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  • Lindahl, Bernt, et al. (författare)
  • A randomized lifestyle intervention with 5-year follow-up in subjects with impaired glucose tolerance : pronounced short-term impact but long-term adherence problems
  • 2009
  • Ingår i: Scandinavian Journal of Public Health. - : SAGE Publications. - 1403-4948 .- 1651-1905. ; 37:4, s. 434-442
  • Tidskriftsartikel (refereegranskat)abstract
    • AIMS: To compare data on cardiovascular risk factor changes in lipids, insulin, proinsulin, fibrinolysis, leptin and C-reactive protein, and on diabetes incidence, in relation to changes in lifestyle. METHODS: The study was a randomized lifestyle intervention trial conducted in northern Sweden between 1995 and 2000, in 168 individuals with impaired glucose tolerance (IGT) and body mass index above 27 at start. The intensive intervention group (n = 83) was subjected to a 1-month residential lifestyle programme. The usual care group (n = 85) participated in a health examination ending with a single counselling session. Follow-up was conducted at 1, 3 and 5 years. RESULTS: At 1-year follow-up, an extensive cardio-metabolic risk factor reduction was demonstrated in the intensive intervention group, along with a 70% decrease of progress to type 2 diabetes. At 5-year follow-up, most of these beneficial effects had disappeared. Reported physical activity and fibre intake as well as high-density lipoprotein cholesterol were still increased, and fasting insulin and proinsulin were lower. CONCLUSIONS: The intervention affected several important cardio-metabolic risk variables beneficially, and reduced the risk for type 2 diabetes, but the effects persisted only as long as the new lifestyle was maintained. Increased physical activity seemed to be the behaviour that was most easy to preserve.
  • Lyssenko, Valeriya, et al. (författare)
  • Validation of a multi-marker model for the prediction of incident type 2 diabetes mellitus: Combined results of the Inter99 and Botnia studies.
  • 2012
  • Ingår i: Diabetes & Vascular Disease Research. - : SAGE Publications. - 1752-8984 .- 1479-1641. ; 9, s. 59-67
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: To assess performance of a biomarker-based score that predicts the five-year risk of diabetes (Diabetes Risk Score, DRS) in an independent cohort that included 15-year follow-up. Method: DRS was developed on the Inter99 cohort, and validated on the Botnia cohort. Performance was benchmarked against other risk-assessment tools comparing calibration, time to event analysis, and net reclassification. Results: The area under the receiver-operating characteristic curve (AUC) was 0.84 for the Inter99 cohort and 0.78 for the Botnia cohort. In the Botnia cohort, DRS provided better discrimination than fasting plasma glucose (FPG), homeostasis model assessment of insulin resistance, oral glucose tolerance test or risk scores derived from Framingham or San Antonio Study cohorts. Overall reclassification with DRS was significantly better than using FPG and glucose tolerance status (p < 0.0001). In time to event analysis, rates of conversion to diabetes in low, moderate, and high DRS groups were significantly different (p < 0.001). Conclusion: This study validates DRS performance in an independent population, and provides a more accurate assessment of T2DM risk than other methods.
  • Nordwall, Maria, 1951- (författare)
  • Long term complications in juvenile diabetes mellitus
  • 2006
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Background/aim. The incidence of microvascular complications has been reported to be unchanged the last decades. However, in randomized clinical trials it has been shown that improved metabolic control can reduce the development of long term complications. It has been debated whether it is possible to achieve the same results in an unselected population. In a previous study we found a decreased incidence of overt nephropathy, but unchanged incidence of severe laser treated retinopathy in a population of patients with type 1 diabetes diagnosed in childhood. The aim of the present study was to investigate the incidence 10 years later in the same population and to analyse the importance of possible risk factors. In another previous study we found a high prevalence of subclinical neuropathy among young diabetic patients despite intensive insulin therapy since diagnosis. The aim of the present study was to examine if intensive treatment is more effective in preventing early diabetic complications other than neuropathy. The incidence of type 1 diabetes has doubled in Sweden the last decades. The reason must be environmental factors. These, as well as more intensive insulin regimens from onset of diabetes, might also lead to different disease process. We wanted to analyse if clinical characteristics at onset had changed the last 25 years and if there was any secular trend of C-peptide secretion. We also intended to investigate if longer persistence of C-peptide secretion could be of importance for prevention of long term complications.Methods. The whole study population consisted of all 478 patients with type 1 diabetes diagnosed before the age of 15 during the years 1961 - 2000, living in the catchment area of the Paediatric Clinic, University Hospital, Linköping, Sweden. For the statistical analysis the population was divided into five–year cohorts according to time of onset of diabetes. The cumulative proportion of severe retinopathy and overt nephropathy in 269 patients with onset of diabetes 1961 - 1985 was computed with survival analysis. Multivariable regression models were used to analyse the importance of metabolic control, diabetes duration, blood pressure, smoking, BMI, lipids and persisting C-peptide secretion. The prevalence of all grades of retinal changes, nephropathy and neuropathy, defined as abnormal nerve conduction, was estimated in the late 1990s in a subgroup of 80 children and adolescents with mean 13 years of diabetes duration. Clinical characteristics at onset, duration of partial remission and regularly measurements of fasting and stimulated C-peptide secretion the first five years after onset were analysed in 316 patients with onset of diabetes 1976 - 2000.Results. The cumulative proportion of severe laser treated retinopathy showed a significant declining trend the last decades. The decrease was significant between the oldest cohort with diabetes onset 1961 - 1965 and the cohorts with diabetes onset 1971 - 1975 and 1976 - 1980. The cumulative proportion of overt nephropathy also declined with a significant decrease between the oldest cohorts and all the following cohorts. After 25 years of diabetes duration it was 30% and 8% in the two oldest cohorts respectively and remained largely unchanged after 30 years. Diabetes duration and long term HbA1c were the only significant independent risk factors for both retinopathy and nephropathy. The risk of overt nephropathy increased substantially when HbA1c was above 8.5%, while the risk of severe retinopathy increased already when HbA1c exceeded 7.5%. The prevalence of neuropathy was 59%, of retinopathy 27% and of nephropathy 5% in the population of young patients after mean 13 years of diabetes duration. During the last 25 years the clinical characteristics at onset were unchanged as well as duration of partial remission and magnitude and persistence of C-peptide secretion.Conclusions. In this unselected population the cumulative proportion of severe retinopathy and overt nephropathy decreased over the last decades. Diabetic nephropathy has probably been prevented and not just postponed. Good glycaemic control was the most important factor to avoid complications, with the necessity of a lower level of HbA1c to escape retinopathy than nephropathy. Intensive insulin regimens from diabetes onset was not sufficient to entirely escape early diabetic complications after mean 13 years of diabetes duration, even if the prevalence of retinopathy and especially nephropathy was lower than usually reported. The clinical picture at onset of diabetes was unchanged the last 25 years. There was no secular trend of partial diabetes remission or C-peptide secretion during the first years after diagnosis.
  • Palmer, Nicholette D, et al. (författare)
  • A genome-wide association search for type 2 diabetes genes in African Americans.
  • 2012
  • Ingår i: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202-
  • Tidskriftsartikel (refereegranskat)abstract
    • African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
  • Rung, Johan, et al. (författare)
  • Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia
  • 2009
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1546-1718 .- 1061-4036. ; 41:10, s. 89-1110
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide association studies have identified common variants that only partially explain the genetic risk for type 2 diabetes (T2D). Using genome-wide association data from 1,376 French individuals, we identified 16,360 SNPs nominally associated with T2D and studied these SNPs in an independent sample of 4,977 French individuals. We then selected the 28 best hits for replication in 7,698 Danish subjects and identified 4 SNPs showing strong association with T2D, one of which (rs2943641, P = 9.3 x 10(-12), OR = 1.19) was located adjacent to the insulin receptor substrate 1 gene (IRS1). Unlike previously reported T2D risk loci, which predominantly associate with impaired beta cell function, the C allele of rs2943641 was associated with insulin resistance and hyperinsulinemia in 14,358 French, Danish and Finnish participants from population-based cohorts; this allele was also associated with reduced basal levels of IRS1 protein and decreased insulin induction of IRS1-associated phosphatidylinositol-3-OH kinase activity in human skeletal muscle biopsies.
  • Sadauskaite-Kühne, Vaiva, 1970- (författare)
  • Genetic and environmental factors in relation to childhood type 1 diabetes mellitus aetiology and clinical presentation in Sweden and Lithuania
  • 2004
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Background. Incidence of Type I diabetes mellitus (DM) is increasing worldwide. It is affecting mostly young people, with the dramatically rising incidence among youngest children (those under age of 5 years). Most evident genetic association with Type I DM so far identified is by HLA (Human Leukocyte Antigen) region on the short arm of human chromosome 6p21.3 encoding class II genes. A higher accumulation of new cases is also seen in the families where already one member has been diagnosed with Type I DM. Still, even monozygotic twins who are HLA identical, have Type I DM concordance rates as low as 30-50 %. Therefore a role of environment as a risk factor for Type I DM is suggested Nutrition, especially early in life, environmental toxins, viruses, perinatal events, stress, social factors, seem to modify risk for the disease. It still remains unclear why the incidence of Type I DM varies so greatly, above 350-fold world wide, why countries in a close neighbourhood sharing similar latitude and climate like Sweden and Lithuania have such an extreme difference in childhood Type I OM incidence (Sweden 34.0/100 000 and Lithuania 8.9/100 000 in year 1999).A simultaneous epidemiological study in these two neighbouring countries with different type 1 DM incidence focused on clinical expression, genetic and environmental background of Type 1 DM diabetes, which could help to detect aetiological factors of the disease.Aims. Compare clinical presentation of childhood Type 1 diabetes mellitus in Sweden and Lithuania, in countries with high and low Type 1 DM incidence. Identify transmission rate of Type I DM related alleles and haplotypes in Lithuanian families with a child with diabetes. Test the hypothesis whether children with AB0 blood group incompatibility have a similar frequency of diabetes risk related HLA alleles as children with type 1 diabetes and healthy children. Identify environmental factors conferring possibly protection or risk for developing Type 1 diabetes mellitus.Material and methods. The study was designed as a case-control study. 517 0-15 years old newly diagnosed children with type I DM during 01 08 1995-01 08 2000 in South-East of Sweden (closest neighbouring part to Lithuania) and all 286 newly diagnosed children during 01 08 1996 - 01 08 2000 in Lithuania participated in the study, with control response rate 72.9% and 94.8%, respectively. Children and their parents filled in questionnaires at the time of diagnosis, as well as population-based age and sex matched randoruly selected three healthy controls. Blood samples were collected from newly diagnosed children with diabetes and their first degree relatives.Results. Swedish children were younger at the moment of diagnosis than were the Lithuanian children. In both countries the status at time of diagnosis was more severe among children without any first degree relative with diabetes. The proportion of children with ketoacidosis was three time higher in Lithuania than in Sweden. In Sweden, age, recent infections and mother's employment status were best predictors for DKA, whereas in Lithuania it was age and maternal education. Childhood type 1 diabetes mellitus presentation was more severe in Lithuania than in Sweden, especially in the young age.Together with a four times higher incidence of Type 1 in Sweden the children diagnosed in the south-east part of Sweden had also twice as often a family member with Type I diabetes. Mainly it was due to the higher prevalence of Type I DM among fathers in Sweden.Frequency of known diabetes risk related alleles was less prevalent among Lithuanian than among Swedish children with Type 1 DM. In Lithuania, DQB1*0302 and DR4 were significantly more frequently transmitted from both parents, but DR3 was transmitted more frequently ouly from mothers. Any of these alleles had similar frequencies among female and male offspring.DR3 allele was increased in patients with AB0 incompatibility when compared to healthy controls. Patients with type I diabetes had significantly higher frequency of DR3, DQ2, DR4 and DQ8 alleles when compared to healthy controls. No significant difference was observed in frequency of DR3 between AB0 blood group incompatibility and type I diabetes patients.Psychosocial stress and infections were risk factors for developing Type 1 DM in both countries. High social mixing of the mothers was also increasing risk for diabetes for the children in both countries. Mother's age over 30 years at birth was a protective factor in Sweden, whereas in Lithuania it was a risk factor.Proportions of breast fed children were similar between cases and controls in both countries. Duration of exclusive and total breast feeding was significantly longer in Sweden than in Lithuania when diabetes status, country, age at diagnosis and sex were included as covariates. Both in Sweden and in Lithuania exclusive breast feeding was found to be protective against diabetes in certain age groups and in Sweden also the duration of total breast feeding was protective. Early introduction of breast milk substitution was a risk factor, when controlled for a group of other known risk factors.Conclusions. There are differences in clinical presentation of Type 1 DM between Sweden and Lithuania. This might be due to increased knowledge of disease in country with higher incidence. Environmental factors, such as suspended breastfeeding, infections or psychosocial stress are uniform risk factors despite the rate of incidence in the country. The way the predisposition of the innnune system is built up is complex and depends not only on differences in genetic background of the disease or different transmission rates of diabetes related risk haplotypes, but also in shared environment.
  • Vistisen, Dorte, et al. (författare)
  • Bimodal distribution of glucose is not universally useful for diagnosing diabetes
  • 2009
  • Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 32:3, s. 397-403
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Bimodality in the distribution of glucose has been used to define the cut point for the diagnosis of diabetes. Previous studies on bimodality have primarily been in populations with a high prevalence of type 2 diabetes, including one study in a white Caucasian population. All studies included participants with known diabetes. The aim of this study was to assess whether a bimodal structure is a general phenomenon in fasting plasma glucose (FPG) and 2-h plasma glucose that is useful for deriving a common cut point for diabetes in populations of different origin, both including and excluding known diabetes. RESEARCH DESIGN AND METHODS: The Evaluation of Screening and Early Detection Strategies for Type 2 Diabetes and Impaired Glucose Tolerance (DETECT-2) project is an international collaboration pooling surveys from all continents. These studies include surveys in which plasma glucose was measured during an oral glucose tolerance test; in total, 43 studies (135,383 participants) from 27 countries were included. A mixture of two normal distributions was fitted to plasma glucose levels, and a cut point for normal glycemia was estimated as their intersection. In populations with a biologically meaningful cut point, bimodality was tested for significance. RESULTS: Distributions of FPG and 2-h plasma glucose did not, in general, produce bimodal structures useful for deriving cut points for diabetes. When present, the cut points produced were inconsistent over geographical regions. CONCLUSIONS: Deriving cut points for normal glycemia from distributions of FPG and 2-h plasma glucose does not appear to be suitable for defining diagnostic cut points for diabetes.
  • Zeggini, Eleftheria, et al. (författare)
  • Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes
  • 2008
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1546-1718 .- 1061-4036. ; 40:5, s. 638-645
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D)(1-11). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and similar to 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P=5.0 x 10(-14)), CDC123-CAMK1D (P=1.2 x 10(-10)), TSPAN8-LGR5 (P=1.1 x 10(-9)), THADA (P=1.1 x 10(-9)), ADAMTS9 (P=1.2 x 10(-8)) and NOTCH2 (P=4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.
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