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A Albrechtsen,
N Grarup,
Y Li,
T Sparsø,
G Tian,
H Cao,
T Jiang,
S Y Kim,
T Korneliussen,
Q Li, [......],
C Christensen,
I Brandslund,
T Lauritzen,
D R Witte,
A Linneberg,
T Jørgensen,
T Hansen,
J Wang,
R Nielsen,
O Pedersen
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ABSTRACT: AIMS/HYPOTHESIS: Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes. METHODS: The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case-control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans. RESULTS: Exome sequencing identified 70,182 polymorphisms with MAF >1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 × 10(-14)), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 × 10(-11)) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 × 10(-10)). CONCLUSIONS/INTERPRETATION: We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.
Diabetologia 11/2012; · 6.81 Impact Factor
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ABSTRACT: AIMS: The aim was to evaluate the impact of family history of diabetes on the phenotype of patients diagnosed with Type 2 diabetes and the frequency of susceptibility genotypes. METHODS: Patients with Type 2 diabetes with family history for both Type 1 and Type 2 diabetes (FH(MIX) , n = 196) or Type 2 diabetes only (FH(T2) , n = 139) matched for age, sex, BMI and age at diagnosis, underwent an oral glucose tolerance test and a combined glucagon test and insulin tolerance test. Glutamic acid decarboxylase (GAD) antibodies and major Type 1 and Type 2 diabetes susceptibility gene variants were analysed. Patients were stratified into groups according to family history or GAD antibody positivity (GADA+, GADA-) or a combination of these (GADA+/FH(MIX,) GADA+/FH(T2,) GADA-/FH(MIX,) GADA-/FH(T2) ). RESULTS: Compared with other patients, those with FH(MIX) more often had GAD antibodies (14.3 vs. 4.3%, P = 0.003), and those with both FH(MIX) and GAD antibodies had the highest frequency of insulin deficiency (stimulated serum C-peptide < 0.7 nmol/l, GADA+/FH(MIX) 46.4% vs. GADA-/FH(MIX) 9.5% (P < 0.00001), GADA-/FH(T2) 4.5% (P < 0.00001), GADA+/FH(T2) 0%). Patients with GADA+/FH(MIX) more often had HLA-DQB1 risk genotypes compared with patients with GADA-/FH(MIX) or GADA-/FH(T2D) (47 vs. 23 or 14%, P = 0.05 and P < 0.00001, respectively). In logistic regression analyses, FH(MIX) , GAD antibody positivity and HLA risk genotypes were independently associated with insulin deficiency. CONCLUSION: A family history for both type 1 and type 2 diabetes was associated with higher prevalence of GAD antibodies and HLA-DQB1 risk genotypes than a family history of type 2 diabetes only, and was associated with earlier and more severe development of insulin deficiency, which was only partially explained by GAD antibodies and HLA. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.
Diabetic Medicine 11/2012; · 2.90 Impact Factor
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ABSTRACT: AIMS/HYPOTHESIS: Voltage-gated calcium channels of the L-type have been shown to be essential for rodent pancreatic beta cell function, but data about their presence and regulation in humans are incomplete. We therefore sought to elucidate which L-type channel isoform is functionally important and its association with inherited diabetes-related phenotypes. METHODS: Beta cells of human islets from cadaver donors were enriched using FACS to study the expression of the genes encoding voltage-gated calcium channel (Ca(v))1.2 and Ca(v)1.3 by absolute quantitative PCR in whole human and rat islets, as well as in clonal cells. Single-cell exocytosis was monitored as increases in cell capacitance after treatment with small interfering (si)RNA against CACNA1D (which encodes Ca(v)1.3). Three single nucleotide polymorphisms (SNPs) were genotyped in 8,987 non-diabetic and 2,830 type 2 diabetic individuals from Finland and Sweden and analysed for associations with type 2 diabetes and insulin phenotypes. RESULTS: In FACS-enriched human beta cells, CACNA1D mRNA expression exceeded that of CACNA1C (which encodes Ca(v)1.2) by approximately 60-fold and was decreased in islets from type 2 diabetes patients. The latter coincided with diminished secretion of insulin in vitro. CACNA1D siRNA reduced glucose-stimulated insulin release in INS-1 832/13 cells and exocytosis in human beta cells. Phenotype/genotype associations of three SNPs in the CACNA1D gene revealed an association between the C allele of the SNP rs312480 and reduced mRNA expression, as well as decreased insulin secretion in vivo, whereas both rs312486/G and rs9841978/G were associated with type 2 diabetes. CONCLUSION/INTERPRETATION: We conclude that the L-type calcium channel Ca(v)1.3 is important in human glucose-induced insulin secretion, and common variants in CACNA1D might contribute to type 2 diabetes.
Diabetologia 11/2012; · 6.81 Impact Factor
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ABSTRACT: Context: Titanium dioxide (TiO2) factory workers' source specific exposure and dose to airborne particles was studied extensively for particles between 5 nm and 10 μm in size. Objective: We defined TiO(2) industry workers' quantitative inhalation exposure levels during the packing of pigment TiO(2) (pTiO(2)) and nanoscale TiO(2) (nTiO(2)) material from concentrations measured at work area. Methods: Particle emissions from different work events were identified by linking work activity with the measured number size distributions and mass concentrations of particles. A lung deposit model was used to calculate regional inhalation dose rates in units of particles min(-1) and μg min(-1) without use of respirators. Results: Workers' average exposure varied from 225 to 700 μg m(-3) and from 1.15 × 10(4) to 20.1 × 10(4) cm(-4). Over 90% of the particles were smaller than 100 nm. These were mainly soot and particles formed from process chemicals. Mass concentration originated primarily from the packing of pTiO(2) and nTiO(2) agglomerates. The nTiO(2) exposure resulted in a calculated dose rate of 3.6 × 10(6) min(-1) and 32 μg min(-1) where 70% of the particles and 85% of the mass was deposited in head airways. Conclusions: The recommended TiO(2) exposure limits in mass by NIOSH and in particle number by IFA were not exceeded. We recommend source-specific exposure assessment in order to evaluate the workers' risks. In nTiO(2) packing, mass concentration best describes the workers' exposure to nTiO(2) agglomerates. Minute dose rates enable the simulation of workers' risks in different exposure scenarios.
Inhalation Toxicology 10/2012; 24(12):839-49. · 1.92 Impact Factor
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ABSTRACT: AIM/HYPOTHESIS: Individuals at risk of developing type 2 diabetes show a progressive decline in insulin secretion and increased insulin resistance over time. However, inability of the beta cells to compensate for the increased insulin resistance represents a key defect leading to overt type 2 diabetes. The aims of the present study were to replicate the association between genetic variants of the PCSK2 gene and insulin secretion, and to explore the effect on risk of type 2 diabetes. METHODS: Replication of PCSK2 variants against insulin secretion included 7,682 non-diabetic Scandinavian individuals. Insulin secretion was measured as the corrected insulin response or disposition index, i.e. insulin secretion adjusted for the degree of insulin resistance. Risk of type 2 diabetes was studied in 28,287 Scandinavian individuals. RESULTS: The C-allele of PCSK2 rs2208203 was associated with reduced insulin secretion measured as the corrected insulin response (n = 8,151; β = -0.112, p = 1.3 × 10(-6)) as well as disposition index (n = 8,078, β = -0.128, p = 1.6 × 10(-7)). The variant was also associated with lower fasting glucagon levels (β = -0.084, p = 0.005) in non-diabetic individuals with a fasting plasma glucose of over 5.5 mmol/l. In human pancreatic islets, PCSK2 expression correlated negatively with HbA(1c) (n = 133, r = -0.196, p = 0.038), and showed a tendency to be lower in hyperglycaemic (HbA(1c) ≥6.0% or type 2 diabetes; n = 47, p = 0.13) than normoglycaemic (HbA(1c) >6.0%; n = 66) donors. The presence of the PCSK2 rs2208203 risk allele did not influence gene expression, nor did it show an apparent risk in terms of type 2 diabetes. CONCLUSIONS/INTERPRETATION: A variant of the PCSK2 gene was associated with reduced glucose-stimulated insulin secretion, but also with lower glucagon levels, which could potentially counteract the effects of decreased insulin secretion on the risk of type 2 diabetes.
Diabetologia 09/2012; · 6.81 Impact Factor
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E Ahlqvist,
F Turrini,
S T Lang,
J Taneera,
Y Zhou,
P Almgren,
O Hansson,
B Isomaa, T Tuomi,
K Eriksson,
J G Eriksson,
V Lyssenko,
L Groop
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ABSTRACT: Impaired glucose tolerance and impaired insulin secretion have been reported in families with PAX6 mutations and it is suggested that they result from defective proinsulin processing due to lack of prohormone convertase 1/3, encoded by PCSK1. We investigated whether a common PAX6 variant would mimic these findings and explored in detail its effect on islet function in man.
A PAX6 candidate single nucleotide polymorphism (rs685428) was associated with fasting insulin levels in the Diabetes Genetics Initiative genome-wide association study. We explored its potential association with glucose tolerance and insulin processing and secretion in three Scandinavian cohorts (N = 8,897 individuals). In addition, insulin secretion and the expression of PAX6 and transcriptional target genes were studied in human pancreatic islets.
rs685428 G allele carriers had lower islet mRNA expression of PAX6 (p = 0.01) and PCSK1 (p = 0.001) than AA homozygotes. The G allele was associated with increased fasting insulin (p (replication) = 0.02, p (all) = 0.0008) and HOMA-insulin resistance (p (replication) = 0.02, p (all) = 0.001) as well as a lower fasting proinsulin/insulin ratio (p (all) = 0.008) and lower fasting glucagon (p = 0.04) and gastric inhibitory peptide (GIP) (p = 0.05) concentrations. Arginine-stimulated (p = 0.02) insulin secretion was reduced in vivo, which was further reflected by a reduction of glucose- and potassium-stimulated insulin secretion (p = 0.002 and p = 0.04, respectively) in human islets in vitro.
A common variant in PAX6 is associated with reduced PAX6 and PCSK1 expression in human islets and reduced insulin response, as well as decreased glucagon and GIP concentrations and decreased insulin sensitivity. These findings emphasise the central role of PAX6 in the regulation of islet function and glucose metabolism in man.
Diabetologia 09/2011; 55(1):94-104. · 6.81 Impact Factor
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ABSTRACT: To study the heritability and familiality of type 2 diabetes and related quantitative traits in families from the Botnia Study in Finland.
Heritability estimates for type 2 diabetes adjusted for sex, age and BMI are provided for different age groups of type 2 diabetes and for 34 clinical and metabolic traits in 5,810 individuals from 942 families using a variance component model (SOLAR). In addition, family means of these traits and their distribution across families are calculated.
The strongest heritability for type 2 diabetes was seen in patients with age at onset 35-60 years (h (2) = 0.69). However, including patients with onset up to 75 years dropped the h (2) estimates to 0.31. Among quantitative traits, the highest h (2) estimates in all individuals and in non-diabetic individuals were seen for lean body mass (h (2) = 0.53-0.65), HDL-cholesterol (0.52-0.61) and suppression of NEFA during OGTT (0.63-0.76) followed by measures of insulin secretion (insulinogenic index [IG(30)] = 0.41-0.50) and insulin action (insulin sensitivity index [ISI] = 0.37-0.40). In contrast, physical activity showed rather low heritability (0.16-0.18), whereas smoking showed strong heritability (0.57-0.59). Family means of these traits differed two- to fivefold between families belonging to the lowest and highest quartile of the trait (p < 0.00001).
To detect stronger genetic effects in type 2 diabetes, it seems reasonable to restrict inclusion of patients to those with age at onset 35-60 years. Sequencing of families with extreme quantitative traits could be an important next step in the dissection of the genetics of type 2 diabetes.
Diabetologia 08/2011; 54(11):2811-9. · 6.81 Impact Factor
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G Thanabalasingham,
N Shah,
M Vaxillaire,
T Hansen, T Tuomi,
D Gašperíková,
M Szopa,
E Tjora,
T J James,
P Kokko, [......],
J Stanik,
P R Njolstad,
M T Malecki,
I Klimes,
L Groop,
O Pedersen,
P Froguel,
M I McCarthy,
A L Gloyn,
K R Owen
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ABSTRACT: An accurate molecular diagnosis of diabetes subtype confers clinical benefits; however, many individuals with monogenic diabetes remain undiagnosed. Biomarkers could help to prioritise patients for genetic investigation. We recently demonstrated that high-sensitivity C-reactive protein (hsCRP) levels are lower in UK patients with hepatocyte nuclear factor 1 alpha (HNF1A)-MODY than in other diabetes subtypes. In this large multi-centre study we aimed to assess the clinical validity of hsCRP as a diagnostic biomarker, examine the genotype-phenotype relationship and compare different hsCRP assays.
High-sensitivity CRP levels were analysed in individuals with HNF1A-MODY (n = 457), glucokinase (GCK)-MODY (n = 404), hepatocyte nuclear factor 4 alpha (HNF4A)-MODY (n = 54) and type 2 diabetes (n = 582) from seven European centres. Three common assays for hsCRP analysis were evaluated. We excluded 121 participants (8.1%) with hsCRP values >10 mg/l. The discriminative power of hsCRP with respect to diabetes aetiology was assessed by receiver operating characteristic curve-derived C-statistic.
In all centres and irrespective of the assay method, meta-analysis confirmed significantly lower hsCRP levels in those with HNF1A-MODY than in those with other aetiologies (z score -21.8, p < 5 × 10(-105)). HNF1A-MODY cases with missense mutations had lower hsCRP levels than those with truncating mutations (0.03 vs 0.08 mg/l, p < 5 × 10(-5)). High-sensitivity CRP values between assays were strongly correlated (r (2) ≥ 0.91, p ≤ 1 × 10(-5)). Across the seven centres, the C-statistic for distinguishing HNF1A-MODY from young adult-onset type 2 diabetes ranged from 0.79 to 0.97, indicating high discriminative accuracy.
In the largest study to date, we have established that hsCRP is a clinically valid biomarker for HNF1A-MODY in European populations. Given the modest costs and wide availability, hsCRP could translate rapidly into clinical practice, considerably improving diagnosis rates in monogenic diabetes.
Diabetologia 08/2011; 54(11):2801-10. · 6.81 Impact Factor
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B Isomaa,
B Forsén,
K Lahti,
N Holmström,
J Wadén,
O Matintupa,
P Almgren,
J G Eriksson,
V Lyssenko,
M-R Taskinen, T Tuomi,
L C Groop
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ABSTRACT: We studied the impact of a family history of type 2 diabetes on physical fitness, lifestyle factors and diabetes-related metabolic factors.
The Prevalence, Prediction and Prevention of Diabetes (PPP)-Botnia study is a population-based study in Western Finland, which includes a random sample of 5,208 individuals aged 18 to 75 years identified through the national Finnish Population Registry. Physical activity, dietary habits and family history of type 2 diabetes were assessed by questionnaires and physical fitness by a validated 2 km walking test. Insulin secretion and action were assessed based upon OGTT measurements of insulin and glucose.
A family history of type 2 diabetes was associated with a 2.4-fold risk of diabetes and lower physical fitness (maximal aerobic capacity 29.2 +/- 7.2 vs 32.1 +/- 7.0, p = 0.01) despite having similar reported physical activity to that of individuals with no family history. The same individuals also had reduced insulin secretion adjusted for insulin resistance, i.e. disposition index (p < 0.001) despite having higher BMI (27.4 +/- 4.6 vs 26.0 +/- 4.3 kg/m(2), p < 0.001).
Individuals with a family history of type 2 diabetes are characterised by lower physical fitness, which cannot solely be explained by lower physical activity. They also have an impaired capacity of beta cells to compensate for an increase in insulin resistance imposed by an increase in BMI. These defects should be important targets for interventions aiming at preventing type 2 diabetes in individuals with inherited susceptibility to the disease.
Diabetologia 05/2010; 53(8):1709-13. · 6.81 Impact Factor
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ABSTRACT: Studies on potential toxicity of engineered nanoparticle (ENP) in biological systems require a proper and accurate particle characterization to ensure the reproducibility of the results and to understand biological effects of ENP. A full characterization of ENP should include various measurements such as particle size and size distribution, shape and morphology, crystallinity, composition, surface chemistry, and surface area of ENP. It is also important to characterize the state of ENP dispersions. In this study, four different ENPs, rutile and anatase titanium dioxides and short single- and multi-walled carbon nanotubes, were characterized in two dispersion media: bronchial epithelial growth medium, used for bronchial epithelial BEAS cells, and RPMI-1640 culture media with 10% of fetal calf serum (FCS) for human mesothelial (MeT-5A) cells. The purpose of this study was to determine the characteristics of ENPs and their dispersions as well as to compare dispersion additives suitable for toxicity tests and thus establish an appropriate way to prepare dispersions that performs well with the selected ENP. Dispersion additives studied in the media were bovine serum albumin (BSA) as a protein resource, dipalmitoyl phosphatidylcholine (DPPC) as a model lung surfactant, and combination of BSA and DPPC. Dispersions were characterized using optical microscopy and transmission electron microscopy. Our results showed that protein addition, BSA or FCS, in cell culture media generated small agglomerates of primary particles with narrow size variations and improved the stability of the dispersions and thus also the relevance of the in-vitro genotoxicity tests to be done.
Human & Experimental Toxicology 06/2009; 28(6-7):377-85. · 1.31 Impact Factor
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ABSTRACT: To investigate the fitness of serum apolipoprotein M (apoM) concentration as a marker for maturity-onset diabetes of the young 3 (MODY3).
This study consisted of two parts. A family study included 71 carriers of the P291fsinsC mutation in hepatocyte nuclear factor-1alpha (HNF-1alpha) from the Finnish Botnia study, 53 of whom were diabetic, and 75 matched family controls. A second, case-control study included 24 MODY3 patients, 17 healthy MODY3 mutation carriers, 11 MODY1 patients, 18 type 2 diabetes patients and 19 healthy control individuals. Subjects in the case-control study were recruited from the Botnia study or the Clinic of Endocrinology, Malmö University Hospital. Serum apoM levels were measured using a novel ELISA based on two monoclonal apoM antibodies.
In the family study, mean serum apoM was 10% lower in female carriers of the P291fsinsC mutation compared to the family controls (P = 0.0058), a difference which remained significant after adjustment for diabetes status. There was no observed difference between groups for men. In the case-control study, no significant difference in apoM concentration was observed between MODY3 and type 2 diabetes patients, neither before nor after adjustment for total cholesterol.
Female carriers of the P291fsinsC mutation in HNF-1alpha displayed slightly lower apoM serum levels. This difference is too small for apoM to be reliably employed as a biomarker for HNF-1alpha mutation status.
Journal of Internal Medicine 06/2009; 267(3):316-21. · 5.48 Impact Factor
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ABSTRACT: This study's database comprised results of volatile organic compound (VOC) measurements from 176 office buildings. In 23 of the 176 buildings, formaldehyde measurements were also conducted. It was suspected that the buildings had indoor air problems, but a walk-through inspection did not reveal any clear, abnormal contaminant sources. The 50 most abundant VOCs and their concentrations in 520 air samples were analyzed. The irritation potency was estimated for 33 out of the 50 common VOCs and their mixtures, as well as for formaldehyde. This information was used to calculate the recommended indoor air levels (RILs) for the VOCs. The RILs were considerably higher than the measured mean indoor air concentrations in the buildings. However, the RIL for formaldehyde was exceeded in most of the 23 buildings studied. According to the evaluation of irritation potency, formaldehyde was a more likely cause of sensory irritation than the mixture of common nonreactive VOCs at the concentrations that occurred in the buildings without abnormal indoor sources. Furthermore, environmental symptoms of office workers were characterized in 20 office buildings (including the database of 176 office buildings) with the aid of an indoor air questionnaire. The most frequent symptoms related to the indoor environment were involved the upper respiratory tract. However, no relationship could be shown between the reported symptoms and the occurrence of VOC and formaldehyde concentrations in these buildings. Generally, the study results indicated that formaldehyde was the more likely agent causing sensory irritation than the mixture of the common nonreactive VOCs at the concentrations occurring in the buildings without abnormal indoor sources.
Journal of Occupational and Environmental Hygiene 05/2009; 6(4):239-47. · 1.19 Impact Factor
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T Rönn,
P Poulsen,
O Hansson,
J Holmkvist,
P Almgren,
P Nilsson, T Tuomi,
B Isomaa,
L Groop,
A Vaag,
C Ling
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ABSTRACT: Reduced oxidative capacity of the mitochondria in skeletal muscle has been suggested to contribute to insulin resistance and type 2 diabetes. Moreover, a set of genes influencing oxidative phosphorylation (OXPHOS) is downregulated in diabetic muscle. Here we studied whether genetic, epigenetic and non-genetic factors influence a component of the respiratory chain, COX7A1, previously shown to be downregulated in skeletal muscle from patients with type 2 diabetes. The specific aims were to: (1) evaluate the impact of genetic (single nucleotide polymorphisms [SNPs]), epigenetic (DNA methylation) and non-genetic (age) factors on the expression of COX7A1 in human skeletal muscle; and (2) investigate whether common variants in the COX7A1 gene are associated with increased risk of type 2 diabetes.
COX7A1 mRNA expression was analysed in muscle biopsies from young (n = 110) and elderly (n = 86) non-diabetic twins and related to measures of in vivo metabolism. Genetic variants (three SNPs) from the COX7A1 locus were genotyped in the twins and in two independent type 2 diabetes case-control cohorts (n = 1466 and 6380, respectively). DNA methylation of the COX7A1 promoter was analysed in a subset of twins (ten young, ten elderly) using bisulphite sequencing.
While DNA methylation of the COX7A1 promoter was increased in muscle from elderly compared with young twins (19.9 +/- 8.3% vs 1.8 +/- 2.7%; p = 0.035), the opposite was found for COX7A1 mRNA expression (elderly 1.00 +/- 0.05 vs young 1.68 +/- 0.06; p = 0.0005). The heritability of COX7A1 expression was estimated to be 50% in young and 72% in elderly twins. One of the polymorphisms investigated, rs753420, influenced basal COX7A1 expression in muscle of young (p = 0.0001) but not of elderly twins. The transcript level of COX7A1 was associated with increased in vivo glucose uptake and VO(2max) (p = 0.009 and p = 0.001, respectively). We did not observe any genetic association between COX7A1 polymorphisms and type 2 diabetes after correcting for multiple testing.
Our results provide further evidence for age as a factor influencing DNA methylation and expression of OXPHOS genes, and thereby in vivo metabolism.
Diabetologia 08/2008; 51(7):1159-68. · 6.81 Impact Factor
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ABSTRACT: To validate a test for independent assessment of insulin secretion and insulin sensitivity during the same occasion for metabolic studies in clinical practice, i.e. combined glucagon-stimulated C-peptide test and insulin tolerance test (GITT).
We measured C-peptide response to 0.5 mg of intravenous glucagon followed 30 min later by administration of 0.05 U kg(-1) insulin (insulin tolerance test, ITT). Ten subjects with normal glucose tolerance participated on different days in an ITT, glucagon-C-peptide test, ITT followed by glucagon-C-peptide test and glucagon-C-peptide test followed by ITT to establish whether and how the tests could be combined. The test was then repeated in nine patients with type 2 diabetes to investigate its reproducibility. In 20 subjects with varying degrees of glucose tolerance, the test was compared with the Botnia clamp (an intravenous glucose tolerance test combined with a euglycaemic hyperinsulinemic clamp).
When ITT preceded the glucagon test, C-peptide response was blunted. Therefore, we first administered glucagon and then insulin (GITT). The K(ITT) from the GITT was reproducible (CV = 13 %) and correlated strongly with the glucose disposal rate from the Botnia clamp (r = 0.87, r(2) = 0.75, P < 0.001). The C-peptide response to glucagon was reproducible (CV = 13 %). The disposition index, providing a measure of beta-cell function adjusted for insulin sensitivity, calculated from the GITT showed good discrimination between individuals with varying degrees of glucose tolerance.
The GITT provides simple, reproducible and independent estimates of insulin sensitivity and secretion on the same occasion for metabolic studies in individuals with normal and abnormal glucose tolerance.
Journal of Internal Medicine 07/2008; 264(1):62-71. · 5.48 Impact Factor
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ABSTRACT: Objective: The aim of the study was to get information on the chemical exposure and the prevalence of skin and respiratory symptoms among Finnish machinists.Methods: A cross-sectional study was carried out on a population of 961 Finnish machinists. Skin and respiratory symptoms, atopy, exposure at work, etc. were inquired by a telephone interview. Working conditions were assessed and the data were combined with the data from the interview. Technical office personnel in the same companies were used as a control group.Results: A third of the interviewees reported prolonged rhinitis. A fifth had continuous or relapsing hand or forearm dermatitis, cough, phlegm production or eye symptoms. Wheezing, dyspnea, laryngeal symptoms, or relapsing low fever were reported by 8–2%. 5% reported having asthma. In total, 35% of the machinists considered the skin or respiratory symptoms as work-related.Conclusion: This study shows that work-related skin and respiratory symptoms are common among machinists in Finland. Those reporting symptoms have been examined in more detail at FIOH. New results of the statistical analysis and medical investigations will be presented.
Contact Dermatitis 06/2008; 50(3):140 - 140. · 3.51 Impact Factor
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ABSTRACT: Glucose-stimulated insulin secretion is dependent on the electrical activity of beta cells; hence, genes encoding beta cell ion channels are potential candidate genes for type 2 diabetes. The gene encoding the voltage-dependent Ca(2+) channel Ca(V)2.3 (CACNA1E), telomeric to a region that has shown suggestive linkage to type 2 diabetes (1q21-q25), has been ascribed a role for second-phase insulin secretion.
Based upon the genotyping of 52 haplotype tagging single nucleotide polymorphisms (SNPs) in a type 2 diabetes case-control sample (n = 1,467), we selected five SNPs that were nominally associated with type 2 diabetes and genotyped them in the following groups (1) a new case-control sample of 6,570 individuals from Sweden; (2) 2,293 individuals from the Botnia prospective cohort; and (3) 935 individuals with insulin secretion data from an IVGTT.
The rs679931 TT genotype was associated with (1) an increased risk of type 2 diabetes in the Botnia case-control sample [odds ratio (OR) 1.4, 95% CI 1.0-2.0, p = 0.06] and in the replication sample (OR 1.2, 95% CI 1.0-1.5, p = 0.01 one-tailed), with a combined OR of 1.3 (95% CI 1.1-1.5, p = 0.004 two-tailed); (2) reduced insulin secretion [insulinogenic index at 30 min p = 0.02, disposition index (D (I)) p = 0.03] in control participants during an OGTT; (3) reduced second-phase insulin secretion at 30 min (p = 0.04) and 60 min (p = 0.02) during an IVGTT; and (4) reduced D (I) over time in the Botnia prospective cohort (p = 0.05).
We conclude that genetic variation in the CACNA1E gene contributes to an increased risk of the development of type 2 diabetes by reducing insulin secretion.
Diabetologia 01/2008; 50(12):2467-75. · 6.81 Impact Factor
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J C Florez,
M Sjögren,
C M Agapakis,
N P Burtt,
P Almgren,
U Lindblad,
G Berglund, T Tuomi,
D Gaudet,
M J Daly,
K G Ardlie,
J N Hirschhorn,
D Altshuler,
L Groop
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ABSTRACT: Activation of the insulin receptor substrate-1 (IRS1) is a key initial step in the insulin signalling pathway. Despite several reports of association of the G972R polymorphism in its gene IRS1 with type 2 diabetes, we and others have not observed this association in well-powered samples. However, other nearby variants might account for the putative association signal.
We characterised the haplotype map of IRS1 and selected 20 markers designed to capture common variations in the region. We genotyped this comprehensive set of markers in several family-based and case-control samples of European descent totalling 12,129 subjects.
In an initial sample of 2,235 North American and Polish case-control pairs, the minor allele of the rs934167 polymorphism showed nominal evidence of association with type 2 diabetes (odds ratio [OR] 1.25, 95% CI 1.03-1.51, p = 0.03). This association showed a trend in the same direction in 7,659 Scandinavian samples (OR 1.16, 95% CI 0.96-1.39, p = 0.059). The combined OR was 1.20 (p = 0.008), but statistical correction for the number of variants examined yielded a p value of 0.086. We detected no differences across rs934167 genotypes in insulin-related quantitative traits.
Our data do not support an association of common variants in IRS1 with type 2 diabetes in populations of European descent.
Diabetologia 07/2007; 50(6):1209-17. · 6.81 Impact Factor
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ABSTRACT: The aim of the present study was to describe the cases of occupational asthma (OA) due to stainless steel welding fumes diagnosed at the Finnish Institute of Occupational Health during the period 1994-2003. OA was diagnosed according to patient history, lung function examinations and welding challenge tests with measurements of the forced expiratory volume in one second (FEV(1)) and peak expiratory flow (PEF) values. The present series comprised 34 patients, all male, with a mean age of 44.7 yrs (range 22-57), mainly working as welders. The mean duration of exposure was 22.4 yrs, and the mean duration of exposure before the onset of respiratory symptoms was 18 yrs. Dyspnoea was the most frequently reported work-related respiratory symptom. During the inhalation challenge tests, the mode of the asthmatic FEV(1)/PEF reaction was delayed in 16 (47%) patients, immediate in nine (26%) patients and dual (both immediate and delayed) in nine (26%) patients. In the follow-up assessment 6 months later, only six patients were considered able to continue performing welding tasks, whereas occupational injury pension was recommended for seven, and measures of vocational rehabilitation for 14 patients. In most cases, after the diagnosis of occupational asthma, the continuation of welding work was not possible.
European Respiratory Journal 02/2007; 29(1):85-90. · 5.89 Impact Factor
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J Holmkvist,
C Cervin,
V Lyssenko,
W Winckler,
D Anevski,
C Cilio,
P Almgren,
G Berglund,
P Nilsson, T Tuomi,
C M Lindgren,
D Altshuler,
L Groop
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ABSTRACT: Mutations in the hepatocyte nuclear factor 1-alpha gene (HNF-1alpha, now known as the transcription factor 1 gene [TCF1]) cause the most common monogenic form of diabetes, MODY3, but it is not known if common variants in HNF-1a are associated with decreased transcriptional activity or phenotypes related to type 2 diabetes, or whether they predict future type 2 diabetes.
We studied the effect of four common polymorphisms (rs1920792, I27L, A98V and S487N) in and upstream of the HNF-1alpha gene on transcriptional activity in vitro, and their possible association with type 2 diabetes and insulin secretion in vivo.
Certain combinations of the I27L and A98V polymorphisms in the HNF-1alpha gene showed decreased transcriptional activity on the target promoters glucose transporter 2 (now known as solute carrier family 2 [facilitated glucose transporter], member 2) and albumin in both HeLa and INS-1 cells. In vivo, these polymorphisms were associated with a modest but significant impairment in insulin secretion in response to oral glucose. Insulin secretion deteriorated over time in individuals carrying the V allele of the A98V polymorphism (n = 2,293; p = 0.003). In a new case-control (n = 1,511 and n = 2,225 respectively) data set, the I27L polymorphism was associated with increased risk of type 2 diabetes, odds ratio (OR) = 1.5 (p = 0.002; multiple logistic regression), particularly in elderly (age > 60 years) and overweight (BMI > 25 kg/m(2)) patients (OR = 2.3, p = 0.002).
This study provides in vitro and in vivo evidence that common variants in the MODY3 gene, HNF-1alpha, influence transcriptional activity and insulin secretion in vivo. These variants are associated with a modestly increased risk of late-onset type 2 diabetes in subsets of elderly overweight individuals.
Diabetologia 01/2007; 49(12):2882-91. · 6.81 Impact Factor
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Diabetologia 10/2006; 49(9):1996-8. · 6.81 Impact Factor
