Role of the FOXC2 -512C>T polymorphism in type 2 diabetes: possible association with the dysmetabolic syndrome.

OBJECTIVE: Overexpression of the human transcription factor FOXC2 gene ( FOXC2) protects against insulin resistance in mice and a common FOXC2 polymorphism (-512C > T) has been suggested to be associated with insulin resistance in humans. Here, we addressed the potential role for FOXC2 as a candidate gene for type 2 diabetes and associated phenotypes. MATERIALS AND METHODS: A case-control study was performed in 390 type 2 diabetic patients and 307 control subjects. The number of patients was increased to a total of 768 subjects for further study of phenotypic differences relating to the dysmetabolic syndrome relative to genetic variation. The FOXC2 -512C > T polymorphism was genotyped by a restriction fragment length polymorphism PCR assay. RESULTS: FOXC2 -512C > T allele and genotype distribution did not differ between patients with type 2 diabetes and control subjects, but the C/C genotype was associated with increased body mass index (BMI, kg/m(2)) (P-a = 0.03) among type 2 diabetic patients. The FOXC2 -512C > T polymorphism was a significant independent predictor of BMI (P = 0.001) in a multiple regression model including age, gender and affection status. We found no significant association with type 2 diabetes-related metabolic parameters but that the C-allele (P = 0.01) and C/C and C/T genotypes (P = 0.03) were significantly over-represented in type 2 diabetic males with a concomitant diagnosis of dysmetabolic syndrome. CONCLUSION: We conclude that FOXC2 is associated with obesity and metabolic deterioration but does not contribute to an increased risk for type 2 diabetes

Cost-effectiveness of insulin detemir compared with NPH insulin in people with type 2 diabetes in Denmark, Finland, Norway, and Sweden.

Abstract Objective: To assess the cost-effectiveness of insulin detemir compared with Neutral Protamine Hagedorn (NPH) insulin when initiating insulin treatment in people with type 2 diabetes mellitus (T2DM) in Denmark, Finland, Norway, and Sweden. Methods: Efficacy and safety data were derived from a 20-week multi-centre randomized controlled head-to-head clinical trial comparing insulin detemir and NPH insulin in insulin naïve people with T2DM, and short-term (1-year) cost effectiveness analyses were performed. As no significant differences in HbA(1c) were observed between the two treatment arms, the model was based on significant differences in favour of insulin detemir in frequency of hypoglycaemia (Rate-Ratio = 0.52; CI = 0.44-0.61) and weight gain (Δ = 0.9 kg). Model outcomes were measured in Quality Adjusted Life Years (QALYs) using published utility estimates. Acquisition costs for insulin and direct healthcare costs associated with non-severe hypoglycaemic events were obtained from National Health Service public sources. One-way and probabilistic sensitivity analyses were performed. Results: Based on lower incidence of non-severe hypoglycaemic events and less weight gain, the QALY gain from initiating treatment with insulin detemir compared with NPH insulin was 0.01 per patient per year. Incremental cost-effectiveness ratios for the individual countries were: Denmark, Danish Kroner 170,852 (€22,933); Finland, €28,349; Norway, Norwegian Kroner 169,789 (€21,768); and Sweden, Swedish Krona 226,622 (€25,097) per QALY gained. Possible limitations of the study are that data on hypoglycaemia and relative weight benefits from a clinical trial were combined with hypoglycaemia incidence data from observational studies. These populations may have slightly different patient characteristics. Conclusions: The lower risk of non-severe hypoglycaemia and less weight gain associated with using insulin detemir compared with NPH insulin when initiating insulin treatment in insulin naïve patients with type 2 diabetes provide economic benefits in the short-term. Based on cost/QALY threshold values, this represents good value for money in the Nordic countries. Using a short-term modelling approach may be conservative, as reduced frequency of hypoglycaemia and less weight gain may also have positive long-term health-related implications

Higher health literacy is associated with better glycemic control in adults with type 1 diabetes:a cohort study among 1399 Danes

Aim: Self-management of diabetes is influenced by a range of factors including the ability to access, understand, appraise, and use of health information in everyday life, which can collectively be called health literacy. We investigated associations between nine domains of health literacy and HbA1c level in people with type 1 diabetes.Methods: A cross-sectional study was conducted with 1399 people with type 1 diabetes attending a Danish specialist diabetes clinic. Health literacy was assessed using the nine-domain Health Literacy Questionnaire. The association between health literacy and HbA1c was analyzed using linear regression with adjustment for age, sex, educational attainment and diabetes duration. Results: Of the 1399 participants, 50% were women, mean age was 54 years, and mean HbA1c was 61 mmol/mol (7.8%). Higher health literacy scores were associated with lower HbA1c levels across eight of nine health literacy domains. This association remained significant after adjusting for educational attainment. Among the domains, \u27Actively managing my health\u27 had the strongest impact on HbA1c. This was in turn predicted by \u27Appraising health information\u27, \u27Having sufficient information to manage health\u27, and \u27Social support for health\u27. Conclusions: Higher health literacy levels are associated with lower HbA1c regardless of educational background. This study highlights the importance of healthcare provision to respond to the health literacy levels of people with diabetes and to the possible need to provide program designed to enhance health literacy

Amino Acid Signatures to Evaluate the Beneficial Effects of Weight Loss

Aims. We investigated the relationship between circulating amino acid levels and obesity; to what extent weight loss followed by weight maintenance can correct amino acid abnormalities; and whether amino acids are related to weight loss. Methods:. Amino acids associated with waist circumference (WC) and BMI were studied in 804 participants from the Malmö Diet and Cancer Cardiovascular Cohort (MDC-CC). Changes in amino acid levels were analyzed after weight loss and weight maintenance in 12 obese subjects and evaluated in a replication cohort (n = 83). Results:. Out of the eight identified BMI-associated amino acids from the MDC-CC, alanine, isoleucine, tyrosine, phenylalanine, and glutamate decreased after weight loss, while asparagine increased after weight maintenance. These changes were validated in the replication cohort. Scores that were constructed based on obesity-associated amino acids and known risk factors decreased in the ≥10% weight loss group with an associated change in BMI (R2 = 0.16–0.22, p < 0.002), whereas the scores increased in the <10% weight loss group (p < 0.0004). Conclusions:. Weight loss followed by weight maintenance leads to differential changes in amino acid levels associated with obesity. Treatment modifiable scores based on epidemiological and interventional data may be used to evaluate the potential metabolic benefit of weight loss

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Genetic Variance in the Adiponutrin Gene Family and Childhood Obesity

AIM: The adiponutrin gene family consists of five genes (PNPLA1-5) coding for proteins with both lipolytic and lipogenic properties. PNPLA3 has previously been associated with adult obesity. Here we investigated the possible association between genetic variants in these genes and childhood and adolescent obesity. METHODS/RESULTS: Polymorphisms in the five genes of the adiponutrin gene family were selected and genotyped using the Sequenom platform in a childhood and adolescent obesity case-control study. Six variants in PNPLA1 showed association with obesity (rs9380559, rs12212459, rs1467912, rs4713951, rs10947600, and rs12199580, p0.05). When analyzing these SNPs in relation to phenotypes, two SNPs in the PNPLA3 gene showed association with insulin sensitivity (rs12483959: beta = -0.053, p = 0.016, and rs2072907: beta = -0.049, p = 0.024). No associations were seen for PNPLA2, PNPLA4, and PNPLA5. CONCLUSIONS: Genetic variation in the adiponutrin gene family does not seem to contribute strongly to obesity in children and adolescents. PNPLA1 exhibited a modest effect on obesity and PNPLA3 on insulin sensitivity. These data, however, require confirmation in other cohorts and ethnic groups