Effects of Metformin and Weight Loss on Serum Alanine Aminotransferase Activity in the Diabetes Prevention Program

Nonalcoholic fatty liver disease (NAFLD) is associated with obesity, insulin resistance, and impaired glucose tolerance. We investigated whether metformin or changes in metabolic measurements (weight, fasting plasma glucose (FPG), or fasting insulin (FI)) improved serum alanine aminotransferase (ALT) activity, as a marker for NAFLD, in the Diabetes Prevention Program (DPP). From 1996 to 1999, 2,153 participants without marked elevations of serum ALT at baseline were randomized (1,081 to placebo, 1,072 to metformin) and treated for an average of 3.2 years. ALT increased during the first 2 years of the study, and was slightly but significantly lower in the participants randomized to metformin. In regression models adjusted for sex, baseline age, FPG, and FI, these differences remained significant, but disappeared after adjustment for weight, FPG, and FI changes at each examination. The 3‐year cumulative incidence for development of abnormal ALT concentrations was not significantly different ((mean ± s.e.) 21.4 ± 1.4% and 24.6 ± 1.4%, P = 0.11) in the metformin vs. placebo groups but was lower in individuals in both groups that lost more weight by the end of year 1 (metformin: 19.4 ± 2.4% vs. 27.5 ± 3.7%, for highest vs. lowest quartile of weight loss; placebo: 18.7 ± 3.4% vs. 28.8 ± 2.6%). Over 3 years of follow‐up in persons at high risk for development of diabetes, serum ALT was consistently lower in those treated with metformin compared with placebo. This effect was mediated by weight loss, indicating that the effects of metformin therapy on ALT is via its effects on weight.     

Single Nucleotide Polymorphisms in the Wnt and BMP Pathways and Colorectal Cancer Risk in a Spanish Cohort

Background

Colorectal cancer (CRC) is considered a complex disease, and thus the majority of the genetic susceptibility is thought to lie in the form of low-penetrance variants following a polygenic model of inheritance. Candidate-gene studies have so far been one of the basic approaches taken to identify these susceptibility variants. The consistent involvement of some signaling routes in carcinogenesis provided support for pathway-based studies as a natural strategy to select genes that could potentially harbour new susceptibility loci.

Methodology/Principal Findings

We selected two main carcinogenesis-related pathways: Wnt and BMP, in order to screen the implicated genes for new risk variants. We then conducted a case-control association study in 933 CRC cases and 969 controls based on coding and regulatory SNPs. We also included rs4444235 and rs9929218, which did not fulfill our selection criteria but belonged to two genes in the BMP pathway and had consistently been linked to CRC in previous studies. Neither allelic, nor genotypic or haplotypic analyses showed any signs of association between the 37 screened variants and CRC risk. Adjustments for sex and age, and stratified analysis between sporadic and control groups did not yield any positive results either.

Conclusions/Significance

Despite the relevance of both pathways in the pathogenesis of the disease, and the fact that this is indeed the first study that considers these pathways as a candidate-gene selection approach, our study does not present any evidence of the presence of low-penetrance variants for the selected markers in any of the considered genes in our cohort.     

An oral health care guideline for institutionalised older people

Institutionalized older people are prone to oral health problems and their negative impact due to frailty, disabilities, multi-morbidity, and multiple medication use. Until recently, no evidence-based oral health care guideline for institutionalized older people has been available. For that reason, the Dutch Association of Nursing Home Physicians developed the Oral health care Guideline for Older people in Long-term care Institutions (OGOLI), meeting the requirements of the AGREE instrument for assessing a guideline's quality. This short report presents the keynotes and the content of the Oral health care Guideline. Most recommendations are based on expert opinions. Only 4 recommendations (education, pneumonia, use of an electric toothbrush, and fluoride rinsing in case of a sudden increase of oral plaque amount) are based on evidence level A2 conclusions. This emphasizes the need for further research on oral health of institutionalized older people.     

QTL analysis of malting quality in barley based on the doubled-haploid progeny of two elite North American varieties representing different germplasm groups

Characterization of the determinants of economically important phenotypes showing complex inheritance should lead to the more effective use of genetic resources. This study was conducted to determine the number, genome location and effects of QTLs determining malting quality in the two North American barley quality standards. Using a doubled-haploid population of 140 lines from the cross of Harrington×Morex, malting quality phenotype data sets from eight environments, and a 107-marker linkage map, QTL analyses were performed using simple interval mapping and simplified composite interval mapping procedures. Seventeen QTLs were associated with seven grain and malting quality traits (percentage of plump kernels, test weight, grain protein percentage, soluble/total protein ratio, α-amylase activity, diastatic power and malt-extract percentage). QTLs for multiple traits were coincident. The loci controlling inflorescence type [vrs1 on chromosome 2(2H) and int-c on chromosome 4(4H)] were coincident with QTLs affecting all traits except malt-extract percentage. The largest effect QTLs, for the percentage of plump kernels, test weight protein percentage, S/T ratio and diastatic power, were coincident with the vrs1 locus. QTL analyses were conducted separately for each sub-population (six-rowed and two-rowed). Eleven new QTLs were detected in the subpopulations. There were significant interactions between the vrs1 and int-c loci for grain-protein percentage and S/T protein ratio. Results suggest that this mating of two different germplasm groups caused a disruption of the balance of traits. Information on the number, position and effects of QTLs determining components of malting quality may be useful for maintaining specific allele configurations that determine target quality profiles. Received: 28 May 1999 / Accepted: 9 November 1999     

Association of N-Terminal Pro-Brain Natriuretic Peptide with Cognitive Function and Depression in Elderly People with Type 2 Diabetes

Background

Type 2 diabetes mellitus is associated with risk of congestive heart failure (CHF), cognitive dysfunction and depression. CHF itself is linked both to poor cognition and depression. The ventricular N-terminal pro-brain natriuretic peptide (NT-proBNP) is a marker of CHF, suggesting potential as a marker for cognitive impairment and/or depression. This was tested in the Edinburgh Type 2 Diabetes Study (ET2DS).

Methodology and Principal Findings

Cross-sectional analysis of 1066 men and women aged 60–75 with type 2 diabetes. Results from seven neuropsychological tests were combined in a standardised general cognitive ability factor, ‘g’. A vocabulary-based test estimated pre-morbid cognitive ability. The Hospital Anxiety and Depression Scale (HADS) assessed possible depression. After adjustment for age and sex, raised plasma NT-proBNP was weakly associated with lower ‘g’ and higher depression scores (ß −0.09, 95% CI −0.13 to −0.03, p = 0.004 and ß 0.08, 95% CI 0.04 to 0.12, p<0.001, respectively). Comparing extreme quintiles of NT-proBNP, subjects in the highest quintile were more likely to have reduced cognitive ability (within the lowest tertile of ‘g’) and ‘possible’ depression (HADS depression ≥8) (OR 1.80; 95% CI: 1.20, 2.70; p = 0.005 and OR 2.18; 95% CI: 1.28, 3.71; p = 0.004, respectively). Associations persisted when pre-morbid ability was adjusted for, but as expected were no longer statistically significant following the adjustment for diabetes-related and vascular co-variates (β −0.02, 95% CI −0.07 to 0.03, p>0.05 for ‘g’; β 0.03, 95% CI −0.02 to 0.07, p>0.05 for depression scores).

Conclusion

Raised plasma NT-proBNP was weakly but statistically significantly associated with poorer cognitive function and depression. The prospective phases of the ET2DS will help determine whether or not NT-proBNP can be considered a risk marker for subsequent cognitive impairment and incident depression and whether it provides additional information over and above traditional risk factors for these conditions.