Summary Background No clinical trials have assessed the effects or cost-effectiveness of sequential screening strategies to detect new cases of type 2 diabetes. We used a mathematical model to ...estimate the cost-effectiveness of several screening strategies. Methods We used person-specific data from a representative sample of the US population to create a simulated population of 325 000 people aged 30 years without diabetes. We used the Archimedes model to compare eight simulated screening strategies for type 2 diabetes with a no-screening control strategy. Strategies differed in terms of age at initiation and frequency of screening. Once diagnosed, diabetes treatment was simulated in a standard manner. We calculated the effects of each strategy on the incidence of type 2 diabetes, myocardial infarction, stroke, and microvascular complications in addition to quality of life, costs, and cost per quality-adjusted life-year (QALY). Findings Compared with no screening, all simulated screening strategies reduced the incidence of myocardial infarction (3–9 events prevented per 1000 people screened) and diabetes-related microvascular complications (3–9 events prevented per 1000 people), and increased the number of QALYs (93–194 undiscounted QALYs) added over 50 years. Most strategies prevented a significant number of simulated deaths (2–5 events per 1000 people). There was little or no effect of screening on incidence of stroke (0–1 event prevented per 1000 people). Five screening strategies had costs per QALY of about US$10 500 or less, whereas costs were much higher for screening started at 45 years of age and repeated every year ($15 509), screening started at 60 years of age and repeated every 3 years ($25 738), or a maximum screening strategy (screening started at 30 years of age and repeated every 6 months; $40 778). Several strategies differed substantially in the number of QALYs gained. Costs per QALY were sensitive to the disutility assigned to the state of having diabetes diagnosed with or without symptoms. Interpretation In the US population, screening for type 2 diabetes is cost effective when started between the ages of 30 years and 45 years, with screening repeated every 3–5 years. Funding Novo Nordisk, Bayer HealthCare, and Pfizer.
Summary Background Intensive treatment of multiple cardiovascular risk factors can halve mortality among people with established type 2 diabetes. We investigated the effect of early multifactorial ...treatment after diagnosis by screening. Methods In a pragmatic, cluster-randomised, parallel-group trial done in Denmark, the Netherlands, and the UK, 343 general practices were randomly assigned screening of registered patients aged 40–69 years without known diabetes followed by routine care of diabetes or screening followed by intensive treatment of multiple risk factors. The primary endpoint was first cardiovascular event, including cardiovascular mortality and morbidity, revascularisation, and non-traumatic amputation within 5 years. Patients and staff assessing outcomes were unaware of the practice's study group assignment. Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00237549. Findings Primary endpoint data were available for 3055 (99·9%) of 3057 screen-detected patients. The mean age was 60·3 (SD 6·9) years and the mean duration of follow-up was 5·3 (SD 1·6) years. Improvements in cardiovascular risk factors (HbA1c and cholesterol concentrations and blood pressure) were slightly but significantly better in the intensive treatment group. The incidence of first cardiovascular event was 7·2% (13·5 per 1000 person-years) in the intensive treatment group and 8·5% (15·9 per 1000 person-years) in the routine care group (hazard ratio 0·83, 95% CI 0·65–1·05), and of all-cause mortality 6·2% (11·6 per 1000 person-years) and 6·7% (12·5 per 1000 person-years; 0·91, 0·69–1·21), respectively. Interpretation An intervention to promote early intensive management of patients with type 2 diabetes was associated with a small, non-significant reduction in the incidence of cardiovascular events and death. Funding National Health Service Denmark, Danish Council for Strategic Research, Danish Research Foundation for General Practice, Danish Centre for Evaluation and Health Technology Assessment, Danish National Board of Health, Danish Medical Research Council, Aarhus University Research Foundation, Wellcome Trust, UK Medical Research Council, UK NIHR Health Technology Assessment Programme, UK National Health Service R&D, UK National Institute for Health Research, Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, Novo Nordisk, Astra, Pfizer, GlaxoSmithKline, Servier, HemoCue, Merck.
OBJECTIVE: The purpose of this study was to develop a model for assessing the 5-year risk of developing type 2 diabetes from a panel of 64 circulating candidate biomarkers. RESEARCH DESIGN AND ...METHODS: Subjects were selected from the Inter99 cohort, a longitudinal population-based study of ~6,600 Danes in a nested case-control design with the primary outcome of 5-year conversion to type 2 diabetes. Nondiabetic subjects, aged greater-than-or-equal39 years, with BMI greater-than-or-equal25 kg/m² at baseline were selected. Baseline fasting serum samples from 160 individuals who developed type 2 diabetes and from 472 who did not were tested. An ultrasensitive immunoassay was used to measure of 58 candidate biomarkers in multiple diabetes-associated pathways, along with six routine clinical variables. Statistical learning methods and permutation testing were used to select the most informative biomarkers. Risk model performance was estimated using a validated bootstrap bias-correction procedure. RESULTS: A model using six biomarkers (adiponectin, C-reactive protein, ferritin, interleukin-2 receptor A, glucose, and insulin) was developed for assessing an individual's 5-year risk of developing type 2 diabetes. This model has a bootstrap-estimated area under the curve of 0.76, which is greater than that for A1C, fasting plasma glucose, fasting serum insulin, BMI, sex-adjusted waist circumference, a model using fasting glucose and insulin, and a noninvasive clinical model. CONCLUSIONS: A model incorporating six circulating biomarkers provides an objective and quantitative estimate of the 5-year risk of developing type 2 diabetes, performs better than single risk indicators and a noninvasive clinical model, and provides better stratification than fasting plasma glucose alone.
The Greenlandic population, a small and historically isolated founder population comprising about 57,000 inhabitants, has experienced a dramatic increase in type 2 diabetes (T2D) prevalence during ...the past 25 years. Motivated by this, we performed association mapping of T2D-related quantitative traits in up to 2,575 Greenlandic individuals without known diabetes. Using array-based genotyping and exome sequencing, we discovered a nonsense p.Arg684Ter variant (in which arginine is replaced by a termination codon) in the gene TBC1D4 with an allele frequency of 17%. Here we show that homozygous carriers of this variant have markedly higher concentrations of plasma glucose (β = 3.8 mmol l(-1), P = 2.5 × 10(-35)) and serum insulin (β = 165 pmol l(-1), P = 1.5 × 10(-20)) 2 hours after an oral glucose load compared with individuals with other genotypes (both non-carriers and heterozygous carriers). Furthermore, homozygous carriers have marginally lower concentrations of fasting plasma glucose (β = -0.18 mmol l(-1), P = 1.1 × 10(-6)) and fasting serum insulin (β = -8.3 pmol l(-1), P = 0.0014), and their T2D risk is markedly increased (odds ratio (OR) = 10.3, P = 1.6 × 10(-24)). Heterozygous carriers have a moderately higher plasma glucose concentration 2 hours after an oral glucose load than non-carriers (β = 0.43 mmol l(-1), P = 5.3 × 10(-5)). Analyses of skeletal muscle biopsies showed lower messenger RNA and protein levels of the long isoform of TBC1D4, and lower muscle protein levels of the glucose transporter GLUT4, with increasing number of p.Arg684Ter alleles. These findings are concomitant with a severely decreased insulin-stimulated glucose uptake in muscle, leading to postprandial hyperglycaemia, impaired glucose tolerance and T2D. The observed effect sizes are several times larger than any previous findings in large-scale genome-wide association studies of these traits and constitute further proof of the value of conducting genetic association studies outside the traditional setting of large homogeneous populations.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
5.
The National Diabetes Register Carstensen, Bendix; Kristensen, Jette Kolding; Marcussen, Morten Munk ...
Scandinavian journal of public health,
07/2011, Letnik:
39, Številka:
7_suppl
Journal Article
Recenzirano
Odprti dostop
Introduction: A National Diabetes Register was established in the National Board of Health in 2006 following a pilot study showing the feasibility of doing so based on existing registers. Content: ...The register contains data of birth, date of inclusion, and date of death as well as information on the criteria met for inclusion. Validity and coverage: The register is more than 90% complete when compared to records of general practitioners, and it covers the entire Danish population. Conclusion: The register is a source of demographic information for the diabetes population in itself, but also a source of linkable information for studies of diabetes as outcome and as determinant.
Diabetes is a diverse and complex disease, with considerable variation in phenotypic manifestation and severity. This variation hampers the study of etiological differences and reduces the ...statistical power of analyses of associations to genetics, treatment outcomes, and complications. We address these issues through deep, fine-grained phenotypic stratification of a diabetes cohort. Text mining the electronic health records of 14,017 patients, we matched two controlled vocabularies (ICD-10 and a custom vocabulary developed at the clinical center Steno Diabetes Center Copenhagen) to clinical narratives spanning a 19 year period. The two matched vocabularies comprise over 20,000 medical terms describing symptoms, other diagnoses, and lifestyle factors. The cohort is genetically homogeneous (Caucasian diabetes patients from Denmark) so the resulting stratification is not driven by ethnic differences, but rather by inherently dissimilar progression patterns and lifestyle related risk factors. Using unsupervised Markov clustering, we defined 71 clusters of at least 50 individuals within the diabetes spectrum. The clusters display both distinct and shared longitudinal glycemic dysregulation patterns, temporal co-occurrences of comorbidities, and associations to single nucleotide polymorphisms in or near genes relevant for diabetes comorbidities.
Adult human height is one of the classical complex human traits. We searched for sequence variants that affect height by scanning the genomes of 25,174 Icelanders, 2,876 Dutch, 1,770 European ...Americans and 1,148 African Americans. We then combined these results with previously published results from the Diabetes Genetics Initiative on 3,024 Scandinavians and tested a selected subset of SNPs in 5,517 Danes. We identified 27 regions of the genome with one or more sequence variants showing significant association with height. The estimated effects per allele of these variants ranged between 0.3 and 0.6 cm and, taken together, they explain around 3.7% of the population variation in height. The genes neighboring the identified loci cluster in biological processes related to skeletal development and mitosis. Association to three previously reported loci are replicated in our analyses, and the strongest association was with SNPs in the ZBTB38 gene.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Low Physical Activity Accentuates the Effect of the FTO rs9939609 Polymorphism on Body Fat Accumulation
Camilla H. Andreasen 1 ,
Kirstine L. Stender-Petersen 1 ,
Mette S. Mogensen 1 ,
Signe S. ...Torekov 1 ,
Lise Wegner 1 ,
Gitte Andersen 1 ,
Arne L. Nielsen 1 ,
Anders Albrechtsen 2 ,
Knut Borch-Johnsen 1 3 4 ,
Signe S. Rasmussen 1 ,
Jesper O. Clausen 1 ,
Annelli Sandbæk 5 ,
Torsten Lauritzen 5 ,
Lars Hansen 6 ,
Torben Jørgensen 3 ,
Oluf Pedersen 1 4 and
Torben Hansen 1
1 Steno Diabetes Center, Gentofte, Denmark
2 Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark
3 Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark
4 Faculty of Health Science, University of Aarhus, Aarhus, Denmark
5 Department of General Practice, University of Aarhus, Aarhus, Denmark
6 Science and Medicine, Novo Nordisk, Bagsværd, Denmark
Address correspondence and reprint requests to Camilla H. Andreasen, Steno Diabetes Center, Niels Steensens Vej 1, NLC2.13,
DK-2820 Gentofte, Denmark. E-mail: cila{at}novonordisk.com
Abstract
OBJECTIVE— Three independent studies have shown that variation in the fat mass and obesity-associated ( FTO ) gene associates with BMI and obesity. In the present study, the effect of FTO variation on metabolic traits including obesity, type 2 diabetes, and related quantitative phenotypes was examined.
RESEARCH DESIGN AND METHODS— The FTO rs9939609 polymorphism was genotyped in a total of 17,508 Danes from five different study groups.
RESULTS— In studies of 3,856 type 2 diabetic case subjects and 4,861 normal glucose-tolerant control subjects, the minor A-allele of
rs9939609 associated with type 2 diabetes (odds ratio 1.13 95% CI 1.06–1.20, P = 9 × 10 −5 ). This association was abolished when adjusting for BMI (1.06 0.97–1.16, P = 0.2). Among 17,162 middle-aged Danes, the A-allele associated with overweight (1.19 1.13–1.24, P = 1 × 10 −12 ) and obesity (1.27 1.20–1.34, P = 2 × 10 −16 ). Furthermore, obesity-related quantitative traits such as body weight, waist circumference, fat mass, and fasting serum
leptin levels were significantly elevated in A-allele carriers. An interaction between the FTO rs9939609 genotype and physical activity ( P = 0.007) was found, where physically inactive homozygous risk A-allele carriers had a 1.95 ± 0.3 kg/m 2 increase in BMI compared with homozygous T-allele carriers.
CONCLUSIONS— We validate that variation in FTO is associated with type 2 diabetes when not adjusted for BMI and with an overall increase in body fat mass. Furthermore,
low physical activity seems to accentuate the effect of FTO rs9939609 on body fat accumulation.
BIGTT, β-cell function, insulin sensitivity, and glucose tolerance testing
BIGTT-AIR, BIGTT acute insulin response
BIGTT-Si, BIGTT insulin sensitivity index
SDC, Steno Diabetes Center
SNP, single-nucleotide polymorphism
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 17 October 2007. DOI: 10.2337/db07-0910.
C.H.A. and K.L.S.-P. contributed equally to this article.
K.B.-J. has received honorarium for invited lectures by Novo Nordisk, Bristol-Myers Squibb, Novartis, Pfizer, Hermedico, and
AstraZeneca.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0910 .
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted October 10, 2007.
Received July 4, 2007.
DIABETES
OBJECTIVE:--The aim of this study was to describe the natural history of insulin secretion and insulin sensitivity in the development of isolated impaired fasting glycemia (i-IFG), isolated impaired ...glucose tolerance (i-IGT), and combined IFG/IGT. RESEARCH DESIGN AND METHODS--Baseline and 5-year follow-up data from the Inter99 study were used. Individuals with normal glucose tolerance (NGT) at baseline and i-IFG, i-IGT, combined IFG/IGT, or NGT at the 5-year follow-up were examined with an oral glucose tolerance test (n = 3,145). Insulin sensitivity index (ISI), homeostasis model assessment of insulin sensitivity (HOMA-IS), early-phase insulin release (EPIR), and insulin secretion relative to insulin action (disposition index) were estimated. RESULTS:--Five years before the pre-diabetes diagnoses (i-IFG, i-IGT, and IFG/IGT), ISI, HOMA-IS, EPIR, and disposition index were lower than in individuals who maintained NGT. During the 5-year follow-up, individuals developing i-IFG experienced a significant decline only in HOMA-IS, whereas individuals developing i-IGT experienced significant declines in ISI, EPIR, and disposition index. Individuals with IFG/IGT exhibited pronounced declines in ISI, HOMA-IS, EPIR, and disposition index during the 5-year follow-up. CONCLUSIONS:--A stationary reduced insulin secretion followed by a decline in primarily hepatic insulin sensitivity characterizes the transition from NGT to i-IFG. In contrast, low whole-body insulin sensitivity with a secondary lack of β-cell compensation is associated with the development of i-IGT. Thereby, i-IFG and i-IGT appear to result from different underlying mechanisms, which may have implications for the prevention and treatment of the diabetes that succeeds them.
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