A gene is considered a candidate gene for type 2 diabetes in Pima Indians if 1) it has a known physiological function in a pathway relevant to type 2 diabetes/obesity or 2) it is associated with diabetes/obesity in another human population or in an animal model. In the past year we have directly sequenced and genotyped all detected variants in more than 30 physiologic candidate genes for associations with BMI or diabetes. We have found Sim1 to be the first major susceptibility gene for obesity in the Pima Indians, where variation in this gene accounts for approximately 16 lbs. We have also studied the FTO gene, which has been reproducibly associated with BMI in multiple populations. This gene shows a similar association with BMI in Pima Indians. In contrast, we have found that genes which have been well-replicated for their association with type 2 diabetes in other ethnic groups (TCF7L2, CDKAL1, SLC30A8, HHEX, EXT2, IGF2BP2 and CDKN2B) do not have a have an impact on type 2 diabetes in the Pima Indians, although variation in some of these genes appear to influence insulin secretion among Pima Indians with normal glucose tolerance.