Genetic architecture of oral glucose-stimulated insulin release provides biological insights into type 2 diabetes aetiology.

The genetics of ß-cell function (BCF) offer valuable insights into the aetiology of type 2 diabetes (T2D)1,2. Previous studies have expanded the catalogue of BCF genetic associations through candidate gene studies3-7, large-scale genome-wide association studies (GWAS) of fasting BCF8,9 or functional islet studies on T2D risk variants10-14. Nonetheless, GWAS focused on BCF traits derived from oral glucose tolerance test (OGTT) data have been limited in sample size15,16 and have often overlooked the potential for related traits to capture distinct genetic features of insulin-producing ß-cells17,18. We reasoned that investigating the genetic basis of multiple BCF estimates could provide a broader understanding of ß-cell physiology. Here, we aggregate GWAS data of eight OGTT-based BCF traits from ~26,000 individuals of European descent, identifying 55 independent genetic associations at 44 loci. By examining the effects of BCF genetic signals on related phenotypes, we uncover diverse disease mechanisms whereby genetic regulation of BCF may influence T2D risk. Integrating BCF-GWAS data with pancreatic islet transcriptomic and epigenomic datasets reveals 92 candidate effector genes. Gene silencing in ß-cell models highlights ACSL1 and FAM46C as key regulators of insulin secretion. Overall, our findings yield insights into the biology of insulin release and the molecular processes linking BCF to T2D risk, shedding light on the heterogeneity of T2D pathophysiology.

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.

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.

Genetic risk clustering increases children's body weight at 2 years of age - the STEPS Study.

BACKGROUND: Genetic determinants have an impact on adult weight but the association between genetic determinants and weight at young age is still poorly understood. OBJECTIVE: The objective of this study was to examine the association between genetic risk scores and early growth from birth to 2 years of age. METHODS: Genetic risk scores of 83 adiposity-related or obesity-related single nucleotide polymorphisms (SNPs) (genetic risk score [GRS]83) were calculated for 1278 children. Specific phenotype score for 16 weight-related SNPs (weightGRS) was calculated. Anthropometric data were obtained at birth, 13 months and 2 years of age. RESULTS: The GRS83 was associated with weight at 13 months (ß = 0.080, P = 0.015) and 2 years (ß = 0.080, P = 0.017) of age and with weight gain from birth to 13 months (ß = 0.069, P = 0.036) and to 2 years of age (ß = 0.074, P = 0.028). At 2 years of age, the GRS83 was also associated with weight for height (ß = 0.065, P = 0.046), weight-for-height standard deviation score (SDS) (ß = 0.074, P = 0.022) and body mass index SDS (ß = 0.068, P = 0.045). WeightGRS was associated with higher body weight at 13 months (ß = 0.081, P = 0.014) and 2 years of age (ß = 0.086, P = 0.011). The genetic effect on weight varied from 0.69 to 1.89 kg at 2 years of age according to number of risk alleles. Children with high genetic risk for adiposity were heavier than children with low genetic risk at 2 years of age (12.8 vs. 13.4 kg, P = 0.017). CONCLUSION: The GRS 83 revealed increased genetic risk for higher weight in children already at 13 months and 2 years of age, which may result in increased obesity risk later in life.

Par6G suppresses cell proliferation and is targeted by loss-of-function mutations in multiple cancers.

Differentiated epithelial structure communicates with individual constituent epithelial cells to suppress their proliferation activity. However, the pathways linking epithelial structure to cessation of the cell proliferation machinery or to unscheduled proliferation in the context of tumorigenesis are not well defined. Here we demonstrate the strong impact of compromised epithelial integrity on normal and oncogenic Myc-driven proliferation in three-dimensional mammary epithelial organoid culture. Systematic silencing of 34 human homologs of Drosophila genes, with previously established functions in control of epithelial integrity, demonstrates a role for human genes of apico-basal polarity, Wnt and Hippo pathways and actin dynamics in regulation of the size, integrity and cell proliferation in organoids. Perturbation of these pathways leads to diverse functional interactions with Myc: manifested as a RhoA-dependent synthetic lethality and Par6-dependent effects on the cell cycle. Furthermore, we show a role for Par6G as a negative regulator of the phosphatidylinositol 3'-kinase/phosphoinositide-dependent protein kinase 1/Akt pathway and epithelial cell proliferation and evidence for frequent inactivation of Par6G gene in epithelial cancers. The findings demonstrate that determinants of epithelial structure regulate the cell proliferation activity via conserved and cancer-relevant regulatory circuitries, which are important for epithelial cell cycle restriction and may provide new targets for therapeutic intervention.

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.

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.

Assessment of early auditory development of very young Finnish children with LittlEARS(®) Auditory Questionnaire and McArthur Communicative Developmental Inventories.

OBJECTIVES: We analysed the Finnish version of the LittlEARS(®) Auditory Questionnaire as a method for assessing very young children's early auditory, pre-verbal and emerging verbal development. We also examined whether any background factors exist that influence the results and thus the usability of this method. To determine its potential in assessment, the Finnish version of the LittlEARS(®) Auditory Questionnaire was analysed in relation to the Finnish McArthur Communicative Developmental Inventories. The latter is currently the method most commonly used together with parental interviews. However, this method is neither designed for infants younger than 8 months nor is its main emphasis on auditory development. Thus, we investigated whether the Finnish version of LittlEARS(®) Auditory Questionnaire could supplement the Finnish McArthur Communicative Developmental Inventories and thereby help in detecting children with hearing impairments. METHODS: Normative data were collected for Finnish children with normal hearing (N=318) using the LittlEARS(®) Auditory Questionnaire and an abridged version of the Finnish McArthur Communicative Developmental Inventories. In addition, background information was collected with a questionnaire designed for this study. The results of these questionnaires were analysed in relation to each other. RESULTS: Statistical analysis showed that the results gained with the Finnish version of LittlEARS(®) Auditory Questionnaire and the abridged version of the Finnish McArthur Communicative Developmental Inventories are closely related. However, the LittlEARS(®) Auditory Questionnaire manages to capture the earlier and subtler changes that occur in infancy, therefore making a good continuum with McArthur Communicative Developmental Inventories. Also, most background factors, such as parents' educational level, did not affect the results significantly, rendering the LittlEARS(®) Auditory Questionnaire a valuable method for assessment of early auditory development in very young children. CONCLUSIONS: The Finnish version of the LittlEARS(®) Auditory Questionnaire is a reliable assessment tool with no confounding background factors. It enables evaluation of the early auditory development in even the youngest of children.

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.

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.

Conjugated bile acids associate with altered rates of glucose and lipid oxidation after Roux-en-Y gastric bypass.

BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (RYGB) induces a more favorable metabolic profile than expected by weight loss alone. In this study, we investigated the effect of RYGB on serum bile acid levels and their relation to clinical outcomes. METHODS: We included 30 obese patients who underwent RYGB (BMI = 46.1 ± 5.9 kg/m(2)). Clinical measurements and laboratory determinations were performed before surgery and 1 year after surgery. Fasting serum bile acids were measured by an enzymatic method and individual bile acids were quantified by HLPC-tandem mass spectrometry. Indirect calorimetry was performed to measure the rates of energy expenditure and substrate oxidation. RESULTS: Fasting total serum bile acid levels increased twofold after RYGB (pre, 3.68 ± 2.03 vs. post, 7.06 ± 9.65 µmol/l, +92 %, p = 0.002). This increase in total bile acids was accompanied by a decrease in conjugated bile acids, which correlated with decreased glucose oxidation (r = 0.571, p = 0.002) and with increased lipid oxidation (r = -0.626, p = 0.0004). The change in taurine-conjugated bile acids correlated with altered DIO2 mRNA expression in adipose tissue (r = -0.498, p = 0.013) potentially linking bile acid conjugation to substrate oxidation through DIO2. CONCLUSIONS: Fasting serum bile acid levels increase after RYGB. More specifically, changes in bile acid conjugation after RYGB associate with altered energy metabolism.

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.

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.

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.

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.

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.