The FOXO3A rs2802292 G-allele associates with improved peripheral and hepatic insulin sensitivity and increased skeletal muscle-FOXO3A mRNA expression in twins.

Objective: The minor G-allele of FOXO3A rs2802292 has been associated with longevity. We aimed to investigate whether a phenotype related to healthy metabolic aging could be identified in individuals carrying the longevity-associated FOXO3A rs2802292 G-allele.

Research Design And Methods: rs2802292 was genotyped in a phenotypically well-characterized population of young and elderly twins (n = 190) and in the population-based Inter99 cohort (n = 5768).

Heart failure severity, as determined by loop diuretic dosages, predicts the risk of developing diabetes after myocardial infarction: a nationwide cohort study.

Aims: Heart failure (HF) is associated with increased insulin resistance, but the consequences of HF for development of diabetes are not well studied. The aim of the present study was to investigate the relationship between HF severity and risk of developing diabetes in a nationwide cohort of patients with myocardial infarction (MI).

Methods And Results: Patients discharged from first-time MI during 1997-2006 and not previously treated with glucose-lowering medications (GLM) or loop diuretics were identified from Danish nationwide registers.

Low birthweight and premature birth are both associated with type 2 diabetes in a random sample of middle-aged Danes.

Aims/hypothesis: We studied the associations of size at birth and prematurity with type 2 diabetes, insulin sensitivity and beta cell function in the Danish population-based Inter99 study (ClinicalTrials.gov NCT00289237).

Methods: Information about size at birth and prematurity was identified from original midwife records in 4,744 middle-aged Danes.

Effects of oral glucose-lowering drugs on long term outcomes in patients with diabetes mellitus following myocardial infarction not treated with emergent percutaneous coronary intervention--a retrospective nationwide cohort study.

Background: The optimum oral pharmacological treatment of diabetes mellitus to reduce cardiovascular disease and mortality following myocardial infarction has not been established. We therefore set out to investigate the association between individual oral glucose-lowering drugs and cardiovascular outcomes following myocardial infarction in patients with diabetes mellitus not treated with emergent percutaneous coronary intervention.

Materials And Methods: All patients aged 30 years or older receiving glucose-lowering drugs (GLDs) and admitted with myocardial infarction (MI) not treated with emergent percutaneous coronary intervention in Denmark during 1997-2006 were identified by individual-level linkage of nationwide registries of hospitalizations and drug dispensing from pharmacies.

Metformin treatment is associated with a low risk of mortality in diabetic patients with heart failure: a retrospective nationwide cohort study.

Aims/hypothesis: The safety of metformin in heart failure has been questioned because of a perceived risk of life-threatening lactic acidosis, though recent studies have not supported this concern. We investigated the risk of all-cause mortality associated with individual glucose-lowering treatment regimens used in current clinical practice in Denmark.

Methods: All patients aged ≥ 30 years hospitalised for the first time for heart failure in 1997-2006 were identified and followed until the end of 2006.

Impact of physical inactivity on subcutaneous adipose tissue metabolism in healthy young male offspring of patients with type 2 diabetes.

Objective: Physical inactivity is a risk factor for type 2 diabetes and may be more detrimental in first-degree relative (FDR) subjects, unmasking underlying defects of metabolism. Using a positive family history of type 2 diabetes as a marker of increased genetic risk, the aim of this study was to investigate the impact of physical inactivity on adipose tissue (AT) metabolism in FDR subjects.

Research Design And Methods: A total of 13 FDR and 20 control (CON) subjects participated in the study.

Insulin resistance induced by physical inactivity is associated with multiple transcriptional changes in skeletal muscle in young men.

Physical inactivity is a risk factor for insulin resistance. We examined the effect of 9 days of bed rest on basal and insulin-stimulated expression of genes potentially involved in insulin action by applying hypothesis-generating microarray in parallel with candidate gene real-time PCR approaches in 20 healthy young men. Furthermore, we investigated whether bed rest affected DNA methylation in the promoter region of the peroxisome proliferator-activated receptor-γ coactivator-1α (PPARGC1A) gene.

Metformin is associated with improved left ventricular diastolic function measured by tissue Doppler imaging in patients with diabetes.

Objective: To examine the association between selected glucose-lowering medications and left ventricular (LV) diastolic function in patients with diabetes.

Design: Retrospective cohort study (years 2005-2008).

Methods: Echocardiograms of 242 patients with diabetes undergoing coronary angiography were analyzed.

Treatment with a proton pump inhibitor improves glycaemic control in Psammomys obesus, a model of type 2 diabetes.

Aims/hypothesis: Gastrin has been implicated in islet growth/neogenesis, and proton pump inhibitors (PPIs) have been shown to increase endogenous gastrin levels in animals and humans. Therefore, we investigated the effect of PPIs in a model of type 2 diabetes, Psammomys obesus.

Methods: P.

Differential aetiology and impact of phosphoinositide 3-kinase (PI3K) and Akt signalling in skeletal muscle on in vivo insulin action.

Aims/hypothesis: Insulin resistance in skeletal muscle is a key factor in the development of type 2 diabetes and although some studies indicate that this could be partly attributed to reduced content and activity of various proximal and distal insulin signalling molecules, consensus is lacking. We therefore aimed to investigate the regulation of proximal insulin signalling in skeletal muscle and its effect on glucose metabolism in a large non-diabetic population.

Methods: We examined 184 non-diabetic twins with gold-standard techniques including the euglycaemic-hyperinsulinaemic clamp.

LMNA rs4641 and the muscle lamin A and C isoforms in twins--metabolic implications and transcriptional regulation.

Context: Lamins are essential for nuclear shape and function. Polymorphisms in LMNA may associate with fat and muscle development and aging.

Objective: Our aim was to determine the influence of LMNA rs4641 on lean body mass (LBM) and fat mass (FM), in vivo metabolism, and expression of LMNA transcripts in human skeletal muscle.

Type 2 diabetes risk alleles near ADCY5, CDKAL1 and HHEX-IDE are associated with reduced birthweight.

Aims/hypothesis: The fetal insulin hypothesis suggests that variation in the fetal genotype influencing insulin secretion or action may predispose to low birthweight and type 2 diabetes. We examined associations between 25 confirmed type 2 diabetes risk variants and birthweight in individuals from the Danish Inter99 population and in meta-analyses including Inter99 data and reported studies.

Methods: Midwife records from the Danish State Archives provided information on mother's age and parity, as well as birthweight, length at birth and prematurity of the newborn in 4,744 individuals of the population-based Inter99 study.

Changes in short- and long-term cardiovascular risk of incident diabetes and incident myocardial infarction--a nationwide study.

Aims/hypothesis: We assessed secular trends of cardiovascular outcomes following first diagnosis of myocardial infarction (MI) or diabetes in an unselected population.

Methods: All Danish residents aged > or = 30 years without prior diabetes or MI were identified by individual-level linkage of nationwide registers. Individuals hospitalised with MI or claiming a first-time prescription for a glucose-lowering medication (GLM) during the period from 1997 to 2006 were included.

Deoxyribonucleic acid methylation and gene expression of PPARGC1A in human muscle is influenced by high-fat overfeeding in a birth-weight-dependent manner.

Context: Low birth weight (LBW) and unhealthy diets are risk factors of metabolic disease including type 2 diabetes (T2D). Genetic, nongenetic, and epigenetic data propose a role of the key metabolic regulator peroxisome proliferator-activated receptor gamma, coactivator 1alpha (PPARGC1A) in the development of T2D.

Objective: Our objective was to investigate gene expression and DNA methylation of PPARGC1A and coregulated oxidative phosphorylation (OXPHOS) genes in LBW and normal birth weight (NBW) subjects during control and high-fat diets.

Sex differences in glucose levels: a consequence of physiology or methodological convenience? The Inter99 study.

Aims/hypothesis: We aimed to examine whether sex differences in fasting plasma glucose (FPG), 2 h post-OGTT plasma glucose (2hPG) and HbA(1c) could be explained by differences in body size and/or body composition between men and women in a general non-diabetic Danish population. Moreover, we aimed to study to what degree the newly suggested high-risk HbA(1c) criteria overlapped with the current OGTT-based criteria of glucose intolerance.

Methods: We used cross-sectional data from 6,006 non-diabetic men and women.

Effect of 10 days of bedrest on metabolic and vascular insulin action: a study in individuals at risk for type 2 diabetes.

Physical inactivity is a known risk factor for type 2 diabetes. We studied whole body and forearm insulin sensitivity in subjects at increased risk for type 2 diabetes [persons with low birth weight (LBW group; n = 20) and first-degree relatives to type 2 diabetic patients (FDR group; n = 13)] as well as a control (CON) group (n = 20) matched for body mass index, age, and physical activity levels before and after 10 days of bedrest. Subjects were studied by hyperinsulinemic isoglycemic clamp combined with arterial and deep venous catheterization of the forearm.

The T-allele of TCF7L2 rs7903146 associates with a reduced compensation of insulin secretion for insulin resistance induced by 9 days of bed rest.

Objective: The aim of this study was to determine whether the type 2 diabetes-associated T-allele of transcription factor 7-like 2 (TCF7L2) rs7903146 associates with impaired insulin secretion to compensate for insulin resistance induced by bed rest.

Research Design And Methods: A total of 38 healthy young Caucasian men were studied before and after bed rest using the hyperinsulinemic-euglycemic clamp technique combined with indirect calorimetry preceded by an intravenous glucose tolerance test. The TCF7L2 rs7903146 was genotyped using allelic discrimination performed with an ABI 7900 system.

Impact of rs361072 in the phosphoinositide 3-kinase p110beta gene on whole-body glucose metabolism and subunit protein expression in skeletal muscle.

Objective: Phosphoinositide 3-kinase (PI3K) is a major effector in insulin signaling. rs361072, located in the promoter of the gene (PIK3CB) for the p110beta subunit, has previously been found to be associated with homeostasis model assessment for insulin resistance (HOMA-IR) in obese subjects. The aim was to investigate the influence of rs361072 on in vivo glucose metabolism, skeletal muscle PI3K subunit protein levels, and type 2 diabetes.

The disposition index: adjustment for peripheral vs. hepatic insulin sensitivity?

The assessment of pancreatic beta cell function in humans is challenging because of a complex interplay between insulin secretion, insulin sensitivity and hepatic insulin extraction. Simplified, the relationship between insulin secretion and insulin sensitivity can be described by an approximate hyperbola with the product of the two variables being constant for individuals with the same degree of glucose tolerance (the disposition index). Strengths and limitations of the disposition index have been widely debated in the literature.

Functional variant disrupts insulin induction of USF1: mechanism for USF1-associated dyslipidemias.

Background: The upstream transcription factor 1 (USF1) gene is associated with familial combined hyperlipidemia, the most common genetic dyslipidemia in humans, as well as with various dyslipidemic changes in numerous other studies. Typical of complex disease-associated genes, neither the explicit mutations have been described nor the functional consequences for risk allele carriers been reported at the cellular or tissue level.

Methods And Results: In this study, we aimed at describing the molecular mechanism through which the strongest associating intronic single-nucleotide polymorphism variant in USF1 is involved in the development of dyslipidemia.

Desaturation of excess intramyocellular triacylglycerol in obesity: implications for glycemic control.

Objective: Excess intramyocellular triacylglycerol (IMTG), found especially in obese women, is slowly metabolized and, therefore, prone to longer exposure to intracellular desaturases. Accordingly, it was hypothesized that IMTG content correlates inversely with IMTG fatty acid (FA) saturation in sedentary subjects. In addition, it was validated if IMTG palmitic acid is associated with insulin resistance as suggested earlier.

Increased rate of whole body lipolysis before and after 9 days of bed rest in healthy young men born with low birth weight.

Individuals born with low birth weight (LBW) are at risk of developing type 2 diabetes mellitus (T2D), which may be precipitated by physical inactivity. Twenty-two LBW subjects and twenty-three controls were studied before and after bed rest by the hyperinsulinemic euglycemic clamp combined with indirect calorimetry and infusion of stable isotope tracers and preceded by an intravenous glucose tolerance test. LBW subjects had a similar body mass index but elevated abdominal obesity compared with controls.

Adding liraglutide to oral antidiabetic drug therapy: onset of treatment effects over time.

Aim: To investigate the onset of treatment effects over time observed for liraglutide in combination with oral antidiabetic drugs (OADs).

Methods: This analysis included patients from three phase 3, 26-week, randomised, double-blind, parallel-group trials. Prior to randomisation, patients underwent a run-in and titration period with metformin (Liraglutide Effect and Action in Diabetes-2, LEAD-2), glimepiride (LEAD-1) or metformin plus rosiglitazone (LEAD-4).

Combining insulin with metformin or an insulin secretagogue in non-obese patients with type 2 diabetes: 12 month, randomised, double blind trial.

Objectives: To study the effect of insulin treatment in combination with metformin or an insulin secretagogue, repaglinide, on glycaemic regulation in non-obese patients with type 2 diabetes.

Design: Randomised, double blind, double dummy, parallel trial.

Setting: Secondary care in Denmark between 2003 and 2006.