Anti-inflammatory effect of lifestyle changes in the Finnish Diabetes Prevention Study.

AIMS/HYPOTHESIS: Subclinical inflammation confers an increased risk of type 2 diabetes, cardiovascular disease, neurodegenerative disorders and other age-related chronic diseases. Physical activity and diet can attenuate systemic immune activation, but it is not known which individual components of a comprehensive lifestyle intervention are most effective in targeting subclinical inflammation. METHODS: We used data from the baseline examination and the 1 year follow-up of a subsample of 406 of 522 participants of the Finnish Diabetes Prevention Study (DPS) to estimate the effect of individual components of lifestyle intervention on C-reactive protein (CRP) and IL-6 levels, which represent the best characterised proinflammatory risk factors for type 2 diabetes. Changes in metabolic markers, dietary patterns and exercise were analysed to determine which were most strongly associated with the anti-inflammatory effect of lifestyle changes. RESULTS: Lifestyle intervention reduced circulating levels of CRP (p < 0.001) and IL-6 (p = 0.060). Increases in fibre intake and moderate to vigorous leisure time physical activity (LTPA), but not total LTPA, predicted decreases in CRP and/or IL-6 and remained associated even after adjustment for baseline BMI or changes in BMI during the first year of the study. Changes in carbohydrate or fat intake were either weakly or not linked to reductions in CRP and IL-6. CONCLUSIONS/INTERPRETATION: The present study assessed the individual effects of dietary and physical activity measures on low-grade inflammation in individuals at high cardiometabolic risk. Our results underline the importance of moderate to vigorous LTPA and a diet rich in natural fibre, and this should be emphasised in lifestyle recommendations.

Physical activity modifies the effect of SNPs in the SLC2A2 (GLUT2) and ABCC8 (SUR1) genes on the risk of developing type 2 diabetes.

Single nucleotide polymorphisms (SNPs) in two genes regulating insulin secretion, SLC2A2 (encoding GLUT2) and ABCC8 (encoding SUR1), were associated with the conversion from impaired glucose tolerance (IGT) to type 2 diabetes (T2D) in the Finnish Diabetes Prevention Study (DPS). We determined whether physical activity (PA), assessed annually with a questionnaire, modified the association of SNPs in SLC2A2 and ABCC8 with the conversion to T2D in the combined intervention and control groups of the DPS. Finnish overweight subjects with IGT (N = 479) were followed for an average of 4.1 yr. The interaction of the SNPs with the change in PA on the conversion to T2D was assessed using Cox regression with adjustments for the other components of the intervention (dietary changes, weight reduction). The carriers of the common homozygous genotype of rs5393, rs5394, or rs5404 of SLC2A2 and rs3758947 of ABCC8 who were in the lower third of the change in moderate-to-vigorous PA during the follow-up had a 2.6- to 3.7-fold increased risk of developing T2D compared with the upper third, whereas the rare allele carriers seemed to be unresponsive to changes in moderate-to-vigorous PA (for the interaction of genotype with change in PA, P = 0.022-0.027 for the SNPs in SLC2A2, and P = 0.007 for rs3758947). We conclude that moderate-to-vigorous PA may modify the risk of developing T2D associated with genes regulating insulin secretion (SLC2A2, ABCC8) in persons with IGT.

Association of the Leu72Met polymorphism of the ghrelin gene with the risk of Type 2 diabetes in subjects with impaired glucose tolerance in the Finnish Diabetes Prevention Study.

AIMS: Ghrelin is a gut-brain regulatory peptide stimulating appetite and controlling energy balance. In previous studies, the Leu72Met polymorphism of the ghrelin gene has been associated with obesity and impaired insulin secretion. We investigated whether the Leu72Met polymorphism is associated with the incidence of Type 2 diabetes in subjects with impaired glucose tolerance (IGT) participating in the Finnish Diabetes Prevention Study (DPS). METHODS: DPS was a longitudinal intervention study carried out in five participating centres in Finland. A total of 522 subjects with IGT were randomized into either an intervention or a control group and DNA was available from 507 subjects. The Leu72Met polymorphism was screened by the restriction fragment length polymorphism method. RESULTS: There were no differences in clinical and anthropometric characteristics among the genotypes at baseline. IGT subjects with the Met72 allele were at higher risk of developing Type 2 diabetes than subjects with the Leu72Leu genotype (P = 0.046). Our data also demonstrated that IGT subjects with the common Leu72Leu genotype developed Type 2 diabetes less frequently under intervention circumstances than subjects with the Met72 allele (OR = 0.28, 95% CI 0.10-0.79; P = 0.016). CONCLUSIONS: Subjects with the Leu72Leu genotype had a lower risk for the development of Type 2 diabetes. This was observed particularly in the study subjects who underwent an intensive diet and exercise intervention. Defective first-phase insulin secretion related to the Met72 allele might be one factor contributing to the conversion to Type 2 diabetes.

Association of sequence variations in the gene encoding adiponectin receptor 1 (ADIPOR1) with body size and insulin levels. The Finnish Diabetes Prevention Study.

AIMS/HYPOTHESIS: Adiponectin is a circulating peptide derived from adipose tissue. It mediates its insulin-sensitising and anti-atherogenic effects on target tissues through two known receptors, adiponectin receptors 1 and 2 (ADIPOR1; ADIPOR2), which are encoded by the genes ADIPOR1 and ADIPOR2. Our aim was to study the association of ADIPOR1 gene variations with body size and risk of type 2 diabetes in subjects with impaired glucose tolerance, who participated in the Finnish Diabetes Prevention Study (DPS). SUBJECTS AND METHODS: We selected seven single nucleotide polymorphisms (SNPs) of the ADIPOR1 gene to perform association studies with anthropometrics and metabolic parameters at baseline, and with the risk of type 2 diabetes during the 3-year follow-up in the DPS study population. Both single SNP analysis and haplotype effects were studied. RESULTS: Three out of seven markers studied (rs10920534, rs22757538 and rs1342387) were significantly associated with various body size measurements including weight, height, waist and hip circumference, sagittal diameter and body mass index. Furthermore, three markers (rs10920534, rs12045862 and rs7539542), of which two were different from those associating with body size, were linked to fasting and 2-h insulin levels, particularly in men at baseline. The haplotype analysis with five markers revealed seven major haplotypes in the DPS study population. The haplotype effects on body size measures were in line with those of single SNP analysis. However, none of the markers were associated with the risk of type 2 diabetes. CONCLUSIONS/INTERPRETATION: Our findings suggest that ADIPOR1 has a putative role in the development of body size, and that traits for central adiposity and insulin resistance may be dissociated from each other.

Improved fibrinolysis by an intensive lifestyle intervention in subjects with impaired glucose tolerance. The Finnish Diabetes Prevention Study.

AIMS/HYPOTHESIS: The aim of this study was to investigate the effects of lifestyle intervention on the levels of plasminogen activator inhibitor (PAI-1) and fibrinogen in subjects participating in the Finnish Diabetes Prevention Study (DPS). METHODS: In five DPS centres, 321 subjects with impaired glucose tolerance (intervention group, n=163; control group, n=158) had their PAI-1 and fibrinogen levels measured at baseline and at the 1-year follow-up. Additional 3-year follow-up assessments were carried out in a sample of 97 subjects in one of the DPS centres (Turku). The intervention programme included an intensive lifestyle intervention aiming at weight reduction, healthy diet and increased physical activity. RESULTS: During the first intervention year, PAI-1 decreased by 31% in the intervention group but showed no change in the control group (p<0.0001). In the Turku subgroup, the decrease in PAI-1 persisted throughout the 3-year follow-up. Changes in PAI-1 were associated with the number of lifestyle changes made during the first year (p=0.008). Weight reduction was the most important factor explaining the decrease in PAI-1. Changes in fibrinogen levels did not differ between the groups. CONCLUSIONS/INTERPRETATION: In addition to the previously reported reduction in the risk of type 2 diabetes in DPS participants with impaired glucose tolerance, the intensive dietary and exercise intervention had beneficial long-term effects on fibrinolysis as indicated by the reduced levels of PAI-1. These results suggest that elevated PAI-1 levels in obese subjects with impaired glucose tolerance are mostly reversible by lifestyle changes, especially those geared to weight reduction.

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.

Prevalence of diabetes and impaired glucose regulation in 45- to 64-year-old individuals in three areas of Finland.

AIMS: To determine the prevalence of diabetes mellitus (DM), impaired glucose tolerance (IGT) and impaired fasting glycaemia (IFG) and possible regional differences in Finnish adults aged between 45 and 64 years. METHODS: A population sample of 2642 subjects aged between 45 and 64 years living in three geographical areas in Finland was invited to an oral glucose tolerance test. RESULTS: The glucose tolerance status of 2087 subjects (79.0%) was determined. The age-standardized prevalence of DM in men and women was 10.2% and 7.4%, respectively (P = 0.020 for difference between sexes), and that of IGT 10.5% in men and 9.2% in women. IFG in men was more than twice as common as in women (13.5% vs. 5.0%, respectively, P < 0.001). Abnormal glucose tolerance was most common in southern compared with southwestern and eastern Finland. Of all diabetic subjects, 44% were previously undiagnosed. CONCLUSIONS: The age-standardized prevalence of DM in 45- to 64-year-old Finns was within the range defined in previous studies on Europid populations. DM and IFG were more common in men than in women. Regional differences in the prevalence of abnormal glucose regulation suggest differences in lifestyle within an ethnically homogenous population.

Variation in the resistin gene is associated with obesity and insulin-related phenotypes in Finnish subjects.

AIMS/HYPOTHESIS: Resistin is a peptide hormone produced by adipocytes that is present at high levels in sera of obese mice and may be involved in glucose homeostasis through regulation of insulin sensitivity. Several studies in humans have found associations between polymorphisms in the resistin gene and obesity, insulin sensitivity and blood pressure. An association between variation in the resistin gene and type 2 diabetes has been reported in some, but not all studies. The aim of this study was to analyse variants of the resistin gene for association with type 2 diabetes and related traits in a Finnish sample. METHODS: In 781 cases with type 2 diabetes, 187 spouse controls and 222 elderly controls of Finnish origin, we genotyped four previously identified non-coding single-nucleotide polymorphisms (SNPs): -420C>G from the promoter region, +156C>T and +298G>A from intron 2, and +1084G>A from the 3' untranslated region. We then tested whether these SNPs were associated with type 2 diabetes and related traits. RESULTS: The SNPs were not significantly associated with type 2 diabetes. However, SNPs -420C>G, +156C>T and +298G>A and the common haplotype for these three markers were associated with increased values of weight-related traits and diastolic blood pressure in cases, lower weight in elderly control subjects, and lower insulin sensitivity and greater acute insulin response in spouses. Furthermore, the +1084G allele was associated with lower HDL cholesterol in both cases and controls, higher systolic blood pressure and waist circumference in cases, and greater acute insulin response in spouse controls. CONCLUSIONS/INTERPRETATION: Our results add to growing evidence that resistin is associated with variation in weight, fat distribution and insulin resistance.

Association between a deletion/insertion polymorphism in the alpha2B-adrenergic receptor gene and insulin secretion and Type 2 diabetes. The Finnish Diabetes Prevention Study.

AIMS/HYPOTHESIS: Impaired insulin secretion has a strong genetic component. In this study we investigated whether the 12Glu9 polymorphism in the gene encoding the alpha2B-adrenergic receptor ( ADRA2B) is associated with insulin secretion and/or the incidence of Type 2 diabetes in individuals with impaired glucose tolerance. METHODS: We investigated a total of 506 subjects with impaired glucose tolerance participating in the Finnish Diabetes Prevention Study (DPS). Participants were randomly assigned to an intervention group or a control group. Anthropometric measurements and an oral glucose tolerance test were performed at baseline and at annual follow-up. In a subgroup of patients (n=83), a frequently sampled intravenous glucose tolerance test (FSIGT) was performed at baseline. RESULTS: All patients had similar anthropometric measurements and insulin and glucose levels at baseline. Multiple logistic regression analysis revealed significant interaction (p=0.003) between study group and genotype across the entire study population. In the control group, subjects with the Glu9 allele had an increased risk of developing Type 2 diabetes compared with subjects with the Glu12/12 genotype (odds ratio [OR]=2.68, 95% CI 1.02-7.09, p=0.047 for Glu12/12, and OR=5.17, 95% CI 1.76-15.21, p=0.003 for Glu9/9). This increased risk was not observed in the intervention group, who showed significant weight loss during the trial. In the subgroup who underwent the FSIGT, subjects with the Glu9/9 genotype showed the lowest acute insulin response (p=0.005 for trend). CONCLUSIONS/INTERPRETATION: The 12Glu9 polymorphism of ADRA2B is associated with impaired first-phase insulin secretion and may predict the development of Type 2 diabetes in subjects with impaired glucose tolerance who are not subjected to a lifestyle intervention.

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. The Finnish Diabetes Prevention Study.

AIMS/HYPOTHESIS: Type 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 p85 alpha [PI3K]; M326I) affect the weight change and development of Type 2 diabetes in the Finnish Diabetes Prevention Study. METHODS: We 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. RESULTS: In 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 polymorphisms in the insulin, PC-1 and PI3K genes did not regulate weight change or conversion to diabetes. CONCLUSIONS/INTERPRETATION: The 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.

Progression to clinically diagnosed and treated diabetes from impaired glucose tolerance and impaired fasting glycaemia.

AIMS: To evaluate the risk of diabetes in subjects with impaired fasting glycemia (IFG) as compared with impaired glucose tolerance (IGT) and normal glucose tolerance. METHODS: Men (1223) and women (1370) aged 45-64 years and free of diabetes at baseline were followed-up for 10 years, with 26 737 person years accumulated. The incident diabetic cases were identified through the national Drug Register and the Hospital Discharge Register. RESULTS: During the 10 years of follow-up, 53 (4.3%) men and 47 (3.4%) women developed diabetes. IFG alone defined 22 (15.5/1000 person years) diabetic cases, which was higher than for subjects with normal fasting glucose. Subjects with isolated IGT identified an additional 34 cases (155% more) which could not be defined by IFG alone. The area under the ROC curve was larger for 2-h glucose (0.77, 95% CI 0.72-0.82) than for fasting glucose (0.65, 0.58-0.71). The multivariate adjusted Cox hazard ratio was higher for isolated IGT (3.9, 95% CI 2.4-6.2) than for isolated IFG (2.3, 0.9-5.7) as compared with subjects with neither IFG nor IGT. CONCLUSION: Both IFG and IGT are risk predictors for diabetes, but IGT defines a much larger target population for prevention.

Occupational, commuting, and leisure-time physical activity in relation to risk for Type 2 diabetes in middle-aged Finnish men and women.

AIM/HYPOTHESIS: Leisure-time physical activity can reduce the risk of Type 2 diabetes, but the potential effect of different types of physical activity is still uncertain. This study is to examine the relationship of occupational, commuting and leisure-time physical activity with the incidence of Type 2 diabetes. METHODS: We prospectively followed 6898 Finnish men and 7392 women of 35 to 64 years of age without a history of stroke, coronary heart disease, or diabetes at baseline. Hazards ratios of incidence of Type 2 diabetes were estimated by levels of occupational, commuting, and leisure-time physical activity. RESULTS: During a mean follow-up of 12 years, there were 373 incident cases of Type 2 diabetes. In both men and women combined, the hazards ratios of diabetes associated with light, moderate and active work were 1.00, 0.70 and 0.74 (p=0.020 for trend) after adjustment for confounding factors (age, study year, sex, systolic blood pressure, smoking, education, the two other types of physical activity and BMI). The multivariate-adjusted hazards ratios of diabetes with none, 1 to 29, and more than 30 min of walking or cycling to and from work were 1.00, 0.96, and 0.64 (p=0.048 for trend). The multivariate-adjusted hazards ratios of diabetes for low, moderate, high levels of leisure-time physical activity were 1.00, 0.67, and 0.61 (p=0.001 for trend); after additional adjustment for BMI, the hazards ratio was no longer significant. CONCLUSIONS/INTERPRETATION: Moderate and high occupational, commuting or leisure-time physical activity independently and significantly reduces risk of Type 2 diabetes among the middle-aged general population.

Linkage disequilibrium between microsatellite markers extends beyond 1 cM on chromosome 20 in Finns.

Linkage disequilibrium (LD) is a proven tool for evaluating population structure and localizing genes for monogenic disorders. LD-based methods may also help localize genes for complex traits. We evaluated marker-marker LD using 43 microsatellite markers spanning chromosome 20 with an average density of 2.3 cM. We studied 837 individuals affected with type 2 diabetes and 386 mostly unaffected spouse controls. A test of homogeneity between the affected individuals and their spouses showed no difference, allowing the 1223 individuals to be analyzed together. Significant (P < 0.01) LD was observed using a likelihood ratio test in all (11/11) marker pairs within 1 cM, 78% (25/32) of pairs 1-3 cM apart, and 39% (7/18) of pairs 3-4 cM apart, but for only 12 of 842 pairs more than 4 cM apart. We used the human genome project working draft sequence to estimate kilobase (kb) intermarker distances, and observed highly significant LD (P < 10(-10)) for all six marker pairs up to 350 kb apart, although the correlation of LD with cM is slightly better than the correlation with megabases. These data suggest that microsatellites present at 1-cM density are sufficient to observe marker-marker LD in the Finnish population.

Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance.

BACKGROUND: Type 2 diabetes mellitus is increasingly common, primarily because of increases in the prevalence of a sedentary lifestyle and obesity. Whether type 2 diabetes can be prevented by interventions that affect the lifestyles of subjects at high risk for the disease is not known. METHODS: We randomly assigned 522 middle-aged, overweight subjects (172 men and 350 women; mean age, 55 years; mean body-mass index [weight in kilograms divided by the square of the height in meters], 31) with impaired glucose tolerance to either the intervention group or the control group. Each subject in the intervention group received individualized counseling aimed at reducing weight, total intake of fat, and intake of saturated fat and increasing intake of fiber and physical activity. An oral glucose-tolerance test was performed annually; the diagnosis of diabetes was confirmed by a second test. The mean duration of follow-up was 3.2 years. RESULTS: The mean (+/-SD) amount of weight lost between base line and the end of year 1 was 4.2+/-5.1 kg in the intervention group and 0.8+/-3.7 kg in the control group; the net loss by the end of year 2 was 3.5+/-5.5 kg in the intervention group and 0.8+/-4.4 kg in the control group (P<0.001 for both comparisons between the groups). The cumulative incidence of diabetes after four years was 11 percent (95 percent confidence interval, 6 to 15 percent) in the intervention group and 23 percent (95 percent confidence interval, 17 to 29 percent) in the control group. During the trial, the risk of diabetes was reduced by 58 percent (P<0.001) in the intervention group. The reduction in the incidence of diabetes was directly associated with changes in lifestyle. CONCLUSIONS: Type 2 diabetes can be prevented by changes in the lifestyles of high-risk subjects.

The peroxisome proliferator-activated receptor-gamma2 Pro12A1a variant: association with type 2 diabetes and trait differences.

Recent studies have identified a common proline-to-alanine substitution (Pro12Ala) in the peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2), a nuclear receptor that regulates adipocyte differentiation and possibly insulin sensitivity. The Pro12Ala variant has been associated in some studies with diabetes-related traits and/or protection against type 2 diabetes. We examined this variant in 935 Finnish subjects, including 522 subjects with type 2 diabetes, 193 nondiabetic spouses, and 220 elderly nondiabetic control subjects. The frequency of the Pro12Ala variant was significantly lower in diabetic subjects than in nondiabetic subjects (0.15 vs. 0.21; P = 0.001). We also compared diabetes-related traits between subjects with and without the Pro12Ala variant within subgroups. Among diabetic subjects, the variant was associated with greater weight gain after age 20 years (P = 0.023) and lower triglyceride levels (P = 0.033). Diastolic blood pressure was higher in grossly obese (BMI >40 kg/m2) diabetic subjects with the variant. In nondiabetic spouses, the variant was associated with higher fasting insulin (P = 0.033), systolic blood pressure (P = 0.021), and diastolic blood pressure (P = 0.045). These findings support a role for the PPAR-gamma2 Pro12Ala variant in the etiology of type 2 diabetes and the insulin resistance syndrome.

The Finland-United States investigation of non-insulin-dependent diabetes mellitus genetics (FUSION) study. I. An autosomal genome scan for genes that predispose to type 2 diabetes.

We performed a genome scan at an average resolution of 8 cM in 719 Finnish sib pairs with type 2 diabetes. Our strongest results are for chromosome 20, where we observe a weighted maximum LOD score (MLS) of 2.15 at map position 69.5 cM from pter and secondary weighted LOD-score peaks of 2.04 at 56.5 cM and 1.99 at 17.5 cM. Our next largest MLS is for chromosome 11 (MLS = 1.75 at 84.0 cM), followed by chromosomes 2 (MLS = 0.87 at 5.5 cM), 10 (MLS = 0.77 at 75.0 cM), and 6 (MLS = 0.61 at 112.5 cM), all under an additive model. When we condition on chromosome 2 at 8.5 cM, the MLS for chromosome 20 increases to 5.50 at 69.0 cM (P=.0014). An ordered-subsets analysis based on families with high or low diabetes-related quantitative traits yielded results that support the possible existence of disease-predisposing genes on chromosomes 6 and 10. Genomewide linkage-disequilibrium analysis using microsatellite marker data revealed strong evidence of association for D22S423 (P=.00007). Further analyses are being carried out to confirm and to refine the location of these putative diabetes-predisposing genes.

The Finland-United States investigation of non-insulin-dependent diabetes mellitus genetics (FUSION) study. II. An autosomal genome scan for diabetes-related quantitative-trait loci.

Type 2 diabetes mellitus is a complex disorder encompassing multiple metabolic defects. We report results from an autosomal genome scan for type 2 diabetes-related quantitative traits in 580 Finnish families ascertained for an affected sibling pair and analyzed by the variance components-based quantitative-trait locus (QTL) linkage approach. We analyzed diabetic and nondiabetic subjects separately, because of the possible impact of disease on the traits of interest. In diabetic individuals, our strongest results were observed on chromosomes 3 (fasting C-peptide/glucose: maximum LOD score [MLS] = 3.13 at 53.0 cM) and 13 (body-mass index: MLS = 3.28 at 5.0 cM). In nondiabetic individuals, the strongest results were observed on chromosomes 10 (acute insulin response: MLS = 3.11 at 21.0 cM), 13 (2-h insulin: MLS = 2.86 at 65.5 cM), and 17 (fasting insulin/glucose ratio: MLS = 3.20 at 9.0 cM). In several cases, there was evidence for overlapping signals between diabetic and nondiabetic individuals; therefore we performed joint analyses. In these joint analyses, we observed strong signals for chromosomes 3 (body-mass index: MLS = 3.43 at 59.5 cM), 17 (empirical insulin-resistance index: MLS = 3.61 at 0.0 cM), and 19 (empirical insulin-resistance index: MLS = 2.80 at 74.5 cM). Integrating genome-scan results from the companion article by Ghosh et al., we identify several regions that may harbor susceptibility genes for type 2 diabetes in the Finnish population.