkage (genotype identical-by-descent sharing test, P = 0.02). However, no association was observed in three independent European diabetic cohorts. EIF4A2 controls specific mRNA translation and protein synthesis rate in pancreatic beta-cells, and our data indicates that EIF4A2 is downregulated by high glucose in rat beta-INS832/13 cells. The potential role of EIF4A2 in glucose homeostasis and its putative contribution to type 2 diabetes in the presence of metabolic stress will require further investigation.

Age of Onset↗

PubMed2006

Monitoring kidney function in type 2 diabetic patients with incipient and overt diabetic nephropathy.

OBJECTIVE: The purpose of this study was to assess agreement between glomerular filtration rate (GFR) and the decline in GFR estimated with the Modification of Diet in Renal Disease (MDRD) Study Group equation or the Cockcroft-Gault formula and measured by the plasma clearance of 51Cr-EDTA. RESEARCH DESIGN AND METHODS: We followed a cohort of 156 microalbuminuric type 2 diabetic patients for 8 years with four measurements of GFR and another cohort of 227 type 2 diabetic patients with overt diabetic nephropathy for 6.5 (range 3-17) years with seven (3-22) measurements of GFR. RESULTS: For patients with microalbuminuria, mean +/- SD baseline GFR was 117 +/- 24 measured, 92 +/- 20 estimated (MDRD equation), or 103 +/- 24 ml x min(-1) per 1.73 m2 estimated (Cockcroft-Gault formula) (both P < 0.001); 95% limits of agreement were -66.1 to 20.3 (MDRD equation) and -58.7 to 30.7 (Cockcroft-Gault formula). The rate of decline in GFR was 4.1 +/- 4.2 measured, 2.9 +/- 2.8 estimated (MDRD equation), or 3.4 +/- 3.2 ml x min(-1) per 1.73 m2 estimated (Cockcroft-Gault formula) (both P < 0.001). For patients with overt nephropathy, baseline GFR was 84 +/- 30 measured, 73 +/- 24 estimated (MDRD equation), or 81 +/- 28 ml x min(-1) per 1.73 m2 estimated (Cockcroft-Gault formula) (both P < 0.001) with 95% limits of agreement -47 to 25 (MDRD equation) and -39 to 33 (Cockcroft-Gault formula). The rate of decline in GFR was 5.2 +/- 4.1 measured, 4.2 +/- 3.8 estimated (MDRD equation), and 4.6 +/- 4.1 ml x min(-1) per 1.73 m2 estimated (Cockcroft-Gault formula) (both P < 0.001). CONCLUSIONS: Particularly in microalbuminuric (hyperfiltering) patients, GFR is significantly underestimated with wide limits of agreement by the MDRD equation as well as by the Cockcroft-Gault formula. The rate of decline in GFR is also significantly underestimated with both equations. This makes GFR estimations based upon these equations unacceptable for monitoring kidney function in type 2 diabetic patients with incipient and overt diabetic nephropathy.

Albuminuria↗

PubMed2005

The prevalence of the metabolic syndrome in a danish population of women with previous gestational diabetes mellitus is three-fold higher than in the general population.

CONTEXT: Diabetes and obesity, components of the metabolic syndrome, are common characteristics of women with prior gestational diabetes mellitus (GDM). Due to increasing incidence of diabetes and obesity, the metabolic syndrome might comprise a major health problem among these women. OBJECTIVE: The objective was to estimate the prevalence of the metabolic syndrome by three different criteria [World Health Organization 1999 (WHO), The National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults 2001, and European Group for the Study of Insulin Resistance 2002] among women with previous GDM. DESIGN: We conducted a follow-up study of a Danish cohort of women admitted in 1978-1996 to the Diabetes and Pregnancy Center, Rigshospitalet, Copenhagen University Hospital, with diet-treated GDM. The follow-up took place in 2000-2002 at median 9.8 yr (interquartile range 6.4-17.2) after pregnancy. Results were compared with a control group of 1000 age-matched women from a population-based sample (Inter99). PARTICIPANTS: Four hundred eighty-one women at median age 43 yr (interquartile range 38-48) participated. MAIN OUTCOME MEASURES: The main outcome measures were body mass index (BMI), glucose tolerance, blood pressure, lipid profile, and insulin resistance. RESULTS: Independent of the criteria, the prevalence of the metabolic syndrome was three times higher in the prior GDM group, compared with the control group (e.g. WHO: 38.4 vs. 13.4%, P < 0.0005). Age- and BMI-adjusted odds ratio for having the WHO-defined metabolic syndrome was 3.4 (95% confidence interval 2.5-4.8) for the prior GDM group vs. the control group. Obese women (BMI > 30 kg/m(2)) with previous GDM had a more than 7-fold increased prevalence of the metabolic syndrome (WHO), compared with normal-weight prior GDM women (BMI < 25 kg/m(2)). In glucose-tolerant women, the prevalence was doubled in the prior GDM group, compared with control group. CONCLUSION: The prevalence of the metabolic syndrome was three times as high in women with prior diet-treated GDM, compared with age-matched control subjects.

Adult↗

PubMed2005

Studies of variations of the cyclin-dependent kinase inhibitor 1C and the cyclin-dependent kinase 4 genes in relation to type 2 diabetes mellitus and related quantitative traits.

CDK4 is involved in the regulation of body weight, pancreatic beta-cell proliferation, insulin responsiveness, and diabetes pathogenesis. CDK4 activity is inhibited by CDKN1C, which is regulated by insulin. In addition, CDKN1C plays an important role in beta-cell proliferation and is involved in the pathogenesis of the Beckwith-Wiedemann syndrome, a disorder characterized by neonatal hyperinsulinaemic hypoglycaemia and pre- and post-natal overgrowth. The aim of this study was to investigate if variations in the proximal promoter and the coding region of the CDKN1C and CDK4 genes are associated with type 2 diabetes or changes in related quantitative phenotypes among glucose-tolerant subjects. Mutation analyses of the two genes in 62 type 2 diabetic patients resulted in the discovery of seven variants of CDKN1C and two variants of CDK4. In a case-control study comprising 717 type 2 diabetic patients and 518 glucose-tolerant subjects the most frequent variants did not show any difference in allele frequencies between the type 2 diabetic patients and the control subjects. However, in two genotype-quantitative trait correlation studies involving 206 glucose-tolerant offspring of type 2 diabetic patients and 359 young, healthy subjects the CDKN1C del171APVA variant associated with increased birth weight (P=0.05 and P=0.05). Furthermore, the same variant tended to be associated with decreased basal glucose oxidation among 16 genotypically discordant dizygotic twins (P=0.03). In a genotype-quantitative trait study involving 500 middle-aged glucose-tolerant subjects the CDK4 IVS2-31G-->A variant was associated with an increased waist circumference (P=0.03) and waist-to-hip ratio (P=0.02) and altered fasting plasma glucose (P=0.03). However, these later findings could not be replicated in additional studies. In conclusion, variants in CDKN1C may contribute to the inter-individual variation in birth weight.

Aged↗