A Web Portal for Communicating Polygenic Risk Score Results for Health Care Use-The P5 Study.

We present a method for communicating personalized genetic risk information to citizens and their physicians using a secure web portal. We apply the method for 3,177 Finnish individuals in the P5 Study where estimates of genetic and absolute risk, based on genetic and clinical risk factors, of future disease are reported to study participants, allowing individuals to participate in managing their own health. Our method facilitates using polygenic risk score as a personalized tool to estimate a person's future disease risk while offering a way for health care professionals to utilize the polygenic risk scores as a preventive tool in patient care.

Association of diabetes type and chronic diabetes complications with early exit from the labour force: register-based study of people with diabetes in Finland.

AIMS/HYPOTHESIS: Diabetes and diabetes complications are a cause of substantial morbidity, resulting in early exits from the labour force and lost productivity. The aim of this study was to examine differences in early exits between people with type 1 and 2 diabetes and to assess the role of chronic diabetes complications on early exit. We also estimated the economic burden of lost productivity due to early exits. METHODS: People of working age (age 17-64) with diabetes in 1998-2011 in Finland were detected using national registers (Ntype 1 = 45,756, Ntype 2 = 299,931). For the open cohort, data on pensions and deaths, healthcare usage, medications and basic demographics were collected from the registers. The outcome of the study was early exit from the labour force defined as pension other than old age pension beginning before age 65, or death before age 65. We analysed the early exit outcome and its risk factors using the Kaplan-Meier method and extended Cox regression models. We fitted linear regression models to investigate the risk factors of lost working years and productivity costs among people with early exit. RESULTS: The difference in median age at early exit from the labour force between type 1 (54.0) and type 2 (58.3) diabetes groups was 4.3 years. The risk of early exit among people with type 1 diabetes increased faster after age 40 compared with people with type 2 diabetes. Each of the diabetes complications was associated with an increase in the hazard of early exit regardless of diabetes type compared with people without the complication, with eye-related complications as an exception. Diabetes complications partly but not completely explained the difference between diabetes types. The mean lost working years was 6.0 years greater in the type 1 diabetes group than in the type 2 diabetes group among people with early exit. Mean productivity costs of people with type 1 diabetes and early exit were found to be 1.4-fold greater compared with people with type 2 diabetes. The total productivity costs of incidences of early exits in the type 2 diabetes group were notably higher compared with the type 1 group during the time period (€14,400 million, €2800 million). CONCLUSIONS/INTERPRETATION: We found a marked difference in the patterns of risk of early exit between people with type 1 and type 2 diabetes. The difference was largest close to statutory retirement age. On average, exits in the type 1 diabetes group occurred at an earlier age and resulted in higher mean lost working years and mean productivity costs. The potential of prevention, timely diagnosis and management of diabetes is substantial in terms of avoiding reductions in individual well-being and productivity.

Antidiabetic Medication, Statins and the Risk and Prognosis of Non-endometrioid Endometrial Cancer in Women with Type 2 Diabetes.

AIM: To determine the incidence and prognosis of non-endometrioid endometrial cancer (EC) in relation to the use of metformin, other antidiabetic medication (ADM) and statins in patients with type 2 diabetes (T2D). MATERIALS AND METHODS: In order to analyze the incidence and prognosis of non-endometrioid EC, two cohorts were obtained from a nationwide diabetes database (FinDM); 57 non-endometrioid ECs were observed in a cohort of 92,366 women with newly-diagnosed T2D during the follow-up (1996 to 2011) to assess the incidence, and a retrospective cohort of 105 women with T2D diagnosed with non-endometrioid EC (1998 to 2011) was used to estimate cumulative mortality from EC and other causes of death. Hazard ratios (HRs) with 95% confidence intervals (CIs) for EC incidence were estimated in the full-cohort analysis and in the nested case-control analysis, matched for age and duration of T2D. Cumulative mortality was estimated by using the Aalen-Johansen estimator. Cause-specific mortality rates were analyzed by using Cox models regarding the pre-diagnostic use of different forms of ADM and statins. RESULTS: In the nested case-control analysis, the use of metformin was not associated with the risk of non-endometrioid EC (HR=1.09, 95% CI=0.59-2.00), whereas statin use was associated with a lower risk (HR=0.47, 95% CI=0.26-0.84). The results from the full-cohort analysis supported these findings. Mortality from non-endometrioid EC was not different between users of metformin and other types of oral ADM (HR=1.56, 95% CI=0.40-6.07) but was observed to be lower in statin users (HR=0.41, 95% CI=0.20-0.82). CONCLUSION: Our findings were inconclusive regarding the association of metformin with the risk and prognosis of non-endometrioid EC. However, statin use was associated with a lower incidence and mortality from this disease.

Prognosis of ovarian cancer in women with type 2 diabetes using metformin and other forms of antidiabetic medication or statins: a retrospective cohort study.

BACKGROUND: Ovarian cancer is one of the most lethal cancers and women with type 2 diabetes (T2D) have even poorer survival from it. We assessed the prognosis of ovarian cancer in women with type 2 diabetes treated with metformin, other forms of antidiabetic medication, or statins. METHODS: Study cohort consisted of women with T2D diagnosed with ovarian cancer in Finland 1998-2011. They were identified from a nationwide diabetes database (FinDM), being linked to several national registers. Patients were grouped according to their medication in the three years preceding ovarian cancer diagnosis. The Aalen-Johansen estimator was used to describe cumulative mortality from ovarian cancer and from other causes in different medication groups. Mortality rates were analysed by Cox models, and adjusted hazard ratios (HR) with 95% confidence intervals (95% CIs) were estimated in relation to the use of different forms of medication. Main outcome measures were death from ovarian cancer and death from other causes. RESULTS: During the accrual period 421 newly diagnosed ovarian cancers were identified in the FinDM database. No evidence was found for any differences in mortality from ovarian cancer or other causes between different antidiabetic medication groups. Pre-diagnostic use of statins was observed to be associated with decreased mortality from ovarian cancer compared with no such use (HR 0.72, 95% CI 0.56-0.93). CONCLUSIONS: Our findings are inconclusive as regards the association between metformin and ovarian cancer survival. However, some evidence was found for improved prognosis of ovarian cancer with pre-diagnostic statin use, requiring cautious interpretation, though.

Antidiabetic medication, statins and the risk of endometrioid endometrial cancer in patients with type 2 diabetes.

OBJECTIVE: To gain further evidence of an association between the incidence of endometrial cancer (EC) and the use of metformin, other antidiabetic medication (ADM) and statins in women with type 2 diabetes (T2D). METHODS: A retrospective cohort of 92,366 women with newly diagnosed T2D was obtained from a diabetes register (FinDM). 590 endometrioid ECs were observed during the follow-up time. Poisson regression was utilized to estimate the hazard ratios (HRs) with 95% confidence intervals (95% CIs) of the endometrioid EC in relation to the use of metformin, other oral ADM, insulin and statins. Nested case-control analyses were performed, where up to 20 controls were matched for age and duration of DM for each EC case. The HRs were estimated by conditional logistic regression for never/ever and cumulative use of different forms of ADM and statins. RESULTS: In the case-control analyses the use of metformin (HR 1.24, 95% CI 1.02-1.51) and other oral ADM (HR 1.25, 95% CI 1.04-1.50) was associated with an increased incidence of endometrioid EC compared to no ADM use. No difference was observed between metformin users and those using other oral ADMs. The use of statins was inversely related to the incidence of endometrioid EC (HR 0.78, 95% CI 0.65-0.94). Results from the full cohort analysis supported this finding. CONCLUSIONS: In our study the use of metformin or other oral forms of ADM was not associated with a lowered risk of endometrioid EC in women with T2D. Instead statins were observed to be inversely associated with endometrioid EC in this population.

Indolepropionic acid and novel lipid metabolites are associated with a lower risk of type 2 diabetes in the Finnish Diabetes Prevention Study.

Wide-scale profiling technologies including metabolomics broaden the possibility of novel discoveries related to the pathogenesis of type 2 diabetes (T2D). By applying non-targeted metabolomics approach, we investigated here whether serum metabolite profile predicts T2D in a well-characterized study population with impaired glucose tolerance by examining two groups of individuals who took part in the Finnish Diabetes Prevention Study (DPS); those who either early developed T2D (n = 96) or did not convert to T2D within the 15-year follow-up (n = 104). Several novel metabolites were associated with lower likelihood of developing T2D, including indole and lipid related metabolites. Higher indolepropionic acid was associated with reduced likelihood of T2D in the DPS. Interestingly, in those who remained free of T2D, indolepropionic acid and various lipid species were associated with better insulin secretion and sensitivity, respectively. Furthermore, these metabolites were negatively correlated with low-grade inflammation. We replicated the association between indolepropionic acid and T2D risk in one Finnish and one Swedish population. We suggest that indolepropionic acid, a gut microbiota-produced metabolite, is a potential biomarker for the development of T2D that may mediate its protective effect by preservation of ß-cell function. Novel lipid metabolites associated with T2D may exert their effects partly through enhancing insulin sensitivity.

Diabetes, glycaemia, and cognition-a secondary analysis of the Finnish Diabetes Prevention Study.

BACKGROUND: Type 2 diabetes is linked with cognitive dysfunction and dementia in epidemiological studies, but these observations are limited by lack of data on the exact timing of diabetes onset. We investigated diabetes, dysglycaemia, and cognition in the Finnish Diabetes Prevention Study, in which the timing and duration of diabetes are well documented. METHODS: The Finnish Diabetes Prevention Study comprised middle-aged, overweight participants with impaired glucose tolerance but no diabetes at baseline (n = 522), randomized to lifestyle intervention or a control group. After an intervention period (mean duration 4 years) and follow-up (additional 9 years), cognitive assessment with the CERAD test battery and Trail Making Test A (TMT) was executed twice within a 2-year interval. Of the 364 (70%) participants with cognitive assessments, 171 (47%) had developed diabetes. RESULTS: Cognitive function did not differ between those who developed diabetes and those who did not. Lower mean 2-h glucose at an oral glucose tolerance test (OGTT) and HbA1C during the intervention period predicted better performance in the TMT (p = 0.012 and 0.024, respectively). Those without diabetes or with short duration of diabetes improved in CERAD total score between the two assessments (p = 0.001) whereas those with long duration of diabetes did not (p = 0.844). CONCLUSIONS: Better glycemic control among persons with baseline impaired glucose tolerance predicted better cognitive performance 9 years later in this secondary analysis of the Finnish Diabetes Prevention Study population. In addition, learning effects in cognitive testing were not evident in people with long diabetes duration. Copyright © 2015 John Wiley & Sons, Ltd.

Cognition in the Finnish diabetes prevention study.

We studied cognition in the Finnish Diabetes Prevention Study (DPS), a trial of lifestyle intervention that prevented diabetes in persons with impaired glucose tolerance. Cognition was similar in the randomization arms 9 years after the intervention in 364 participants, suggesting that the intervention did not benefit cognition.

The association between HbA1c, fasting glucose, 1-hour glucose and 2-hour glucose during an oral glucose tolerance test and cardiovascular disease in individuals with elevated risk for diabetes.

OBJECTIVE: To determine the association between HbA1c, fasting plasma glucose (FPG), 1-hour (1 hPG) and 2-hour (2 hPG) glucose after an oral glucose tolerance test (OGTT) and cardiovascular disease in individuals with elevated risk for diabetes. DESIGN: We studied the relationship between baseline, updated mean and updated (last) value of HbA1c, FPG, 1 hPG and 2 hPG after an oral 75 g glucose tolerance test (OGTT) and acute CVD events in 504 individuals with impaired glucose tolerance (IGT) at baseline enrolled in the Finnish Diabetes Prevention Study. SETTING: Follow-up of clinical trial. PARTICIPANTS: 504 individuals with IGT were followed with yearly evaluations with OGTT, FPG and HbA1c. MAIN OUTCOME MEASURE: Relative risk of CVD. RESULTS: Over a median follow-up of 9.0 years 34 (6.7%) participants had a CVD event, which increased to 52 (10.3%) over a median follow-up of 13.0 years when including events that occurred among participants following a diagnosis of diabetes. Updated mean HbA1c, 1 hPG and 2 hPG, HR per 1 unit SD of 1.57 (95% CI 1.16 to 2.11), p = 0.0032, 1.51 (1.03 to 2.23), p = 0.036 and 1.60 (1.10 to 2.34), p = 0.014, respectively, but not FPG (p = 0.11), were related to CVD. In analyses of the last value prior to the CVD event the same three glycaemic measurements were associated with the CVD events, with HRs per 1 unit SD of 1.45 (1.06 to 1.98), p = 0.020, 1.55 (1.04 to 2.29), p = 0.030 and 2.19 (1.51 to 3.18), p<0.0001, respectively but only 2 hPG remained significant in pairwise comparisons. Including the follow-up period after diabetes onset updated 2 hPG (p = 0.003) but not updated mean HbA1c (p = 0.08) was related to CVD. CONCLUSIONS AND RELEVANCE: Current 2 hPG level in people with IGT is associated with increased risk of CVD. This supports its use in screening for prediabetes and monitoring glycaemic levels of people with prediabetes.

Monitoring the use of lipid-lowering medication among persons with newly diagnosed diabetes: a nationwide register-based study.

OBJECTIVES: To develop a register-based monitoring system to provide information on the use of lipid-lowering medication among persons with diabetes in different patient groups and by socioeconomic position. DESIGN: Longitudinal and register-based, before and after diabetes diagnosis. SETTING: Finnish population. PARTICIPANTS: A total of 121 053 persons aged 30-79 years with a new diagnosis of diabetes during 2000-2006. The annual cohorts were divided at the time of diabetes diagnosis by coronary heart disease (CHD) status. PRIMARY AND SECONDARY OUTCOME MEASURES: Lipid-lowering medication purchases after diabetes diagnosis and prior to the diagnosis. RESULTS: According to the health insurance reimbursement data the use of lipid-lowering medication advanced rapidly among people with diabetes in the early 2000s in Finland. Of the patients diagnosed with diabetes in 2000 only one-fourth used lipid-lowering medication in 6-12 months after their diagnosis. For those diagnosed in 2006, the utilization rate was 46%. Among those with a history of CHD the use of medication was markedly higher; 51-58% in 2000 and 77-79% in 2006. Taking into account the increasing trend and measuring the independent effect of the diagnosis of diabetes on lipid-lowering medication, setting the diagnosis increased the use by 10-50%. Despite increasing overall utilisation rates, socioeconomic difference in the use of lipid-lowering medication remained throughout the study period. In particular, the lowest income quintile differed from other income groups and in 2006 its use of lipid-lowering medication remained approximately 10% points lower compared with the overall level. CONCLUSIONS: The lipid-lowering medication is being applied in an increasing population of new diabetes cases; however, modelling the independent effect of the diagnosis of diabetes on lipid-lowering medication shows that the diagnosis increased use, but did not abolish socioeconomic differences.

Increased cancer mortality in diabetic people treated with insulin: a register-based follow-up study.

BACKGROUND: The national 10-year Development Programme for the Prevention and Care of Diabetes (DEHKO) was launched in Finland in 2000. The program focused on improving early diagnosis of type 2 diabetes and preventing diabetes-related complications. The FinDM database was established for epidemiological monitoring of diabetes and its complications. This study monitors mortality trends among people with diabetes during the DEHKO programme. METHODS: A database obtained from a compilation of several administrative national health registers was used to study mortality in people with diabetes in 1998-2007. Relative excess mortality between people with and without diabetes was analyzed using Poisson regression models. RESULTS: The number of diabetic people in Finland increased by 66% from 1997 reaching 284 832 in 2007. Like among non-diabetic people, all-cause mortality decreased in people with diabetes. Overall excess mortality remained high in people with diabetes; in 2003-2007 RRs in the non-insulin treated was 1.82 for men and 1.95 for women and in the insulin treated 3.45 and 4.29, and excess coronary heart disease mortality in the insulin treated: RR was 4.71 in men and 7.80 in women. A striking result was mortality from neoplasms; an increase in mortality emerged in almost every age group of insulin treated women. CONCLUSION: Compared to non-diabetic people our monitoring showed declining excess mortality in non-insulin treated diabetic people mainly due to a decrease in mortality from cardiovascular diseases. For insulin treated, relative overall excess mortality remained unchanged and mortality from neoplasms increased among women.

Importance of weight loss maintenance and risk prediction in the prevention of type 2 diabetes: analysis of European Diabetes Prevention Study RCT.

BACKGROUND: Prevalence of type 2 diabetes (T2D) is increasing worldwide. T2D prevention by lifestyle intervention is effective. Pragmatic scalable interventions are needed, with evidence to efficiently target and monitor such interventions. We report pooled analyses of data from three European trial cohorts: to analyse T2D incidence, sustained weight loss and utility of risk predictors. METHODS: We analysed data on 749 adults with impaired glucose tolerance (278 men and 471 women, mean age 56 years, mean BMI 31 kgm(-2)) recruited between 1993 and 2003, and randomised to intensive lifestyle intervention (I) or lifestyle advice control (C). The intervention aimed to increase physical activity, modify diet, and promote weight loss≥5%. Using Cox-regression survival analysis, we assessed T2D incidence and the impact on T2D incidence of sustained weight loss, and of baseline cut-point values of FINDRISC score, fasting plasma glucose (FPG), and HbA1c. RESULTS: Mean follow-up duration was 3.1 years. T2D was diagnosed in 139 participants (I = 45/379, C = 94/370). Cumulative T2D incidence was 57% lower in the intervention compared with the control group (HR 0.42 (95% CI 0.29 to 0.60) P<0.001). Participants with ≥5% weight loss at one year had 65% lower T2D incidence (HR 0.35 (95% CI 0.22 to 0.56) P<0.001); maintaining ≥5% weight loss for two and three years further reduced T2D incidence. Recommended cut-points to identify those at high risk for T2D would have identified different proportions of European Diabetes Prevention Study (EDIPS) participants with similar hazard-ratios for intervention effect. CONCLUSIONS: Pooled analysis of EDIPS trial data reinforces evidence for T2D prevention by lifestyle intervention. Analysis showed the preventive effect of ≥5% weight loss, especially if maintained long term, which has utility for intervention monitoring. Analysis of proposed cut-points demonstrates difficulties in balancing risk and benefit, to efficiently target interventions and suggests evidence is needed to define clinical policy. TRIAL REGISTRATIONS: THE FINNISH DIABETES PREVENTION STUDY, HELSINKI, FINLAND: ClinicalTrials.gov; NCT00518167 The SLIM diabetes prevention study, Maastricht, The Netherlands: Clinical Trials.gov; NCT00381186 The EDIPS-Newcastle diabetes prevention study, Newcastle upon Tyne, UK: International Standard Randomised Controlled Trial Number; ISRCTN15670600.

Leukocyte telomere length in the Finnish Diabetes Prevention Study.

Leukocyte telomere length (TL) is considered a biomarker for biological aging. Shortened TL has been observed in many complex diseases, including type 2 diabetes (T2DM). Lifestyle intervention studies, e.g. the Diabetes Prevention Study (DPS), have shown a decrease in the incidence of T2DM by promoting healthy lifestyles in individuals with impaired glucose tolerance (IGT). Our aim was to study in the DPS the influence of the lifestyle intervention on TL. TL was measured by quantitative PCR-based method at two time points (N = 334 and 343) on average 4.5 years apart during the active intervention and post-intervention follow-up. TL inversely correlated with age. Our main finding was that TL increased in about two thirds of the individuals both in the intervention and in the control groups during follow-up; TL increased most in individuals with the shortest TL at the first measurement. TL was not associated with development of T2DM, nor did lifestyle intervention have an effect on TL. No association between insulin secretion or insulin resistance indices and TL was observed. We did not detect an association between TL and development of T2DM in the DPS participants. It could be due to all participants being overweight and having IGT at baseline, both of which have been found to be independently associated with shorter leukocyte TL in some earlier studies. TL had no substantial role in worsening of glucose tolerance in people with IGT. Our study confirms that leukocyte TL can increase with time even in obese people with impaired glucose metabolism.

Insulin secretion and its determinants in the progression of impaired glucose tolerance to type 2 diabetes in impaired glucose-tolerant individuals: the Finnish Diabetes Prevention Study.

OBJECTIVE: We investigated the effect of early-phase insulin secretion on the incidence of type 2 diabetes in individuals with impaired glucose tolerance (IGT) participating in the Finnish Diabetes Prevention Study (DPS). We examined how a lifestyle intervention affected early-phase insulin secretion (ratio of total insulin area under the curve [AUC] and total glucose AUC [AIGR] from 0 to 30 min) during a 4-year follow-up intervention trial and whether AIGR(0-30) response was modified by insulin sensitivity (IS) and obesity. RESEARCH DESIGN AND METHODS: A total of 443 participants with IGT originally randomized to a lifestyle intervention or control group were studied. IS and AIGR(0-30) were estimated from an oral tolerance glucose test administered annually during the 4-year follow-up trial and were related to the risk of diabetes onset over a 6-year follow-up. RESULTS: Lifestyle intervention resulted in higher IS (P = 0.02) and lower unadjusted AIGR(0-30) (P = 0.08) during the 4-year follow-up. A higher IS and a lower BMI during the follow-up were associated with a lower unadjusted AIGR(0-30) during the follow-up, independently of study group (P < 0.001). A greater increase in IS on the median cutoff point of a 0.69 increase was associated with higher IS-adjusted AIGR(0-30) during the follow-up (P = 0.002). In multivariate models, IS and IS-adjusted AIGR(0-30) were both inversely associated with diabetes incidence (P < 0.001). Participants who progressed to type 2 diabetes were more obese and had lower IS and Matsuda IS index-AIGR(0-30) than nonprogressors. CONCLUSIONS: Our results indicate that the reduction in the risk of developing type 2 diabetes after lifestyle intervention is related to the improvement of IS along with weight loss. Improved IS may also have beneficial effects on preservation of ß-cell function.

Association of ADIPOR2 gene variants with cardiovascular disease and type 2 diabetes risk in individuals with impaired glucose tolerance: the Finnish Diabetes Prevention Study.

BACKGROUND: Adiponectin is an adipokine with insulin-sensitising and anti-atherogenic effects. Two receptors for adiponectin, ADIPOR1 and ADIPOR2, have been characterized that mediate effects of adiponectin in various tissues. We examined whether genetic variation in ADIPOR2 predicts the development of cardiovascular disease (CVD) and/or Type 2 Diabetes (T2DM) in individuals with impaired glucose tolerance (IGT) participating the Finnish Diabetes Prevention Study (DPS). METHODS: CVD morbidity and mortality data were collected during a median follow-up of 10.2 years (range 1-13 years) and conversion from IGT to T2DM was assessed during a median follow-up of 7 years (range 1-11 years). Altogether eight SNPs in the ADIPOR2 locus were genotyped in 484 participants of the DPS. Moreover, the same SNPs were genotyped and the mRNA expression levels of ADIPOR2 were determined in peripheral blood mononuclear cells and subcutaneous adipose tissue samples derived from 56 individuals participating in the Genobin study. RESULTS: In the DPS population, four SNPs (rs10848554, rs11061937, rs1058322, rs16928751) were associated with CVD risk, and two remained significant (p = 0.014 for rs11061937 and p = 0.020 for rs1058322) when all four were included in the same multi-SNP model. Furthermore, the individuals homozygous for the rare minor alleles of rs11061946 and rs11061973 had increased risk of converting from IGT to T2DM. Allele-specific differences in the mRNA expression levels for the rs1058322 variant were seen in peripheral blood mononuclear cells derived from participants of the Genobin study. CONCLUSIONS: Our results suggest that SNPs in the ADIPOR2 may modify the risk of CVD in individuals with IGT, possibly through alterations in the mRNA expression levels. In addition an independent genetic signal in ADIPOR2 locus may have an impact on the risk of developing T2DM in individuals with IGT. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT00518167.

Association of ADIPOQ gene variants with body weight, type 2 diabetes and serum adiponectin concentrations: the Finnish Diabetes Prevention Study.

BACKGROUND: Adiponectin, secreted mainly by mature adipocytes, is a protein with insulin-sensitising and anti-atherogenic effects. Human adiponectin is encoded by the ADIPOQ gene on the chromosomal locus 3q27. Variations in ADIPOQ are associated with obesity, type 2 diabetes (T2DM) and related phenotypes in several populations. Our aim was to study the association of the ADIPOQ variations with body weight, serum adiponectin concentrations and conversion to T2DM in overweight subjects with impaired glucose tolerance. Moreover, we investigated whether ADIPOQ gene variants modify the effect of lifestyle changes on these traits. METHODS: Participants in the Finnish Diabetes Prevention Study were randomly assigned to a lifestyle intervention group or a control group. Those whose DNA was available (n = 507) were genotyped for ten ADIPOQ single nucleotide polymorphisms (SNPs). Associations between SNPs and baseline body weight and serum adiponectin concentrations were analysed using the univariate analysis of variance. The 4-year longitudinal weight data were analysed using linear mixed models analysis and the change in serum adiponectin from baseline to year four was analysed using Kruskal-Wallis test. In addition, the association of SNPs with the risk of developing T2DM during the follow-up of 0-11 (mean 6.34) years was analysed by Cox regression analysis. RESULTS: rs266729, rs16861205, rs1501299, rs3821799 and rs6773957 associated significantly (p < 0.05) with body weight at baseline and in the longitudinal analyses. The rs266729 C allele and the rare minor alleles of rs2241766 and rs2082940 were associated with an increased adjusted hazard ratio of developing T2DM. The differences in baseline serum adiponectin concentrations were seen according to rs16861210, rs17366568, rs2241766, rs6773957 and rs2082940 and differences in the change of serum adiponectin levels from baseline to the four year examination were seen according to rs16861205, especially in subjects who were able to lose weight during the first year of intervention. CONCLUSIONS: These results from the Finnish Diabetes Prevention Study support the concept that genetic variation in ADIPOQ locus contributes to variation in body size and serum adiponectin concentrations and may also modify the risk of developing T2DM. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT00518167.

Impact of positive family history and genetic risk variants on the incidence of diabetes: the Finnish Diabetes Prevention Study.

OBJECTIVE: We aimed to investigate the influence of positive family history (FH+) of diabetes and 19 known genetic risk loci on the effectiveness of lifestyle changes and their predictive value on the incidence of type 2 diabetes in the Finnish Diabetes Prevention Study (DPS). RESEARCH DESIGN AND METHODS: A total of 522 subjects with impaired glucose tolerance (IGT) were randomized into the control (n = 257) and intervention (n = 265) groups. The mean follow-up was 6.2 years (median 7 years), and the lifestyle intervention, aimed at weight reduction, healthy diet, and increased physical activity, lasted for 4 years (range 1-6 years). An oral glucose tolerance test (OGTT) and assessment of basic clinical variables were performed annually. RESULTS: The effect of intervention on the incidence of diabetes was almost similar in subjects with FH+ compared with subjects with a negative family history (FH-) of diabetes during the entire follow-up. In the Cox model, including FH, genetic risk SNPs, and randomization group, and adjusted for the effects of age, sex, BMI, and study center, only lifestyle intervention had a significant effect (hazard ratio 0.55, 95% CI 0.41-0.75, P < 0.001) on the incidence of diabetes. Further analyses showed that in addition to the baseline glucose and insulin values, 1-year changes in 2-h glucose and 2-h insulin achieved by lifestyle intervention had a significant effect on the incidence of diabetes. CONCLUSIONS: These results emphasize the effectiveness of lifestyle intervention in reducing the risk of diabetes in high-risk individuals independently of genetic or familial risk of type 2 diabetes.

Leisure-time physical activity and the metabolic syndrome in the Finnish diabetes prevention study.

OBJECTIVE: To assess the effects of leisure-time physical activity (LTPA) and resistance training on metabolic syndrome (MetS) and its components in a post hoc analysis of the Finnish Diabetes Prevention Study, a randomized controlled lifestyle counseling trial. RESEARCH DESIGN AND METHODS: A cohort of 486 middle-aged overweight men and women with impaired glucose tolerance were followed for an average of 4.1 years. The intervention and control groups were combined in the analyses. LTPA was assessed by questionnaires, dietary intake by food records, and features of the MetS by anthropometric and biochemical measures annually. Resistance training sessions were documented for 137 participants. RESULTS: Increased moderate-to-vigorous LTPA, even after adjustments for changes in dietary intakes of total and saturated fat, fiber, and energy, and change in BMI was associated with a greater likelihood for resolution (29.7 vs. 19.1%; P = 0.004 in the upper versus lower third of change) and a lesser likelihood for development (23.5 vs. 44.7%; P = 0.041) of the MetS. Of the components of the MetS, the increase in moderate-to-vigorous LTPA was associated most strongly with improvement of glycemia. Among the 137 participants who participated in resistance training, MetS components were favorable in individuals who were in the upper third of participation rate (median 51 times/year) compared with individuals in the lowest third (median 8.5 times/year). CONCLUSIONS: Increased moderate-to-vigorous LTPA was associated with a decreased likelihood of developing the MetS and an increased likelihood of its resolution in individuals at high risk for type 2 diabetes.

Variation in the UCP2 and UCP3 genes associates with abdominal obesity and serum lipids: the Finnish Diabetes Prevention Study.

BACKGROUND: We explored the associations of three variants in the uncoupling protein 2 (UCP2) gene, one variant in the UCP2-UCP3 intergenic region and five variants in the uncoupling protein 3 (UCP3) gene with obesity and diabetes related traits in subjects with impaired glucose tolerance participating in Finnish Diabetes Prevention Study. Altogether 507 overweight individuals (body mass index: 31.2 +/- 4.5 kg/m2, age: 55 +/- 7 years) for whom DNA was available were randomized to either an intensified diet and physical activity group or to a conventional care control group. METHODS: We analysed the data from the baseline and annual follow-up visits from years 1, 2 and 3. Measurements of anthropometry, plasma glucose and serum insulin in oral glucose tolerance test, serum total cholesterol, HDL-cholesterol and triglycerides were included. The median follow-up time for type 2 diabetes incidence was 7 years. Genetic variants were screened by restriction fragment length polymorphism or Illumina method. RESULTS: UCP3 gene variant rs3781907 was associated with increased serum total and LDL-cholesterol levels, at baseline and during the follow-up period. The same variant was associated with a higher risk of type 2 diabetes. Variants rs1726745, rs11235972 and rs1800849 in the UCP3 gene associated with serum total and LDL-cholesterol at baseline. Haploblock including variants rs659366, rs653529, rs15763, and rs1726745 was associated with measures of abdominal obesity at baseline and in the longitudinal analysis. The haplotype comprising alleles rs659366-G, rs653529-A, rs15763-G and rs1726745-A was associated with higher waist-to-hip ratio, and haplotype comprising alleles rs3781907-G, rs11235972-A, and rs1800849-T was associated with increased serum total and LDL-cholesterol concentrations. CONCLUSION: Genetic variation in the UCP2-UCP3 gene cluster may act as a modifier increasing serum lipid levels and indices of abdominal obesity, and may thereby also contribute to the metabolic aberrations observed in obesity and type 2 diabetes.