Infertility as a lonely struggle? Coping stories of previously infertile women.

In this narrative study, we explored the meaning infertile women attribute to social support in coping with their infertility-related challenges. Written accounts and episodic interviews with 26 previously infertile Finnish women were used as data. Two different coping story types emerged: coping alone and coping with support. In the coping alone type women neither sought nor received support. Their coping appeared as a lonely struggle. In the coping with stories, women turned to their spouses, peers, or professionals, but still emphasized that they would have needed more support. Based on our findings, we underline the need for individually tailored support.

Clinical profiles of post-load glucose subgroups and their association with glycaemic traits over time: An IMI-DIRECT study.

AIM: To examine the hypothesis that, based on their glucose curves during a seven-point oral glucose tolerance test, people at elevated type 2 diabetes risk can be divided into subgroups with different clinical profiles at baseline and different degrees of subsequent glycaemic deterioration. METHODS: We included 2126 participants at elevated type 2 diabetes risk from the Diabetes Research on Patient Stratification (IMI-DIRECT) study. Latent class trajectory analysis was used to identify subgroups from a seven-point oral glucose tolerance test at baseline and follow-up. Linear models quantified the associations between the subgroups with glycaemic traits at baseline and 18 months. RESULTS: At baseline, we identified four glucose curve subgroups, labelled in order of increasing peak levels as 1-4. Participants in Subgroups 2-4, were more likely to have higher insulin resistance (homeostatic model assessment) and a lower Matsuda index, than those in Subgroup 1. Overall, participants in Subgroups 3 and 4, had higher glycaemic trait values, with the exception of the Matsuda and insulinogenic indices. At 18 months, change in homeostatic model assessment of insulin resistance was higher in Subgroup 4 (ß = 0.36, 95% CI 0.13-0.58), Subgroup 3 (ß = 0.30; 95% CI 0.10-0.50) and Subgroup 2 (ß = 0.18; 95% CI 0.04-0.32), compared to Subgroup 1. The same was observed for C-peptide and insulin. Five subgroups were identified at follow-up, and the majority of participants remained in the same subgroup or progressed to higher peak subgroups after 18 months. CONCLUSIONS: Using data from a frequently sampled oral glucose tolerance test, glucose curve patterns associated with different clinical characteristics and different rates of subsequent glycaemic deterioration can be identified.

Voxel-based morphometry study on monozygotic twins discordant for Alzheimer's disease.

OBJECTIVES: We set to investigate the possible role of genes and environment in developing Alzheimer's disease (AD) in monozygotic twin pairs discordant for AD. METHODS: Three pairs of twins discordant for AD, who were enrolled in the Finnish Twin Cohort, were used in the study and compared with 13 controls. Gray matter changes were assessed with magnetic resonance images using voxel-based morphometry with statistical parametric mapping. RESULTS: In the affected twins, the peaks of volume loss were located bilaterally in the temporal (including the hippocampus), the frontal, and the parietal lobes, while in the unaffected siblings, the peaks were located in the frontal gyri and in the parietal lobule. Thus, in the unaffected twins, the pattern of volume loss overlaps with the neocortical but not with the medial temporal areas. DISCUSSION: These findings suggest that genetic factors more largely control neocortical regions, whereas environmental factors more strongly affect medial temporal regions.

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.

Diagnosis of dementias by high-field 1H MRS of cerebrospinal fluid.

OBJECTIVE: To test whether the information obtained from cerebrospinal fluid (CSF) and analysed with high-field proton ((1)H) MR spectroscopy (MRS) would help the diagnosis of most common forms of dementia. SETTING: A total of 31 metabolites from CSF from 222 controls and patients suffering from various dementias (Alzheimer's disease (AD), vascular dementia, Lewy body disease (LBD) and frontotemporal dementia (FTD)) were quantified using (1)H MRS. MAIN OUTCOME MEASURE: Clinical diagnosis. RESULTS: AD was classified with an accuracy of 85.5%. For a group of very early stage patients with AD, the result was significantly higher, 92.3%. Vascular dementia, LBD and FTD were all diagnosed with 100% accuracy in controls and from AD with an accuracy ranging between 85.5% and 93.4%. CONCLUSIONS: The results indicate that the composition of CSF contains enough information of the neurological state of a given patient with a given dementia to be diagnosed with extremely high accuracy. This approach might provide potentially a very powerful diagnostic tool to help the diagnostic process of dementias.

Arithmetic fluency and number processing skills in identifying students with mathematical learning disabilities.

BACKGROUND: Students with mathematical learning disabilities (MLD) struggle with number processing skills (e.g., enumeration and number comparison) and arithmetic fluency. Traditionally, MLD is identified based on arithmetic fluency. However, number processing skills are suggested to differentiate low achievement (LA) from MLD. AIMS: This study investigated the accuracy of number processing skills in identifying students with MLD and LA, based on arithmetic fluency, and whether the classification ability of number processing skills varied as a function of grade level. METHODS AND PROCEDURES: The participants were 18,405 students (girls = 9080) from Grades 3-9 (ages 9-15). Students' basic numerical skills were assessed with an online dyscalculia screener (Functional Numeracy Assessment -Dyscalculia Battery, FUNA-DB), which included number processing and arithmetic fluency as two factors. OUTCOMES AND RESULTS: Confirmatory factor analyses supported a two-factor structure of FUNA-DB. The two-factor structure was invariant across language groups, gender, and grade levels. Receiver operating characteristics curve analyses indicated that number processing skills are a fair classifier of MLD and LA status across grade levels. The classification accuracy of number processing skills was better when predicting MLD (cut-off < 5 %) compared to LA (cut-off < 25 %). CONCLUSIONS AND IMPLICATIONS: Results highlight the need to measure both number processing and arithmetic fluency when identifying students with MLD.

A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity.

The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a transcription factor that has a pivotal role in adipocyte differentiation and expression of adipocyte-specific genes. The PPARgamma1 and gamma2 isoforms result from alternative splicing and have ligand-dependent and -independent activation domains. PPARgamma2 has an additional 28 amino acids at its amino terminus that renders its ligand-independent activation domain 5-10-fold more effective than that of PPARgamma1. Insulin stimulates the ligand-independent activation of PPARgamma1 and gamma2 (ref. 5), however, obesity and nutritional factors only influence the expression of PPARgamma2 in human adipocytes. Here, we report that a relatively common Pro12Ala substitution in PPARgamma2 is associated with lower body mass index (BMI; P=0.027; 0.015) and improved insulin sensitivity among middle-aged and elderly Finns. A significant odds ratio (4.35, P=0.028) for the association of the Pro/Pro genotype with type 2 diabetes was observed among Japanese Americans. The PPARgamma2 Ala allele showed decreased binding affinity to the cognate promoter element and reduced ability to transactivate responsive promoters. These findings suggest that the PPARgamma2 Pro12Ala variant may contribute to the observed variability in BMI and insulin sensitivity in the general population.

Linkage of familial combined hyperlipidaemia to chromosome 1q21-q23.

More than half of the patients with angiographically confirmed premature coronary heart disease (CHD) have a familial lipoprotein disorder. Familial combined hyperlipidaemia (FCHL) represents the most common genetic dyslipidemia with a prevalence of 1.0-2.0%. FCHL is estimated to cause 10-20% of premature CHD and is characterized by elevated levels of cholesterol, triglycerides, or both. Attempts to characterize genes predisposing to FCHL have been hampered by its equivocal phenotype definition, unknown mode of inheritance and genetic heterogeneity. In order to minimize genetic heterogeneity, we chose 31 extended FCHL families from the isolated Finnish population that fulfilled strictly defined criteria for the phenotype status. We performed linkage analyses with markers from ten chromosomal regions that contain lipid-metabolism candidate genes. One marker, D1S104, adjacent to the apolipoprotein A-II (APOA2) gene on chromosome 1, revealed a lod score of Z = 3.50 assuming a dominant mode of inheritance. Multipoint analysis combining information from D1S104 and the neighbouring marker D1S1677 resulted in a lod score of 5.93. Physical positioning of known genes in the area (APOA2 and three selectin genes) outside the linked region suggests a novel locus for FCHL on 1q21-q23. A second paper in this issue (Castellani et al.) reports the identification of a mouse combined hyperlipidaemia locus in the syntenic region of the mouse genome, thus further implicating a gene in this region in the aetiology of FCHL.

Serine/threonine protein kinase 25 (STK25): a novel negative regulator of lipid and glucose metabolism in rodent and human skeletal muscle.

AIMS/HYPOTHESIS: This study investigates the role of serine/threonine protein kinase 25 (STK25), a member of the sterile 20 (STE20) superfamily of kinases, in the regulation of skeletal muscle metabolism. METHODS: The effect of depleting STK25 in muscle cells was studied by reducing the mRNA and protein content of this target in the rat myoblast cell line L6 by small interfering (si)RNA. The changes in the mRNA and protein levels of several members of the fatty acid oxidative and glucose metabolic pathways were measured by quantitative real-time (qRT)-PCR and western blot. The rate of palmitate oxidation and glucose uptake was measured after transfection with siRNA for Stk25. Expression of STK25 was also evaluated in skeletal muscle biopsies from 41 white Europid men and women with normal and impaired glucose tolerance and type 2 diabetes using qRT-PCR. RESULTS: We demonstrate that partial depletion of STK25 increases the expression of uncoupling protein 3 (Ucp3), accompanied by increased lipid oxidation, in myoblasts. In addition, a reduced level of STK25 enhances the expression of Slc2a1 (also known as Glut1), Slc2a4 (also known as Glut4) and hexokinase 2, and correspondingly, improves insulin-stimulated glucose uptake in muscle cells. Consistent with these results, significantly higher STK25 levels were observed in the skeletal muscle of type 2 diabetic patients, compared with individuals with normal glucose tolerance. CONCLUSIONS/INTERPRETATION: This is the first study indicating a possible role for STK25 in the regulation of glucose and lipid metabolism in L6 myoblasts. This kinase appears to be an interesting new mediator to be evaluated for therapeutic intervention in type 2 diabetes and related complications, as controlled increase in lipid oxidation and insulin-stimulated glucose uptake in skeletal muscle is favourable and can restore energy balance in metabolically compromised states.

Glucose control in diabetes: which target level to aim for?

The most important goal in the treatment of patients with diabetes is to lower the risk of long-term diabetes complications. Hyperglycaemia is the most important risk factor for microvascular complications in diabetes, but, in addition to hyperglycaemia, several other risk factors, particularly dyslipidaemia, elevated blood pressure and smoking, also determine the risk of macrovascular complications. In this review, we present evidence from longitudinal population-based studies that hyperglycaemia is an important risk factor for long-term complications of diabetes and discuss the results from clinical trials of the effects of the treatment of hyperglycaemia on the prevention of long-term micro- and macrovascular complications in type 1 and type 2 diabetes. An HbA(1c) target of <7.0% for the treatment of diabetes is generally accepted on the basis of evidence from several trials, whereas a target of <6.5% may be reasonable for patients with a short duration of type 2 diabetes and without extensive atherosclerosis.

Proteinuria modifies the effect of systolic blood pressure on total and cardiovascular disease mortality in patients with type 2 diabetes.

OBJECTIVES: Hypertension and proteinuria are major risk factors for cardiovascular disease (CVD) mortality in patients with type 2 diabetes. Blood pressure (BP) targets have been progressively lowered in these patients to prevent or delay the progression of nephropathy. However, no long-term population-based studies have been reported on the interaction between BP and proteinuria with respect to total and CVD mortality in patients with type 2 diabetes. DESIGN: We prospectively followed 881 middle-aged type 2 diabetic patients, free of CVD events at baseline, for up to 18 years. Participants were categorized into four groups according to baseline systolic BP (<130, 130-139, 140-159 and ≥160 mmHg) and further stratified by proteinuria (≤150 or >150 mg L(-1)). Cox proportional hazards model was used to estimate the joint association between systolic BP and proteinuria and the risk of mortality. RESULTS: During follow-up, 607 patients died including 395 because of CVD. After adjustment for confounding factors, total and CVD mortality were significantly higher in patients with proteinuria and systolic BP <130 mmHg compared with those with systolic BP between 130 and 160 mmHg. The prognosis was similar in patients with systolic BP <130 mmHg or ≥160 mmHg. Among patients without proteinuria, systolic BP <130 mmHg was associated with a nonsignificant reduction in mortality. CONCLUSIONS: Type 2 diabetic patients with proteinuria and with systolic BP <130 mmHg may have an increased risk of CVD mortality. The presence of proteinuria should be taken into account when defining the target systolic BP level for the prevention of fatal CVD events in patients with type 2 diabetes.

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.

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.

Manifestly non-Gaussian fluctuations in superconductor-normal metal tunnel nanostructures.

We propose a mesoscopic setup which exhibits strong and manifestly non-Gaussian fluctuations of energy and temperature when suitably driven out of equilibrium. The setup consists of a normal metal island (N) coupled by tunnel junctions (I) to two superconducting leads (S), forming a SINIS structure, and is biased near the threshold voltage for quasiparticle tunneling, eV≈2Δ. The fluctuations can be measured by monitoring the time-dependent electric current through the system. This makes the setup suitable for the realization of feedback schemes which can be used to stabilize the temperature to the desired value.

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.

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.

Natural history and physiological determinants of changes in glucose tolerance in a non-diabetic population: the RISC Study.

AIMS/HYPOTHESIS: The natural history and physiological determinants of glucose intolerance in subjects living in Europe have not been investigated. The aim of this study was to increase our understanding of this area. METHODS: We analysed the data from a population-based cohort of 1,048 non-diabetic, normotensive men and women (aged 30-60 years) in whom insulin sensitivity was measured by the glucose clamp technique (M/I index; average glucose infusion rate/steady-state insulin concentration) and beta cell function was estimated by mathematical modelling of the oral glucose tolerance test at baseline and 3 years later. RESULTS: Seventy-seven per cent of the participants had normal glucose tolerance (NGT) and 5% were glucose intolerant both at baseline and follow up; glucose tolerance worsened in 13% (progressors) and improved in 6% (regressors). The metabolic phenotype of the latter three groups was similar (higher prevalence of familial diabetes, older age, higher waist-to-hip ratio, higher fasting and 2 h plasma glucose, higher fasting and 2 h plasma insulin, lower insulin sensitivity and reduced beta cell glucose sensitivity with increased absolute insulin secretion). Adjusting for these factors in a logistic model, progression was predicted by insulin resistance (bottom M/I quartile, OR 2.52 [95% CI 1.51-4.21]) and beta cell glucose insensitivity (bottom quartile, OR 2.39 [95% CI 1.6-3.93]) independently of waist-to-hip ratio (OR 1.44 [95% CI 1.13-1.84] for one SD). At follow up, insulin sensitivity and beta cell glucose sensitivity were unchanged in the stable NGT and stable non-NGT groups, worsened in progressors and improved in regressors. CONCLUSIONS/INTERPRETATION: Glucose tolerance deteriorates over time in young, healthy Europids. Progressors, regressors and glucose-intolerant participants share a common baseline phenotype. Insulin sensitivity and beta cell glucose sensitivity predict and track changes in glucose tolerance independently of sex, age and obesity.

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.

High-density lipoprotein-cholesterol and not HbA1c was directly related to cardiovascular outcome in PROactive.

AIM: In PROactive, pioglitazone reduced the incidence of death, myocardial infarction and stroke, and significantly improved HbA1c, systolic blood pressure (SBP), triglycerides and high-density lipoprotein (HDL)-cholesterol relative to placebo. As these glycaemic and lipid parameters are major cardiovascular (CV) risk factors, we assessed their separate contribution to the reduced incidence of CV outcomes. METHODS: Patients (n = 5238) with type 2 diabetes and macrovascular disease were randomized to 45 mg pioglitazone or placebo. Relationships among treatment, outcome (time to first event of all-cause mortality, myocardial infarction and stroke) and 10 laboratory measurements and vital signs were investigated using log-linear models. Continuous variable measurements (percent changes from baseline to average of all postbaseline values prior to censoring) were made discrete by categorizing into tertiles. Log-linear models were fitted to multiway tables of discrete data and analysis of deviance used to summarize sources of variation in the data. RESULTS: Although pioglitazone treatment was associated with a decrease in HbA1c and an increase in HDL-cholesterol (HDL-C), only the change from baseline HDL-C predicted the outcome (χ(2) = 28.89, p < 0.0001). No other variables, including HbA1c, triglycerides and systolic blood pressure, showed significant direct associations with outcome. When the analysis was extended to include baseline statin use, this was associated with an improved outcome independently of HDL-C changes. CONCLUSIONS: This post hoc analysis suggests that HDL-C, but probably not HbA1c, is a driver of pioglitazone's favourable influence on CV outcome.