Type 2 Diabetes Mellitus (T2DM) is a complex metabolic disease characterized by increased blood glucose levels in response to increased insulin resistance in muscle and fat cells and/or early phase insulin secretion. One-third of those afflicted with the disease go undiagnosed which may progress to complications that include retinopathy, neuropathy, nephropathy, and amputation of limbs. Diabetes is a major risk factor for cardiovascular disease, accounting for 65% of type 2 diabetics' mortality. A number of genes have been associated with development of T2DM, including calpain-10, adiponectin, and plasma cell glycoprotein 1 (PC-1). A candidate gene approach using four single nucleotide polymorphisms (SNPs) of the calpain-10 gene (SNP-44, -43, -19, -63), two SNPs of the adiponectin gene (SNP-45, -276), and SNP-121 of the PC-1 gene was investigated for genetic associations between and among genotype and haplotype association with T2DM and its risk phenotypes, obesity, metabolic syndrome, hyperglycemia, and insulin resistance in a cohort of 344 African-American and 295 Euro-Caucasian girls. Beginning at age 9-10 years (mean age 10.0), measurements of height, weight, and waist circumference, and blood pressure were assessed at 15 annual visits with measurement of insulin and glucose after an overnight fast at visits 1, 7, and 10-15, and for measures of lipids at visits 1, 3, 5, 7, 10, and 15. Early predictors for risk factors (metabolic syndrome, obesity, and insulin resistance) of T2DM are insulin and glucose levels, HOMA IR, waist circumference, and body mass index (BMI) in white girls. In black girls, only waist circumference was an early predictor for risk factor phenotypes of hyperglycemia, obesity, and insulin resistance but not for metabolic syndrome at Visit 15. Early waist circumference (Visit 2) and BMI percentile (Visit 1) predicted (p=0.0208 and p=0.0197, respectively) the disease outcome, T2DM, in black girls at Visit 15. At Visit 15 (mean age 23.7 years), there were two (1%) white girls and seven (3%) black girls with T2DM. For genotypic comparisons, adiponectin SNP-45 (TT vs. GG, OR 123.0, CI 3.4-6207.2) in white girls showed promise although there were too few cases and too few girls of both races with the G/G genotype for proper statistical analysis with T2DM as the outcome variable. Logistic regression analysis of risk phenotypes was associated with a 3-fold increase in risk for calapain-10 SNP-44 (TT genotype) and adiponectin SNP-276 (GG genotype) for obesity in white girls while nearly 5-fold increase in risk of insulin resistance of the PC-1 SNP-121 (KK vs QQ) polymorphism; insulin levels were also predictive between the two polymorphisms. For white girls, the adiponectin SNP-276 gene (GG vs GT genotype) was predictive for insulin, waist circumference, BMI. Logistic regression analysis of calpain-10 haplotypes 1111 and 1121 (SNP-44 -43, -19, and -63) were significantly associated for both white and black girls for the obesity phenotype. The calpain-10 haplotypes 1111 and 1121 were also significant for the outcome variables, waist circumference and BMI in white girls. Adiponectin gene haplotypes were not significant for any of the five phenotypes for either white or black girls.