Family history of type 2 diabetes increases the risk of both obesity and its complications: is type 2 diabetes a disease of inappropriate lipid storage?

OBJECTIVES: The aim of this study was to characterize diabetes risk in relation to amount and distribution of body fat (environmental factors) and genetic risk defined as having first-degree (FH1) or second-degree relatives with diabetes. DESIGN: We analysed the METSIM population of 10 197 middle-aged, randomly selected men. At baseline, information about family history of diabetes was registered and all individuals underwent extensive phenotyping. A follow-up study was conducted after 6 years. The metabolic consequences of increased visceral versus subcutaneous fat were characterized in a separate cohort of 158 healthy men (the Kuopio Cohort of the EUGENE2 study). RESULTS: At baseline, individuals with a family history of diabetes (FH+) had approximately a twofold increase in the prevalence of type 2 diabetes compared with individuals without a family history of the disease (FH-) (18.0% vs. 9.9%; P = 1.3 × 10(-31) ). FH1 individuals were more commonly overweight and obese compared with FH- (69.2% vs. 64.8%; P = 1.3 × 10(-4) ) and, for a given body mass index, showed an increased risk profile for both type 2 diabetes and cardiovascular disease as well as a greater susceptibility to the negative consequences of increased body fat also when nonobese. Subgroup analyses indicated that the metabolic consequences were due primarily to increased ectopic/visceral fat rather than subcutaneous fat. The increased risk profile in FH+ individuals was not altered by adjusting for 43 major diabetes risk genes. CONCLUSIONS: Family history of type 2 diabetes (particularly FH1) is associated with both increased risk of becoming overweight/obese and with a greater susceptibility to the negative consequences of increasing body fat, probably as a consequence of an increased propensity to accumulate ectopic (nonsubcutaneous) fat.

Associations of erythrocyte membrane fatty acids with the concentrations of C-reactive protein, interleukin 1 receptor antagonist and adiponectin in 1373 men.

Dietary and endogenous fatty acids could play a role in low-grade inflammation. In this cross-sectional study the proportions of erythrocyte membrane fatty acids (EMFA) and the concentrations of C-reactive protein (CRP), interleukin-1 receptor antagonist (IL-1Ra) and adiponectin were measured and their confounder-adjusted associations examined in 1373 randomly selected Finnish men aged 45-70 years participating in the population based Metsim study in Eastern Finland. The sum of n-6 EMFAs, without linoleic acid (LA), was positively associated with concentrations of CRP and IL-1Ra (r partial=0.139 and r partial=0.115, P<0.001). These associations were especially strong among lean men (waist circumference <94 cm; r partial=0.156 and r partial=0.189, P<0.001). Total n-3 EMFAs correlated inversely with concentrations of CRP (r partial=-0.098, P<0.001). Palmitoleic acid (16:1n-7) correlated positively with CRP (r partial=0.096, P<0.001). Cis-vaccenic acid (18:1n-7) was associated with high concentrations of adiponectin (r partial=0.139, P<0.001). In conclusion, n-6 EMFAs, except for LA, correlated positively with the inflammatory markers. Palmitoleic acid was associated with CRP, whereas, interestingly, its elongation product, cis-vaccenic acid, associated with anti-inflammatory adiponectin.

Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes.

AIMS/HYPOTHESIS: Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes. METHODS: The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case-control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans. RESULTS: Exome sequencing identified 70,182 polymorphisms with MAF >1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 × 10(-14)), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 × 10(-11)) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 × 10(-10)). CONCLUSIONS/INTERPRETATION: We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.

Lipoprotein subclass profiles in individuals with varying degrees of glucose tolerance: a population-based study of 9399 Finnish men.

OBJECTIVES: We investigated serum concentrations of lipoprotein subclass particles and their lipid components determined by proton nuclear magnetic resonance spectroscopy in a population-based study. DESIGN AND METHODS: A total of 9399 Finnish men were included in the study: 3034 men with normal fasting glucose and normal glucose tolerance; 4345 with isolated impaired fasting glucose (IFG); 312 with isolated impaired glucose tolerance (IGT); 1058 with both IFG and IGT; and 650 with newly diagnosed type 2 diabetes (New DM). Lipoprotein subclasses included chylomicrons (CM) and largest VLDL particles, other VLDL particles (five subclasses), intermediate-density lipoprotein (IDL), LDL (three subclasses) and HDL (four subclasses). The phospholipid, triglyceride (TG), cholesterol, free cholesterol and cholesterol ester levels of the lipoprotein particles were measured. RESULTS: Abnormal glucose tolerance (especially IGT and New DM) was significantly associated with increased concentrations of VLDL subclass particles and their components (with the exception of very small VLDL particles). After further adjustment for total TGs and HDL cholesterol, increased lipid concentrations in the CM/largest VLDL particles and in most of the other VLDL particles remained significant in individuals with isolated IGT, IFG+IGT and New DM. There was a consistent trend towards a decrease in large and an increase in small HDL particle concentrations in individuals with hyperglycaemia even after adjustment for serum total TGs and HDL cholesterol. CONCLUSIONS: Abnormal glucose tolerance modifies the concentrations of lipoprotein subclass particles and their lipid components in the circulation and is also related to compositional changes in these particles.

Association between liver insulin resistance and cardiovascular risk factors.

OBJECTIVES: The objective of this study was to examine the associations between indices of liver insulin resistance (IR) and whole-body insulin sensitivity and different cardiovascular disease (CVD) risk factors. DESIGN AND SUBJECTS: A total of 8750 nondiabetic men (age 57.2 ± 7.1 years, body mass index 26.8 ± 3.8 kg m(-2) ) were included in this study from the population-based cross-sectional Metabolic Syndrome In Men (METSIM) cohort. Liver IR index and Matsuda insulin sensitivity index (ISI) were used as markers of liver IR and whole-body insulin sensitivity, respectively. Pearson correlation analysis was performed to examine the associations between these indices and various CVD risk factors. RESULTS: Total cholesterol (r = -0.088 vs. r = 0.020; P < 0.0019), high-sensitivity C-reactive protein (CRP) (r = 0.284 vs. r = -0.219; P < 0.0019) and total triglycerides (r = 0.507 vs. r = -0.477; P < 0.05) were more highly correlated with liver IR index than with Matsuda ISI. By contrast, Matsuda ISI was nominally more highly correlated with systolic and diastolic blood pressure (r = -0.234 and r = -0.275 vs. r = 0.202 and r = 0.239, respectively) compared to liver IR index. Furthermore, the variance explained by liver IR index was larger than that explained by Matsuda ISI for the majority of CVD risk factors measured. CONCLUSIONS: Liver IR index correlated more strongly than Matsuda ISI with levels of total cholesterol, CRP and triglycerides. Therefore, liver IR might be a significant indicator of CVD risk amongst men.

Glomerular filtration rate and parathyroid hormone are associated with 1,25-dihydroxyvitamin D in men without chronic kidney disease.

BACKGROUND AND AIM: Vitamin D, estimated glomerular filtration rate (eGFR) and parathyroid hormone (PTH) are related to cardiovascular disease risk. We examined the associations between the levels of 25-hydroxyvitamin D (25-D) and 1,25-dihydroxyvitamin D (1,25-D) and both eGFR and PTH. DESIGN AND SETTING: Cross-sectional population-based study in Kuopio, Eastern Finland. SUBJECTS: A total of 909 men without known chronic kidney disease (CKD) and not receiving antidiabetic medication, aged from 45 to 73 years, were included in the study. Main outcome measures. Fasting levels of 25-D, 1,25-D, creatinine and PTH were measured, and an oral glucose tolerance test (OGTT) was performed. RESULTS: High levels of 25-D were associated with low levels of eGFR and PTH (ß = -0.17, P = 9 × 10(-7) and ß = -0.28, P = 6 × 10(-17) , respectively, adjusted for age, body mass index and levels of calcium, phosphorus and glucose in a 2-h OGTT, and also for either eGFR or PTH). By contrast, high 1,25-D levels were associated with high levels of eGFR and PTH (ß = 0.17, P = 2 × 10(-6) and ß = 0.19, P = 5 × 10(-8) , respectively, adjusted as mentioned earlier and additionally for 25-D). Eighteen per cent of men in the highest 25-D quartile were in the lowest 1,25-D quartile and also had a lower eGFR than men with high levels of both 25-D and 1,25-D (P = 4 × 10(-5) ). Finally, 15% of men in the lowest 25-D quartile were in the highest 1,25-D quartile and also had higher PTH levels than men with low levels of both 25-D and 1,25-D (P = 2 × 10(-3) ). CONCLUSION: Our findings suggest that both eGFR and PTH are significantly associated with vitamin D metabolism in men without known CKD.

Glucose tolerance, insulin sensitivity and insulin release in European non-diabetic carriers of a polymorphism upstream of CDKN2A and CDKN2B.

AIMS/HYPOTHESIS: The aim of this study was to investigate the association of the rs10811661 polymorphism near the CDKN2B/CDKN2A genes with glucose tolerance, insulin sensitivity and insulin release in three samples of white people with European ancestry. METHODS: Sample 1 comprised 845 non-diabetic offspring of type 2 diabetes patients recruited in five European centres participating in the EUGENE2 study. Samples 2 and 3 comprised, respectively, 864 and 524 Italian non-diabetic participants. All individuals underwent an OGTT. Screening for the rs10811661 polymorphism was performed using a TaqMan allelic discrimination assay. RESULTS: The rs10811661 polymorphism did not show a significant association with age, BMI and insulin sensitivity. Participants carrying the TT genotype showed a significant reduction in insulin release, measured by an OGTT-derived index, compared with carriers of the C allele, in the three samples. When these results were pooled with those of three published studies, and meta-analysed with a random-effects model, the T allele was significantly associated with reduced insulin secretion (-35.09 [95% CI 14.68-55.52], p = 0.0008 for CC+CT vs TT; and -29.45 [95% CI 9.51-49.38], p = 0.0038, for the additive model). In addition, in our three samples, participants carrying the TT genotype exhibited an increased risk for impaired glucose tolerance (IGT) compared with carriers of the C allele (OR 1.55 [95% CI 1.20-1.95] for the meta-analysis of the three samples). CONCLUSIONS/INTERPRETATION: Our data, together with the meta-analysis of previously published studies, show that the rs10811661 polymorphism is associated with impaired insulin release and IGT, suggesting that this variant may contribute to type 2 diabetes by affecting beta cell function.

A role for coding functional variants in HNF4A in type 2 diabetes susceptibility.

AIMS/HYPOTHESIS: Rare mutations in the gene HNF4A, encoding the transcription factor hepatocyte nuclear factor 4α (HNF-4A), account for ~5% of cases of MODY and more frequent variants in this gene may be involved in multifactorial forms of diabetes. Two low-frequency, non-synonymous variants in HNF4A (V255M, minor allele frequency [MAF] ~0.1%; T130I, MAF ~3.0%)-known to influence downstream HNF-4A target gene expression-are of interest, but previous type 2 diabetes association reports were inconclusive. We aimed to evaluate the contribution of these variants to type 2 diabetes susceptibility through large-scale association analysis. METHODS: We genotyped both variants in at least 5,745 cases and 14,756 population controls from the UK and Denmark. We also undertook an expanded association analysis that included previously reported and novel genotype data obtained in Danish, Finnish, Canadian and Swedish samples. A meta-analysis incorporating all published association studies of the T130I variant was subsequently carried out in a maximum sample size of 14,279 cases and 26,835 controls. RESULTS: We found no association between V255M and type 2 diabetes in either the initial (p = 0.28) or the expanded analysis (p = 0.44). However, T130I demonstrated a modest association with type 2 diabetes in the UK and Danish samples (additive per allele OR 1.17 [95% CI 1.08-1.28]; p = 1.5 × 10⁻4), which was strengthened in the meta-analysis (OR 1.20 [95% CI 1.10-1.30]; p = 2.1 × 10⁻5). CONCLUSIONS/INTERPRETATION: Our data are consistent with T130I as a low-frequency variant influencing type 2 diabetes risk, but are not conclusive when judged against stringent standards for genome-wide significance. This study exemplifies the difficulties encountered in association testing of low-frequency variants.

Association of the FTO gene variant (rs9939609) with cardiovascular disease in men with abnormal glucose metabolism--the Finnish Diabetes Prevention Study.

BACKGROUND AND AIM: The common single nucleotide polymorphism (SNP) in the FTO (fat mass and obesity associated) gene has been consistently associated with an increased risk of obesity. We investigated whether the SNP rs9939609 (T/A) of the FTO is associated with risk factors of cardiovascular diseases (CVD), including serum levels of C - reactive protein (CRP), the chemokine RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted; CCL5), and serum and lipoprotein lipids in the Finnish Diabetes Prevention Study (DPS). Furthermore, we examined whether the rs9939609 increased the CVD risk in the DPS and if these results could be replicated in a larger cross-sectional population-based random sample of Finnish men (the METSIM). METHODS AND RESULTS: In the DPS, altogether 490 (BMI≥25kg/m(2)) subjects with impaired glucose tolerance were genotyped for rs9939609. Cardiovascular morbidity and mortality data were collected during the median follow-up of 10.2 years. The replication study was a population-based cross-sectional study of 6214 men. In the DPS, the AA genotype of rs9939609 was associated, independently of BMI, with increased RANTES (p=0.002) and decreased HDL cholesterol concentrations (p=0.007) in men. During the follow-up, the AA genotype was associated with an adjusted 2.09-fold risk (95% CI 1.17-3.73, p=0.013) of CVD in men. In the METSIM Study, the association with a history of myocardial infarction was replicated in the subgroup of men with type 2 diabetes. CONCLUSION: We suggest that the variation in the FTO gene may contribute to the development of CVD in men with an abnormal glucose metabolism.

Association of indices of liver and adipocyte insulin resistance with 19 confirmed susceptibility loci for type 2 diabetes in 6,733 non-diabetic Finnish men.

AIMS/HYPOTHESIS: Of the confirmed type 2 diabetes susceptibility loci only a few are known to affect insulin sensitivity. We examined the association of indices of hepatic and adipocyte insulin resistance (IR) with 19 confirmed type 2 diabetes risk loci in a large population-based study. METHODS: Non-diabetic participants (n = 8,460, age 57.3 ± 7.0 years, BMI 26.8 ± 3.8 kg/m(2); mean ± SD) from a population-based cohort underwent an OGTT. Of them, 6,733 non-diabetic men were genotyped for single nucleotide polymorphisms (SNPs) in or near PPARG2 (also known as PPARG), KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2B, IGF2BP2, CDKAL1, HNF1B, WFS1, JAZF1, CDC123, TSPAN8, THADA, ADAMTS9, NOTCH2, KCNQ1, MTNR1B and SNP rs7480010. We investigated hepatic IR with a new index of liver IR. The adipocyte IR index was defined as a product of fasting NEFA and plasma insulin levels. RESULTS: Type 2 diabetes risk SNPs in or near KCNJ11 and HHEX were significantly (p < 0.0013), and those in or near CDKN2B, NOTCH2 and MTNR1B were nominally (p < 0.05), associated with decreased liver IR index. The Pro12 allele of PPARG2 was significantly associated with a high adipocyte IR index and nominally associated with high liver IR. CONCLUSIONS/INTERPRETATION: The Pro12 allele of PPARG2 seems to impair insulin's antilipolytic effect, leading to high NEFA release in the fasting state and IR. In addition, the type 2 diabetes risk alleles of KCNJ11 and HHEX, which are known to impair insulin secretion, were associated with increased hepatic insulin sensitivity.

A novel surrogate index for hepatic insulin resistance.

AIMS/HYPOTHESIS: In epidemiological and genetic studies surrogate indices are needed to investigate insulin resistance in different insulin-sensitive tissues. Our objective was to develop a surrogate index for hepatic insulin resistance. METHODS: A sample of 368 non-diabetic participants (age 43.0 ± 8.2 years, BMI 26.0 ± 4.0 kg/m(2); mean ± SD) whose endogenous glucose production (EGP) was measured with [6-6(2)H(2)]glucose in the fasting state and during the euglycaemic-hyperinsulinaemic clamp were included in the study. EGP multiplied by fasting plasma insulin (FPI) concentration was the reference measurement for liver insulin resistance (liver IR). Liver IR index was calculated with linear regression analysis including age, obesity indices, lipids, lipoproteins and several variables regulating glucose metabolism. RESULTS: The following variables were significantly associated with liver IR in multiple forward stepwise regression analysis: insulin AUC in an OGTT, fat mass, HDL-cholesterol and BMI. Liver IR index correlated significantly with EGP×FPI (r = 0.65, p < 0.001). In participants with abnormal glucose tolerance, the correlation of liver IR with EGP×FPI was slightly stronger (r = 0.69, p < 0.001) than in those with normal glucose tolerance (r = 0.62, p < 0.001). CONCLUSIONS/INTERPRETATION: We generated a novel surrogate index for liver insulin resistance correlating strongly with EGP × FPI.

Diverse associations of 25-hydroxyvitamin D and 1,25-dihydroxy-vitamin D with dyslipidaemias.

BACKGROUND AND AIM: Previous studies have suggested a link between circulating levels of 25-hydroxyvitamin D (25-D) and dyslipidaemias. However, it is not known whether 25-D and the active hormone 1,25-dihydroxyvitamin D (1,25-D) have similar associations with dyslipidaemias. Therefore, we studied the associations between both 25-D and 1,25-D and total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides in a population-based study. DESIGN: Cross-sectional population-based study. SETTING: Kuopio, Eastern Finland. SUBJECTS: A total of 909 men, aged from 45 to 70 years, who were not receiving antidiabetic medication were enrolled. MAIN OUTCOME MEASURES: Fasting serum samples were obtained for measurement of 25-D, 1,25-D and lipid levels. An oral glucose tolerance test was performed, and insulin sensitivity was evaluated using the Matsuda insulin sensitivity index (Matsuda ISI). RESULTS: We found a significant inverse association between 25-D and total-C, LDL-C and triglycerides (ß = -0.15, -0.13 and -0.17, respectively, P < 0.001), but no association between 25-D and HDL-C was observed. By contrast, 1,25-D was associated with HDL-C (ß = 0.18, P < 0.001), whereas no relationship was found between 1,25-D and LDL-C or triglycerides. The associations remained significant after the exclusion of subjects receiving statin treatment and after adjustment for age, waist circumference, body mass index, alcohol consumption, smoking, renal function, glucose tolerance and Matsuda ISI. CONCLUSION: Low levels of active vitamin D (1,25-D) are associated with low HDL-C levels, whereas low levels of the storage form 25-D are associated with high levels of total-C, LDL-C and triglycerides. Our findings may provide new insights into the understanding of the link between vitamin D deficiency and cardiovascular disease.

Association of sequence variations in the gene encoding insulin-like growth factor binding protein 5 with adiponectin.

BACKGROUND: Insulin-like growth factor binding protein 5 (IGFBP5) binds to IGF and thus modulates IGF signaling pathway. We have shown earlier that the IGFBP5 gene was downregulated in the adipose tissue after 12-week carbohydrate diet with low insulinemic response. OBJECTIVE: The aim was to examine the putative contribution of genetic variation of the IGFBP5 gene to the characteristics of metabolic syndrome and incidence of type 2 diabetes (T2DM) in the Finnish Diabetes Prevention Study (DPS). METHODS: DPS is a longitudinal study where 522 subjects with impaired glucose tolerance were randomized to either lifestyle intervention group or control group. DNA was available from 507 subjects (mean body mass index (BMI) 31.2+/-4.5 kg/m(2), age 55+/-7 years). The eight single-nucleotide polymorphisms (SNPs) were selected from HapMap database and genotyped by Taqman allelic discrimination protocol. The main results were confirmed in a larger cross-sectional study population (METSIM). In addition, the gene expression of IGFBP5 was studied in two previously published study populations (FUNGENUT and GENOBIN) of 124 subjects with insulin resistance (BMI 32.2+/-3.5 kg/m(2), age 57.7+/-7.4 years). RESULTS: Three out of eight IGFBP5 markers (rs9341234, rs3276 and rs11575134) were significantly associated with circulating adiponectin concentrations in men. Furthermore, mRNA expression studies of subcutaneous adipose tissue showed that mRNA concentrations of IGFBP5 correlated with adiponectin concentrations in all subjects and in women. None of the IGFBP5 SNPs were associated with T2DM. CONCLUSIONS: Our findings show that IGFBP5 has a gender-specific association with adiponectin, which may modulate the development of metabolic syndrome.

The genetic variation in the tenomodulin gene is associated with serum total and LDL cholesterol in a body size-dependent manner.

We have reported that the sequence variation in the tenomodulin (TNMD) gene is associated with the risk of type 2 diabetes (T2DM), central obesity and serum levels of systemic immune mediators in the Finnish Diabetes Prevention Study (DPS), which is a longitudinal lifestyle intervention study on 522 middle-aged persons with impaired glucose tolerance (IGT). The aim of this study was to investigate whether the association with T2DM, observed in the DPS could be replicated in a larger, cross-sectional population-based random sample of 5298 men (3020 with normoglycaemia, 984 with impaired fasting glucose, 436 with IGT and 811 with T2DM) from the region of Kuopio, eastern Finland. To further explore the putative mechanisms linking TNMD to T2DM and metabolic syndrome, we studied the associations of TNMD sequence variation with lipid abnormalities characteristic to metabolic syndrome. The association with T2DM risk was not replicated, but significant associations were found with serum low-density lipoprotein and total cholesterol in a body mass index-dependent manner. These associations were also observed in the men of DPS, whereas in women these associations were not significant. These results from two independent study populations suggest that the genetic variation in TNMD could modulate cholesterol metabolism in obese men.

Variants of transcription factor 7-like 2 (TCF7L2) gene predict conversion to type 2 diabetes in the Finnish Diabetes Prevention Study and are associated with impaired glucose regulation and impaired insulin secretion.

AIMS/HYPOTHESIS: We investigated the association of variants of the transcription factor 7-like 2 (TCF7L2) gene with: (1) incident diabetes in the Finnish Diabetes Prevention Study (DPS, Study I); (2) type 2 diabetes and impaired glucose regulation (i.e. IGT or IFG) in a cross-sectional study (Study II); and (3) insulin secretion, insulin sensitivity and adipose tissue expression of TCF7L2 in offspring of type 2 diabetic probands (III). SUBJECTS AND METHODS: Study I (the DPS) included 507 individuals with IGT who were randomly allocated to control and intervention groups and followed for an average of 3.9 years to monitor for progression to diabetes. Study II was a population-based cross-sectional study of 1,766 men, aged 50-70 years, randomly selected from the population of Kuopio, eastern Finland. Study III included 238 non-diabetic offspring of patients with type 2 diabetes. Genotyping of rs12255372 and rs7903146 of TCF7L2 was carried out. RESULTS: In the DPS, the TT genotype of rs12255372 was significantly associated with an adjusted 2.85-fold risk (95% CI 1.17-6.95, p = 0.021) of incident diabetes in the control group, but not in the intervention group. In Study II, the adjusted odds ratio in subjects with the TT genotype was 3.40 (1.45-7.97, p = 0.005) for the comparison of diabetic subjects with normoglycaemic subjects. The T allele of rs12255372 was significantly associated with decreased insulin secretion (Studies II, III). Expression of TCF7L2 in adipose tissue tended to be lower in subjects with the TT risk genotypes of rs12255372 and rs7903146. CONCLUSIONS/INTERPRETATION: The variant of rs12255372 of TCF7L2 was associated with incident type 2 diabetes in the DPS and in a separate population-based cross-sectional study. Impaired insulin secretion is likely to be the main cause for our findings.

Association of metabolic syndrome with Alzheimer disease: a population-based study.

OBJECTIVE: To assess the association of metabolic syndrome (MetS) with Alzheimer disease (AD). METHODS: The authors derived subjects from a population-based study of 980 randomly selected elderly subjects. After exclusion of all non-Alzheimer dementia cases, the final study population included 959 subjects (337 men and 622 women) aged 69 to 78 years. The presence of MetS was defined according to the National Cholesterol Education Program (Adult Treatment Panel III) criteria, and the diagnosis of AD was based on the criteria of the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association. RESULTS: Of the study subjects, 418 (43.6%) had MetS. Probable or possible AD was diagnosed in 45 subjects (4.7%). AD was more frequently detected in subjects with MetS than in subjects without MetS (7.2 vs 2.8%; p < 0.001). The prevalence of AD was higher in women with MetS vs women without the syndrome (8.3 vs 1.9%; p < 0.001), but in men with MetS, the prevalence of AD was not increased (3.8 vs 3.9%; p = 0.994). In univariate logistic regression analysis, MetS was significantly associated with AD (odds ratio [OR] 2.71; 95% CI 1.44 to 5.10). In multivariate logistic regression analysis including also apolipoprotein E4 phenotype, education, age, and total cholesterol, MetS was significantly associated with AD (OR 2.46; 95% CI 1.27 to 4.78). If only nondiabetic subjects were included in the multivariate analysis, MetS was still significantly associated with AD (OR 3.26; 95% CI 1.45 to 7.27). CONCLUSION: Metabolic syndrome is associated with Alzheimer disease in elderly subjects.

Common polymorphisms of calpain-10 are associated with abdominal obesity in subjects at high risk of type 2 diabetes.

AIMS/HYPOTHESIS: The mechanisms by which the calpain-10 gene (CAPN10) affects the risk of type 2 diabetes are unclear. Therefore, we investigated the effects of four polymorphisms in CAPN10 (single nucleotide polymorphism [SNP]-43, SNP-44, Insertion/Deletion [Indel]-19 and SNP-63) on insulin secretion, insulin action and abdominal fat distribution in offspring of patients with type 2 diabetes. SUBJECTS AND METHODS: Insulin secretion was determined by an IVGTT, insulin action by the hyperinsulinaemic-euglycaemic clamp and abdominal fat distribution by computed tomography in 158 non-diabetic offspring (age 34.9+/-6.3 years [mean+/-SD], BMI 26.2+/-4.9 kg/m(2)) of type 2 diabetic patients. RESULTS: SNP-43 (p=0.009 over the three genotypes, adjusted for age, sex, BMI and family relationship) and haplotypes carrying the A allele of SNP-43 were associated with intra-abdominal fat area. The A allele of SNP-43 was associated with intra-abdominal fat area in men (p=0.014) but not in women. SNP-44, InDel-19 and SNP-63 were not associated with intra-abdominal fat area or insulin action. Furthermore, we demonstrated in a separate sample of middle-aged men (n=234) who had a history of type 2 diabetes in first-degree relatives that the A allele of SNP-43 was associated with a large waist circumference, and high insulin levels in an OGTT. CONCLUSIONS/INTERPRETATION: SNP-43 of CAPN10 may contribute to the risk of diabetes by regulating abdominal obesity in subjects with high risk of type 2 diabetes.

Atherosclerosis-like lesions of the aortic valve are common in adults of all ages: a necropsy study.

OBJECTIVE: To determine the presence and size of atherosclerosis-like lesions in aortic valves of unselected adults of all ages. DESIGN: Necropsy study. SETTING: Departments of Forensic Medicine and Pathology at the University of Oulu and the Oulu University Hospital in Finland. SUBJECTS: 48 consecutive unselected adult subjects (15 subjects aged 20-40 years, 17 aged 41-60, and 16 aged >or= 61) undergoing necropsy. MAIN OUTCOME MEASURES: Detection of the presence of atherosclerosis-like lesions and mineralisation in aortic valves, and morphometrical measurement of the size of lesions. RESULTS: None of the necropsy subjects had aortic stenosis and only two subjects had macroscopic calcification of the aortic valve. Of 48 subjects, however, 45 had an atherosclerosis-like subendothelial thickening above the elastic lamina on the aortic side of at least one of the valve leaflets. Of 15 young subjects aged 20-40 years, eight had a lesion in the right coronary cusp of the aortic valve and 12 had a lesion in at least one of the three aortic valve leaflets. Of 17 middle aged subjects, 16 had an early lesion in the right coronary cusp and all had a lesion in at least one of the valve leaflets. In the oldest age group, all 16 subjects had a lesion in every valve leaflet. The mean lesion area in the three valve leaflets varied from 0.1-0.2 mm(2) in young subjects, 0.5-0.8 mm(2) in middle aged, and 1.3-2.3 mm(2) in elderly subjects (p < 0.001). Microscopic calcification in the right coronary cusp of the aortic valve was observed in 12 of 17 middle aged and 14 of 16 elderly subjects but only in one young subject. CONCLUSIONS: Atherosclerosis-like lesions in the aortic valve are prevalent in adults of all age groups, including young subjects aged 20-40 years, suggesting that the disease process leading to aortic stenosis is common, often beginning in early adulthood.