This is a natural history, hypothesis-generating protocol designed to improve detection of diabetes and cardiometabolic disease in African descent populations. If our protocol generates new diagnostic paradigms, our data can be used for power analyses for new protocols and validations studies conducted in both the United States and Africa. As our work continues with traditional risk factors such as triglyceride (TG), insulin resistance and body fat content and distribution, we are actively searching for better diagnostic markers so the chances for early intervention and improved outcomes African descent populations are achieved. Currently we are focusing on the identification in African descent populations: (1) best screening tests to detect pre-diabetes and diabetes; (2) the effect of SCT, HbC trait and G6PD deficiency on A1Cs performance of a diagnostic test for both prediabetes and diabetes; (3) the psychosocial determinants of diabetes and heart disease; (4) Influence of BMI on the balance between Insulin Resistance and Beta-cell Failure Best screening tests to detect prediabetes and diabetes in Africans. As A1C has a diagnostic sensitivity for the detection of abnormal glucose tolerance of <50% we have focused on alternative diagnostic tests such as: glycated albumin, fructosamine and fasting plasma glucose alone or in combination with A1C. In our recent publication in Diabetes Care, we demonstrated that A1C combined with glycated albumin markedly improved detection of abnormal glucose tolerance in nonobese Africans. Interestingly, the combination was ineffective in obese Africans. This has great implications for understanding the diversity in African descent populations. For African Americans, diabetes is more common than the obese. But emerging data demonstrates in Africans suggests that diabetes is more common in the nonobese and that is the group who would specifically benefit from the combined tests. In addition, we performed duplicate testing of glycated albumin and fructosamine (meaning same tests 1 week apart). We observed that diagnoses made by glycated albumin were highly reproducible but this was not the care for fructosamine. Therefore, allocation of resources could be improved by investing in glycated albumin rather than fructosamine. Effect of HbC trait and G6PD deficiency on the diagnostic efficacy of A1C We have previously shown that Sickle Cell Trait does not impact the diagnostic efficacy of A1C. However, there is no published data on the effect of HbC trait on the diagnostic efficacy of A1C. This is because most studies either exclude people with HbC trait or combine them with SCT. So far in our study we have 14 people with HbC trait, 50 percent of whom had either prediabetes or diabetes. In this small sample the diagnostic sensitivity of A1C was 0% and the specificity was 100%. We need to continue to recruit participants. If this finding holds, areas of the world where the prevalence of both diabetes and HbC trait are high, will need to develop diagnostic alternatives to A1C. In the last year, we did not identify anyone with HbC trait but did find one person who was homozygous and had HbCC. He was very athletic and healthy with normal glucose tolerance. But his A1C was spuriously reported by the laboratory as >15%. This re-enforces the need to find proper diagnostic tests for diabetes in the presence of hemoglobin C. Genetic studies suggest that G6PD deficiency may be associated with normal A1C levels even in the presence of hyperglycemia. This finding needs to be tested clinically. Therefore, we obtained permission to assay for G6PD deficiency to test this. Our current sample suggests this may be true but continued consecutive testing of African immigrants should provide a more definitive answer. Psychosocial determinants of diabetes and heart disease in African immigrants Metabolic stress can be measured by allostatic load score equations. As TG levels are low in African descent populations despite obesity, and insulin resistance, we have discovered that the allostatic load score which are most effective in Africans include HDL levels but exclude TG levels. In the last year working with the Africans in America cohort, we have found cardiometabolic health and stress are worse in Africans if they came to the United States as a refugee, emigrated after age 30 years, have three or more children, or lived in the United States for greater than 10 years. We are now examining the cardiometabolic effects in adulthood of coming to the United States as child versus arriving in the United States as adult. The Influence of BMI on the balance between Insulin Resistance and Beta-cell Failure in African Descent Populations We are working on identifying if differences exist in the physiologic reasons for the development of abnormal glucose tolerance in African descent populations. In African Americans, the etiology may be obesity and insulin resistance. In African immigrants the reason for abnormal glucose tolerance may be beta-cell failure without obesity or insulin resistance. If further recruitment and analyses confirms this, then diagnostic and treatment paradigms will need to be modified according to the population of origin. Overall, there is great public health significance to our work. Our research should lead to results which improve screening paradigms for diabetes, convert undiagnosed diabetes into diagnosed diabetes and decrease the rate of complications in African descent populations worldwide.