Mauri Laakso

Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study.

BACKGROUND Lifestyle interventions can prevent the deterioration of impaired glucose tolerance to manifest type 2 diabetes, at least as long as the intervention continues. In the extended follow-up of the Finnish Diabetes Prevention Study, we assessed the extent to which the originally-achieved lifestyle changes and risk reduction remain after discontinuation of active counselling. METHODS Overweight, middle-aged men (n=172) and women (n=350) with impaired glucose tolerance were randomly assigned to intensive lifestyle intervention or control group. After a median of 4 years of active intervention period, participants who were still free of diabetes were further followed up for a median of 3 years, with median total follow-up of 7 years. Diabetes incidence, bodyweight, physical activity, and dietary intakes of fat, saturated fat, and fibre were measured. FINDINGS During the total follow-up, the incidence of type 2 diabetes was 4.3 and 7.4 per 100 person-years in the intervention and control group, respectively (log-rank test p=0.0001), indicating 43% reduction in relative risk. The risk reduction was related to the success in achieving the intervention goals of weight loss, reduced intake of total and saturated fat and increased intake of dietary fibre, and increased physical activity. Beneficial lifestyle changes achieved by participants in the intervention group were maintained after the discontinuation of the intervention, and the corresponding incidence rates during the post-intervention follow-up were 4.6 and 7.2 (p=0.0401), indicating 36% reduction in relative risk. INTERPRETATION Lifestyle intervention in people at high risk for type 2 diabetes resulted in sustained lifestyle changes and a reduction in diabetes incidence, which remained after the individual lifestyle counselling was stopped.

Prevention of Type II diabetes in subjects with impaired glucose tolerance: the Diabetes Prevention Study (DPS) in Finland. Study design and 1-year interim report on the feasibility of the lifestyle intervention programme.

Aims/hypothesis. The aim of the Diabetes Prevention Study is to assess the efficacy of an intensive diet-exercise programme in preventing or delaying Type II (non-insulin-dependent) diabetes mellitus in subjects with impaired glucose tolerance, to evaluate the effects of the intervention programme on cardiovascular risk factors and to assess the determinants for the progression to diabetes in persons with impaired glucose tolerance. Methods. A total of 523 overweight subjects with impaired glucose tolerance ascertained by two oral glucose tolerance tests were randomised to either a control or intervention group. The control subjects received general information at the start of the trial about the lifestyle changes necessary to prevent diabetes and about annual follow-up visits. The intervention subjects had seven sessions with a nutritionist during the first year and a visit every 3 months thereafter aimed at reducing weight, the intake of saturated fat and increasing the intake of dietary fibre. Intervention subjects were also guided individually to increase their physical activity. Results. During the first year, weight loss in the first 212 study subjects was 4.7 ± 5.5 vs 0.9 ± 4.1 kg in the intervention and control group, respectively (p < 0.001). The plasma glucose concentrations (fasting: 5.9 ± 0.7 vs 6.4 ± 0.8 mmol/l, p < 0.001; and 2-h 7.8 ± 1.8 vs 8.5 ± 2.3 mmol/l, p < 0.05) were significantly lower in the intervention group after the first year of intervention. Favourable changes were also found in blood pressure, serum lipids and anthropometric indices in the intervention group. Conclusion/interpretation. The interim results show the efficacy and feasibility of the lifestyle intervention programme. [Diabetologia (1999) 42: 793–801]

Prevention of Diabetes Mellitus in Subjects with Impaired Glucose Tolerance in the Finnish Diabetes Prevention Study: Results From a Randomized Clinical Trial

Type 2 diabetes mellitus is increasing worldwide largely as a result from increasing obesity and sedentary lifestyle. The Finnish Diabetes Prevention Study (DPS) is the first individually randomized controlled clinical trial to test the feasibility and efficacy of lifestyle modification in high-risk subjects. We randomly assigned 522 (172 men, 350 women) middle-aged (mean age 55 yr), overweight (mean body mass index 31 kg/m(2)) subjects with impaired glucose tolerance either to the lifestyle intervention or control group. Each subject in the intervention group received individualized counseling aimed at reducing weight and intake of total and saturated fat, and increasing intake of fiber and physical activity. An oral glucose tolerance test was performed annually to detect incident cases of diabetes and to measure changes in metabolic parameters. The mean (+/- SD) weight reduction from baseline to year 1 and to year 2, respectively, was 4.2 +/- 5.1 kg and 3.5 +/- 5.5 in the intervention group and 0.8 +/- 3.7 kg and 0.8 +/- 4.4 in the control group (P < 0.001 between the groups). At the time of first analysis of the outcome data the mean duration of follow-up was 3.2 yr. The risk of diabetes was reduced by 58% (P < 0.001) in the intervention group compared with the control group. The reduction in the incidence of diabetes was directly associated with number and magnitude of lifestyle changes made. In conclusion, the DPS is the first controlled trial demonstrating that type 2 diabetes can be prevented by changes in lifestyle in high-risk subjects.

Association of neck circumference with insulin resistance-related factors

Aim: Overall and central obesity are associated with disorders in lipid and glucose metabolism, insulin resistance, hypertension, atherosclerosis and type 2 diabetes. Waist circumference and abdominal sagittal diameter have been suggested as the best simple anthropometric indexes of abdominal visceral fat accumulation. The aim of the present study was to test the association of neck circumference with abdominal and general obesity as well as with insulin resistance related factors.Method: Neck circumference was measured in addition to the traditional anthropometric measures and blood lipids, insulin and glucose concentrations and blood pressure.Results: The prevalence rates of disorders in lipid or glucose metabolism and high fasting insulin concentrations were highest in the highest quintiles of all the anthropometric measures.Conclusion: We conclude that neck circumference is associated with the metabolic disorders related to insulin resistance. The measurement of neck circumference could be useful in clinical screening for persons at an enhanced risk for insulin resistance.

Impairment of diastolic function in middle-aged Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetic patients free of cardiovascular disease

SummaryLeft ventricular systolic and diastolic function was studied using systolic time intervals and echocardiography in 19 male and 17 female patients with Type 1 (insulin-dependent) diabetes, 24 male and 15 female patients with Type 2 (non-insulin-dependent) diabetes and 24 male and 24 female control subjects. The subjects for the present study were selected from a population based study in which 117 Type 1 and 510 Type 2 diabetic patients and 649 non-diabetic subjects were originally examined. After exclusions, none of the subjects had any evidence of coronary heart disease, hypertension or other diseases known to affect left ventricular function. There were no consistent differences in systolic time intervals or echocardiographic variables of systolic function between patients with Type 1 diabetes and non-diabetic control subjects; but patients with Type 2 diabetes showed an increased fractional shortening. Female patients with Type 2 diabetes showed an increased left ventricular mass not explicable by hypertension. Isovolumic relaxation period was longer in male (86±3 ms; mean±SEM) and female patients (84±6 ms) with Type 2 diabetes than in male (76±3 ms; p<0.05) and female (71±3 ms; p<0.05) control subjects. Peak diastolic filling rate was lower in female patients with Type 1 diabetes (12.8±0.8 cm/s, p<0.05) and in male (11.5±0.8 cm/s; p<0.01) and female patients (11.5±0.6 cm/s; p<0.001) with Type 2 diabetes as compared to male (14.4±0.7 cm/s) and female (14.9±0.5 cm/s) control subjects. In male patients with Type 1 diabetes the respective value (12.7±0.6 cm/s) did not differ significantly from that in male control subjects. Altogether 14 diabetic patients (26%) showed an abnormal low peak diastolic filling rate. The impaired diastolic filling among diabetic patients did not show any relationship to the duration and metabolic control of diabetes or the presence of microangiopathy, but a weak correlation was found between the peak diastolic filling rate and the diminution of heart rate variation suggestive of the presence of diabetic autonomic neuropathy.

Postchallenge Glucose, A1C, and Fasting Glucose as Predictors of Type 2 Diabetes and Cardiovascular Disease A 10-year prospective cohort study

OBJECTIVE A1C has been proposed as a new indicator for high risk of type 2 diabetes. The long-term predictive power and comparability of elevated A1C with the currently used high-risk indicators remain unclear. We assessed A1C, impaired glucose tolerance (IGT), and impaired fasting glucose (IFG) as predictors of type 2 diabetes and cardiovascular disease (CVD) at 10 years. RESEARCH DESIGN AND METHODS This prospective population-based study of 593 inhabitants from northern Finland, born in 1935, was conducted between 1996 and 2008. An oral glucose tolerance test (OGTT) was conducted at baseline and follow-up, and A1C was determined at baseline. Those with a history of diabetes were excluded from the study. Elevated A1C was defined as 5.7–6.4%. Incident type 2 diabetes was confirmed by two OGTTs. Cardiovascular outcome was measured as incident CVD or CVD mortality. Multivariate log-binomial regression models were used to predict diabetes, CVD, and CVD mortality at 10 years. Receiver operating characteristic curves compared predictive values of A1C, IGT, and IFG. RESULTS Incidence of diabetes during the follow-up was 17.1%. Two of three of the cases of newly diagnosed diabetes were predicted by a raise in ≥1 of the markers. Elevated A1C, IGT, or IFG preceded diabetes in 32.8, 40.6, and 21.9%, respectively. CVD was predicted by an intermediate and diabetic range of 2-h glucose but only by diabetic A1C levels in women. CONCLUSIONS A1C predicted 10-year risk of type 2 diabetes at a range of A1C 5.7–6.4% but CVD only in women at A1C ≥6.5%.

Prevalence of Retinopathy in People With Diabetes, Impaired Glucose Tolerance, and Normal Glucose Tolerance

OBJECTIVE Recently, an international expert committee published new revised criteria for diagnosing diabetes. According to the new criteria, the 2-h glucose level for diabetes in the oral glucose tolerance test (OGTT) is the same as in the previous World Health Organization criteria, but the cut point for the fasting blood glucose level has been lowered to be equivalent to the 2-h OGTT level. Measurement of the fasting blood glucose level is preferred to the 2-h OGTT glucose level. The ability of the new cut point for fasting blood glucose to discriminate between those at a high and a low risk for retinopathy was tested in a population-based study. RESEARCH DESIGN AND METHODS The population consisted of all the 1,008 subjects (456 men) born in 1935 and living in a Finnish city. A screening for type 2 diabetes was carried out in the first phase. All participants who were not on antidiabetic medication were invited for an OGTT in the second phase. A fasting blood glucose value was measured from the diabetic subjects on antidiabetic medication. In addition, measurements of serum cholesterol, HDL cholesterol, and triglycerides were made, and fundus photographs were taken. Altogether, 831 subjects (368 men) (82%) participated and constitute the eligible study population for the present analyses. Fundus photographs were available for 790 subjects (347 men) (95%). RESULTS There were 28 subjects (3.5%) who had mild retinopathic changes in the fundus photographs. Retinopathic changes were associated with higher fasting blood glucose levels, but not with any of the other background factors. The prevalence of retinopathy was 10.2% (95% CI 4.8−18.5) in subjects with a fasting blood glucose of ≥6.1 mmol/l, while it was 2.6% (1.5–4.0) in those with a lower fasting blood glucose level. In the former group, a majority (seven of nine) of the subjects with retinopathy were previously diagnosed diabetic patients. Some cases of retinopathy were found regardless the level of glycemia, and measurement of the 2-h OGTT glucose levels did not increase information. CONCLUSIONS The results of this population study give support to the use of fasting blood glucose levels in diagnosing type 2 diabetes. The lower limit of the highest decile of the fasting glucose level was 6.1 mmol/l, and it discriminated subjects at a high risk for retinopathy from those at a low risk. Because of the limited number of subjects with retinopathy in this study, the level of hyperglycemia associated with retinopathy cannot be estimated accurately.

Genetic variation in leptin receptor gene is associated with type 2 diabetes and body weight: The Finnish Diabetes Prevention Study

OBJECTIVE:Genetic variation in leptin receptor (LEPR) gene has been reported to associate with insulin and glucose metabolism and adiposity in different study settings and various populations. We wanted to evaluate the association between LEPR polymorphisms, diabetes risk and body weight in Finnish subjects with impaired glucose tolerance (IGT).METHODS:We investigated the associations of the three LEPR polymorphisms (Lys109Arg, Gln223Arg, 3′UTR Del/Ins) with the conversion to type 2 diabetes and the changes in body weight in 507 individuals with IGT participating in the Finnish Diabetes Prevention Study. Participants were randomized to either an intensive diet and exercise intervention group or a control group.RESULTS:After 3 years, the odds ratio for the development of type 2 diabetes in individuals in the control group with the Lys109Lys genotype was 2.38-fold higher than in individuals with other genotype combinations (P=0.016). Irrespective of group individuals with the Gln223Gln genotype had higher conversion to type 2 diabetes (OR 2.01 (95% CI 1.03–3.93)) than the Arg223 allele carriers (P=0.042). The risk was more pronounced in the control group than in the intervention group. Individuals having the 3′UTR Del/Del genotype had a slightly higher body weight throughout the study than those with the insertion allele (P=0.020), although no difference in weight change was observed.CONCLUSION:Two polymorphisms (Lys109Arg, Gln223Arg) in the extracellular domain of the leptin receptor predicted the conversion to type 2 diabetes in high-risk individuals with IGT. The Del/Ins polymorphism in the 3′UTR of LEPR was associated with body weight.

Common polymorphisms in the genes regulating the early insulin signalling pathway: effects on weight change and the conversion from impaired glucose tolerance to Type 2 diabetes.

Aims/hypothesisType 2 diabetes is a complex disorder with strong heritability. The aim of our study was to investigate whether common polymorphisms in the genes regulating the early insulin signalling pathway (insulin; A-23T, insulin-like growth factor 1 receptor [IGF-1R]; GAG1013GAA, plasma cell membrane glycoprotein 1 [PC-1]; K121Q, insulin receptor substrate [IRS-1]; G972R, insulin receptor substrate 2 [IRS-2]; G1057D and phosphatidylinositol 3-kinase p85α [PI3K]; M326I) affect the weight change and development of Type 2 diabetes in the Finnish Diabetes Prevention Study.MethodsWe screened for the polymorphisms in 490 overweight subjects with impaired glucose tolerance whose DNA was available from the Finnish Diabetes Prevention Study. These subjects were randomly allocated into a control group and an intervention group characterised by intensive, individualised diet and exercise.ResultsIn carriers of the GAA1013GAA genotype of IGF-1R, the R972 allele of IRS-1 and the D1057D genotype of IRS-2, lifestyle intervention did not lead to significant differences in weight loss between the intervention and control groups, implying a role of these risk genotypes in the regulation of body weight. We observed a statistically significant difference in the conversion rate from IGT to diabetes between the genotypes of the IGF-1R gene (GAG1013GAG: 18.6%, GAG1013GAA: 10.4%, GAA1013GAA: 19.5%, p=0.033). Common polymorporphisms in the insulin, PC-1 and PI3K genes did not regulate weight change or conversion to diabetes.Conclusions/interpretationThe common polymorphisms of the IGF-1R, IRS-1 and IRS-2 genes may modify the weight change response to a lifestyle intervention but not the conversion from IGT to Type 2 diabetes, whereas IGF-1R may also regulate the risk of developing Type 2 diabetes.

Interaction between prenatal growth and high-risk genotypes in the development of type 2 diabetes

Aims/hypothesisEarly environmental factors and genetic variants have been reported to be involved in the pathogenesis of type 2 diabetes. The aim of this study was to investigate whether there is an interaction between birthweight and common variants in the TCF7L2, HHEX, PPARG, KCNJ11, SLC30A8, IGF2BP2, CDKAL1, CDKN2A/2B and JAZF1 genes in the risk of developing type 2 diabetes.MethodsA total of 2,003 participants from the Helsinki Birth Cohort Study, 311 of whom were diagnosed with type 2 diabetes by an OGTT, were genotyped for the specified variants. Indices for insulin sensitivity and secretion were calculated.ResultsLow birthweight was associated with type 2 diabetes (p = 0.008) and impaired insulin secretion (p = 0.04). Of the tested variants, the risk variant in HHEX showed a trend towards a low birthweight (p = 0.09) and the risk variant in the CDKN2A/2B locus was associated with high birthweight (p = 0.01). The TCF7L2 risk allele was associated with increased risk of type 2 diabetes. Pooling across all nine genes, each risk allele increased the risk of type 2 diabetes by 11%. Risk variants in the HHEX, CDKN2A/2B and JAZF1 genes interacted with birthweight, so that the risk of type 2 diabetes was highest in those with lower birthweight (p ≤ 0.05). The interaction was also present in the pooled data.Conclusions/interpretationLow birthweight might affect the strength of the association of some common variants (HHEX, CDKN2A/2B and JAZF1) with type 2 diabetes. These findings need to be replicated in independent cohorts.