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.
Aims
The metabolic syndrome (MetS) is defined as a clustering of cardiovascular risk factors characterized by insulin resistance. We investigated the relationship of the MetS and its single ...components, defined by all six different criteria, with coronary heart disease (CHD), cardiovascular disease (CVD), and all-cause mortality in a prospective population-based study.
Methods and results
The MetS was defined according to the World Health Organization (WHO), the European Group for the Study of Insulin Resistance (EGIR), the National Cholesterol Education Program (NCEP), the American College of Endocrinology (ACE), the International Diabetes Federation (IDF), and the American Heart Association (updated NCEP) criteria. We investgated the relationship of the MetS defined by aforementioned six criteria with CHD, CVD, and all-cause mortality with Cox regression analyses in a non-diabetic Finnish population of 1025 subjects, aged 65-74 years, during the 13-year follow-up. The MetS defined by all aforementioned criteria was associated with a statistically significant risk for CVD mortality when adjusted for all confounding variables (Hazards Ratios, HRs from 1.31 to 1.51). The MetS defined by the WHO, ACE, and IDF criteria was associated with an increased risk of CHD mortality (HRs from 1.42 to 1.58). There was no association between the MetS by any criteria and all-cause mortality. Of the single components of the MetS, the following predicted CVD mortality in multivariable models: impaired fasting glucose by the WHO, NCEP, and ACE criteria (HR 1.34) and by the IDF and updated NCEP criteria (HR 1.29); impaired glucose tolerance by the WHO and ACE criteria (HR 1.55); low HDL cholesterol by the EGIR criteria (HR 1.50) and by the NCEP, IDF, and updated NCEP criteria (HR 1.29); and microalbuminuria according to the WHO definition (HR 1.86).
Conclusion
The MetS defined by all six current criteria predicts CVD mortality in elderly subjects. However, of the single components of the MetS, IFG, IGT, low HDL cholesterol, and microalbuminuria predicted CVD mortality with equal or higher HRs when compared with the different definitions of the MetS. Therefore, our study suggests that the MetS is a marker of CVD risk, but not above and beyond the risk associated with its individual components.
. Karhapää P, Pihlajamäki J, Pörsti I, Kastarinen M, Mustonen J, Niemelä O, Kuusisto J (University of Eastern Finland, Kuopio; University of Tampere, Tampere; and Laboratory and Medical Research ...Unit, University of Tampere, Tampere; Finland). Diverse associations of 25‐hydroxyvitamin D and 1,25‐dihydroxyvitamin D with dyslipidaemias. J Intern Med 2010; 268: 604–610.
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 (β = −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 (β = 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.
. Wang J, Stančáková A, Soininen P, Kangas AJ, Paananen J, Kuusisto J, Ala‐Korpela M, Laakso M (University of Eastern Finland and Kuopio University Hospital, Kuopio; Institute of Clinical Medicine, ...University of Oulu, Oulu; University of Eastern Finland, Kuopio; and Clinical Research Center, University of Oulu, Oulu; Finland). Lipoprotein subclass profiles in individuals with varying degrees of glucose tolerance: a population‐based study of 9399 Finnish men. J Intern Med 2012; doi: 10.1111/j.1365‐2796.2012.02562.x.
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.
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.
To assess the association of metabolic syndrome (MetS) with Alzheimer disease (AD).
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.
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).
Metabolic syndrome is associated with Alzheimer disease in elderly subjects.
. Vangipurapu J, Stančáková A, Kuulasmaa T, Soininen P, Kangas AJ, Ala‐Korpela M, Kuusisto J, Laakso M (University of Eastern Finland and Kuopio University Hospital, Kuopio; University of Oulu and ...Biocenter Oulu, Oulu, Finland). Association between liver insulin resistance and cardiovascular risk factors. J Intern Med 2012; 272: 402–408.
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.
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/m²; mean ± SD) whose endogenous glucose production (EGP) was measured with 6-6²H₂glucose 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.
Several amino acids (AAs) have been shown to be associated with insulin resistance and increased risk of type 2 diabetes, but no previous studies have investigated the association of AAs with insulin ...secretion in a longitudinal setting. Our study included 5,181 participants of the cross-sectional METabolic Syndrome In Men (METSIM) study having metabolomics data on 20 AAs. A total of 4,851 had a 7.4-year follow-up visit. Nine AAs (phenylalanine, tryptophan, tyrosine, alanine, isoleucine, leucine, valine, aspartate, and glutamate) were significantly (
< 5.8 × 10
) associated with decreases in insulin secretion (disposition index) and the elevation of fasting or 2-h glucose levels. Five of these AAs (tyrosine, alanine, isoleucine, aspartate, and glutamate) were also found to be significantly associated with an increased risk of incident type 2 diabetes after adjustment for confounding factors. Our study is the first population-based large cohort to report that AAs are associated not only with insulin resistance but also with decreased insulin secretion.
Abstract Objective: To determine the association between features of the insulin resistance syndrome and Alzheimer's disease. Design: Cross sectional population based study. Subjects: 980 people aged ...69 to 78 (349 men, 631 women). Setting: Population of Kuopio, eastern Finland. Main outcome measures: Presence of features of the insulin resistance syndrome and diagnosis of Alzheimer's disease by detailed neurological and neuropsychological evaluation. Results: 46 (4.7%) subjects were classified as having probable or possible Alzheimer's disease. In univariate analyses, apolipoprotein E4 phenotype (odds ratio; 95% confidence interval 3.24: 1.77 to 5.92), age (1.16; 1.05 to 1.29), low level of education (0.82; 0.72 to 0.93), low total cholesterol concentration (0.77; 0.59 to 1.00), high systolic blood pressure (1.01; 1.00 to 1.03), high fasting and 2 hour plasma glucose concentrations (1.11; 1.01 to 1.23 and 1.08; 1.03 to 1.13, respectively), high fasting and 2 hour insulin concentrations (1.05; 1.02 to 1.08 and 1.003; 1.00 to 1.01, respectively), and abnormal glucose tolerance (1.86; 1.23 to 2.80) were significantly associated with Alzheimer's disease. In multivariate analysis including apolipoprotein E4 phenotype, age, education, systolic blood pressure, total cholesterol concentration, fasting glucose concentration, and insulin concentration, apolipoprotein E4 phenotype, age, education, total cholesterol, and insulin were significantly associated with Alzheimer's disease. In 532 non-diabetic subjects without the e4 allele hyperinsulinaemia was associated with an increased risk for Alzheimer's disease (prevalence of disease 7.5% v 1.4% in normoinsulinaemic subjects, P=0.0004). In contrast, in the 228 with the e4 allele hyperinsulinaemia had no effect on the risk of disease (7.0% v 7.1%, respectively). Conclusion: Features of the insulin resistance syndrome are associated with Alzheimer's disease independently of apolipoprotein E4 phenotype. Key messages Apolipoprotein E4 phenotype is a risk factor for Alzheimer's disease Other risk factors for Alzheimer's disease are not well documented in previous studies In this study, hyperinsulinaemia and other features of the insulin resistance syndrome were associated with Alzheimer's disease Insulin resistance is affected by modifications in lifestyle, so the risk of Alzheimer's disease might be reducible by the same measures
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