The potential risks and benefits, the profile of adverse events, and the costs of these three drugs should all be considered to help inform the choice of pharmacotherapy for patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00279045 [ClinicalTrials.gov].).

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The Eye Diseases Prevalence Research Group* Objective: To determine the prevalence of diabetic retinopathy among adults 40 years and older in the United States. Methods: Pooled analysis of data from 8 populationbased eye surveys was used to estimate the prevalence, among persons with diabetes mellitus (DM), of retinopathy and of vision-threatening retinopathy-defined as proliferative or severe nonproliferative retinopathy and/or macular edema. Within strata of age, race/ethnicity, and gender, US prevalence rates were estimated by multiplying these values by the prevalence of DM reported in the 1999 National Health Interview Survey and the 2000 US Census population. Results: Among an estimated 10.2 million US adults 40 years and older known to have DM, the estimated crude prevalence rates for retinopathy and vision-threatening retinopathy were 40.3% and 8.2%, respectively. The estimated US general population prevalence rates for retinopathy and vision-threatening retinopathy were 3.4% (4.1 million persons) and 0.75% (899000 persons). Future projections suggest that diabetic retinopathy will increase as a public health problem, both with aging of the US population and increasing age-specific prevalence of DM over time. Conclusion: Approximately 4.1 million US adults 40 years and older have diabetic retinopathy; 1 of every 12 persons with DM in this age group has advanced, visionthreatening retinopathy.

OBJECTIVE -To prospectively investigate predictors of the incident metabolic syndrome in nondiabetic adults. RESEARCH DESIGN AND METHODS -This analysis included 714 white, black, andHispanic participants in the Insulin Resistance Atherosclerosis Study (IRAS) who were free of the metabolic syndrome at baseline; 139 of these developed the metabolic syndrome in the subsequent 5 years. We examined measures of glucose (fasting and 2 h), insulin (fasting and 2 h, acute insulin response, insulin sensitivity [S i ], and proinsulin), lipids (HDL and triglycerides), blood pressure (systolic and diastolic), waist circumference, and baseline physical activity (total energy expenditure) as predictors of the metabolic syndrome. Logistic regression models were adjusted for age, sex, study site, ethnicity, and impaired glucose tolerance. Signal detection analysis was used to identify the characteristics of the highest risk group. CONCLUSIONS -These findings suggest that obesity may precede the development of other metabolic syndrome components. Interventions that address obesity and reduce waist circumference may reduce the incidence of the metabolic syndrome in nondiabetic adults. RESULTS Diabetes Care 27:788 -793, 2004

The prevalence of non-insulin-dependent diabetes mellitus (NIDDM) is higher in Mexican Americans than in non-Hispanic white Americans, even after adjustment for the former's greater overall and more centralized adiposity. We postulated that this excess risk of NIDDM could be due to resistance to insulin. We performed oral glucose-tolerance tests with measurements of serum insulin concentrations in 225 Mexican Americans and 180 non-Hispanic whites without diabetes as part of the San Antonio Heart Study, a population-based study of risk factors for diabetes. Changes in serum insulin concentrations in response to the glucose challenge were quantified by the area under the serum insulin curve. Overall adiposity was characterized by body-mass index, and regional body-fat distribution by the ratio of subscapular to triceps skinfolds and the ratio of waist to hip circumference. After adjustment for these indicators of adiposity and also for differences in glucose tolerance, Mexican Americans were found to have significantly greater areas under the serum insulin curve than non-Hispanic whites. These data suggest that, like other populations at high risk for NIDDM such as Pima Indians and Micronesians, Mexican Americans have more hyperinsulinemia than can be accounted for by their adiposity.

Increased androgenicity as assessed by increased testosterone and decreased SHBG is strongly associated with an unfavorable body fat distribution and increased glucose and insulin concentrations and insulin resistance in both preand postmenopausal women. However, the temporal direction of the association between androgens and insulin is uncertain. In men, the association between SHBG and insulin levels is much weaker and is probably inverse.

Family-based linkage analysis has been a powerful tool for identification of genes contributing to traits with monogenic patterns of inheritance. These approaches have been of limited utility in identification of genes underlying complex traits. In contrast, searches for common genetic variants associated with complex traits have been highly successful. It is now widely recognized that common variations frequently explain only part of the inter-individual variation in populations. 'Rare' genetic variants have been hypothesized to contribute significantly to phenotypic variation in the population. We have developed a combination of family-based linkage, whole-exome sequencing, direct sequencing and association methods to efficiently identify rare variants of large effect. Key to the successful application of the method was the recognition that only a few families in a sample contribute significantly to a linkage signal. Thus, a search for mutations can be targeted to a small number of families in a chromosome interval restricted to the linkage peak. This approach has been used to identify a rare (1.1%) G45R mutation in the gene encoding adiponectin, ADIPOQ. This variant explains a strong linkage signal (LOD > 8.0) and accounts for ∼17% of the variance in plasma adiponectin levels in a sample of 1240 Hispanic Americans and 63% of the variance in families carrying the mutation. Individuals carrying the G45R mutation have mean adiponectin levels that are 19% of non-carriers. We propose that rare variants may be a common explanation for linkage peaks observed in complex trait genetics. This approach is applicable to a wide range of family studies and has potential to be a discovery tool for identification of novel genes influencing complex traits.

P rotein phosphorylation at tyrosine is a key regulatory event that modulates intracellular signaling pathways involved in signal transduction. Protein tyrosine phosphatase (PTP)-1B is a ubiquitously expressed protein (1) that catalyzes the dephosphorylation of proteins at tyrosyl residues. PTP-1B has been implicated (2-4) in negatively regulating insulin signaling by dephosphorylating the phosphotyrosine residues of the insulin receptor kinase activation segment of the insulin receptor. In mouse models, disruption of the PTPN1 gene resulted in increased insulin sensitivity and resistance to diet-induced obesity (5,6). Further evidence for the role of PTP-1B in insulin sensitivity is seen in knockout mice, in which there was increased phosphorylation of the insulin receptor in liver and muscle tissue (5,6). These observations suggest that PTP-1B plays a role in modulating signal transduction, and defects in PTP-1B expression could lead to insulin resistance.The 10 exons of PTPN1 span Ͼ74 kb of chromosome 20q13.13, with the first intron containing Ͼ50 kb of the sequence. Several investigators (7-9) have searched PTPN1 for DNA sequence variants, e.g., single nucleotide polymorphisms (SNPs). Variation within the coding region of PTPN1 is relatively uncommon. Echwald et al. (7) identified a P387L variant that was found in 2.6% of type 2 diabetic individuals and 1% of healthy control subjects, which showed evidence of impaired in vitro serine phosphorylation of the PTP-1B peptide. Mok et al. (8) identified a 981C3 T polymorphism (5% minor allele frequency) that corresponded to a silent mutation in the PTP-1B protein