Role of Established Type 2 Diabetes–Susceptibility Genetic Variants in a High Prevalence American Indian Population

Several single nucleotide polymorphisms (SNPs) associated with type 2 diabetes mellitus (T2DM) have been identified, but there is little information on their role in populations at high risk for T2DM. We genotyped SNPs at 63 T2DM loci in 3,421 individuals from a high-risk American Indian population. Nominally significant (P < 0.05) associations were observed at nine SNPs in a direction consistent with the established association. A genetic risk score derived from all loci was strongly associated with T2DM (odds ratio 1.05 per risk allele, P = 6.2 × 10⁻⁶) and, in 292 nondiabetic individuals, with lower insulin secretion (by 4% per copy, P = 4.1 × 10⁻⁶). Genetic distances between American Indians and HapMap populations at T2DM markers did not differ significantly from genomic expectations. Analysis of U.S. national survey data suggested that 66% of the difference in T2DM prevalence between African Americans and European Americans, but none of the difference between American Indians and European Americans, was attributable to allele frequency differences at these loci. These analyses suggest that, in general, established T2DM loci influence T2DM in American Indians and that risk is mediated in part through an effect on insulin secretion. However, differences in allele frequencies do not account for the high population prevalence of T2DM.     

Technique for fabricating a prosthetic tooth on a removable partial denture framework

When removable partial dentures are fabricated, a custom-made tooth may be needed to fill a space too small or irregularly shaped to allow the use of a prefabricated prosthetic tooth. This article describes a simple technique in which visible light-polymerized composite is used to custom build a prosthetic tooth that is both esthetic and durable.     

Chronic toxicity of thiram in rats

The results of a chronic 2-years experiment of thiram on Wistar-rats are given. On the basis of clinical, biochemical and pathomorphological investigations a Noel of 5 mg/kg bw were proposed.     

An autosomal genomic scan for loci linked to plasma leptin concentration in Pima Indians

OBJECTIVE: To identify chromosomal regions linked to plasma leptin concentrations. DESIGN: Autosomal genome-wide scan, including 516 microsatellite markers. Sib-pair (Haseman-Elston) and variance components methods were used to assess genetic linkage. SUBJECTS: 770 Pima Indians comprising 239 nuclear families (for a total of 1199 sibling-pairs). MEASUREMENTS: Plasma leptin concentrations and body mass index (BMI), adjusted for age and sex. RESULTS: The strongest evidence for linkage with plasma leptin concentration was on chromosome 6p logarithm of odds (LOD) = 2.1 by variance components analysis). There was no evidence for linkage to BMI in this region. Additional regions with marginal evidence for linkage to plasma leptin concentration (LOD > or =1.0) were detected on chromosomes 3, 11, 13, 15 and 16. CONCLUSIONS: The results suggest that a locus on chromosome 6p influences plasma leptin concentrations. Replication studies are needed to exclude the possibility that linkage has been falsely detected.     

Differential expression of matrix metalloproteinase 3 (MMP3) in preadipocytes/stromal vascular cells from nonobese nondiabetic versus obese nondiabetic Pima Indians

Prior microarray studies comparing global gene expression patterns in preadipocytes/stromal vascular cells isolated from nonobese nondiabetic versus obese nondiabetic Pima Indians showed that matrix metalloproteinase 9 (MMP9) is upregulated in obese subjects. The current study targeted analysis of nine additional MMP genes that cluster to a region on chromosome 11q22 that is linked to BMI and percent body fat. Differential-display PCR showed that MMP3 is downregulated in preadipocytes/stromal vascular cells from obese subjects, and real-time PCR showed that MMP3 expression levels are negatively correlated with percent body fat. To determine whether variants within MMP3 are responsible for its altered expression, MMP3 was sequenced, and seven representative variants were genotyped in 1,037 Pima subjects for association analyses. Two variants were associated with both BMI and type 2 diabetes, and two additional variants were associated with type 2 diabetes alone; however, none of these variants were associated with MMP3 expression levels. We propose that the MMP3 pathway is altered in human obesity, but this alteration may be the result of a combination of genetic variation within the MMP3 locus itself, as well as variation in additional factors, either primary or secondary to obesity, that regulate expression of the MMP3 gene.     

Gestational glucose tolerance and risk of type 2 diabetes in young Pima Indian offspring

The in utero environment is a powerful risk factor for type 2 diabetes in offspring, but little is known about the risk conveyed by nondiabetic gestational glucose levels. This issue was explored in 911 nondiabetic Pima Indian mothers and 1,436 of their children. Associations were assessed in multivariate models between maternal third trimester glucose tolerance and indexes of body composition and glycemic control in their children. At parturition, the mothers' ages ranged from 14 to 43 years. Offspring were studied at age 0-39 years. An SD (1.3 mmol/l) of maternal glucose was associated with 56 g higher birth weight (P = 0.0002). This effect persisted when only offspring of normal glucose tolerant mothers were examined (57 g, P < 0.0001). In Cox proportional hazards models, the adjusted hazard rate ratio for offspring risk of diabetes per SD maternal glucose was 1.6 (95% CI 1.3-2.0, P < 0.0001). When only offspring of normal glucose tolerant mothers were examined, the risk was reduced but remained significant (1.3 [1.04-1.71], P = 0.026). In conclusion, maternal glycemia during pregnancy is associated with increased birth weight and risk of diabetes in Pima Indian offspring, even when mothers are normal glucose tolerant during pregnancy. Thus, prevention of offspring type 2 diabetes may require strategies that focus on improving gestational glucose tolerance even within the normal range.