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. Candidate genes analyzed in the past year include: ADRB2, CART, CB1 receptor, ENPP1, GRL, H19, MMP3, DIO2, KLF-2, KLF-7, KLF-15, KLF-11, PTPN1, SIM1, and THR. Poymorphisms were identified in all of these genes and analyzed for association with type 2 diabetes, obesity, or metabolic traits that predict these diseases. Among these genes, the most promising results were obtained with KLF-11 and SIM1. A Q62R variant in KLF-11 was reported to be associated with type 2 diabetes among the French. Genotyping of this variant in Pima Indians showed that it is also associated with type 2 diabetes in this Native American population, using both a population-based and a within family, association anaysis. Among normal glcusoe tolerant Pima Indians, this variant is also associated with insulin secretion and plasma glucose levels in response to an oral glucose tolerance test. SIM1 is the human homolog of the Drosophila single-minded (sim) gene that is a master regulator of fruit fly neurogenesis. The sim protein is a transcription factor that is essential for formation of supraoptic and paraventricular (PVN) nuclei of the hypothalamus. PVN is important for regulation of body weight. PVN neurons express the melanocortin-4 receptor and are targets of alpha-melanocyte-stimulating hormone, which inhibits food intake. SIM1 heterozygous (+/-) mice develop early-onset obesity, with hyperinsulinemia and hyperleptinemia. Sequencing of the SIM1 gene in a morbidly obese case/control group of Pima Indians identified several variants that are associated with morbid obesity. Philippe Froguel has also recently identified variants in this gene that are associated with obesity among the French. Our laboratories plan to collaborate on this project to try to determine the functional variant(s) in this gene.