This protocol enrolls and compares diabetes and heart disease risk in African-Americans and African immigrants. One hundred ninety-two African Americans and 210 African immigrants have enrolled. The African-Americans cohort is known as TARA for: Triglyceride and Cardiovascular Risk in African-Americans. The African immigrant cohort is known as BART for: Black Africans and Cardiovascular Risk from Triglyceride. The sample of African-Americans participating can be considered representative of the African-American population of the United States because the prevalence of obesity (43%), pre-diabetes (22%) and hypertension (21%) is similar to National Health and Nutrition Examination Survey data. However, there is no national data on the metabolic and diabetic health of African immigrants. To explore risk for diabetes, we are relying not just on fasting glucose but are also performing oral glucose tolerance tests and measuring A1C levels. In performing these tests, we discovered that the prevalence of pre-diabetes and hypertension is twice as high in African men as African-American men. Furthermore, the rate of undiagnosed diabetes was 7% in African men vs. 0% in African American men. In contrast the rate of hypertension, diabetes and pre-diabetes are similar in African women and African American women. Identifying the reasons for why African immigrant men are less metabolically healthy than African-American men has become a major focus of research in this protocol. To improve and then maintain good health in African men, it is essential to understand why pre-diabetes, diabetes and hypertension is occurring in African men even though African men are less obese, more likely to be non-smokers, more likely to be married and have similar educational levels and income as African-American men. We are also working on determining whether A1C which has been recommended by the American Diabetes Association as a diagnostic test for diabetes, can replace the oral glucose tolerance test in people of African descent. A1C is a hemoglobin dependent test and African immigrants have a prevalence of both sickle cell trait and hemoglobin C. Therefore before widespread use of A1C as a diagnostic test for diabetes is instituted in Africa, validation is necessary. When we evaluated A1C in African immigrants, we found that the sensitivity was only 55%. When the Africans are subdivided by presence or absence of variant hemoglobin, the sensitivity of A1C as a diagnostic test fell to 40%. Therefore, our results suggest that A1C is not an ideal test to use to detect diabetes in Africans. We are in the process of examining alternatives such as fructosamine and glycated albumin. The relationship of body size to cardiovascular and diabetes risk is another area of investigation. In our cohorts, the mean body mass index (BMI) in African Americans is 30.6 kg/m2 but only 26.4 kg/m2 in African immigrants. BMI is a mathematical method used to correct weight for height. Due to the broad range of BMI in the participants in this cohort, it is possible to evaluate the relationship of body size to insulin resistance, a major factor in the development of diabetes, and heart disease. We have found in African American men a waist circumference (WC) of 102 cm predicts both insulin resistance and obesity. This is in agreement with the National Cholesterol Education Program values for whites. But in African men, insulin resistance occurs at a much lower WC, specifically 92 cm. This difference between African-American and African immigrant men, suggests that a single WC of risk does not apply to all African descent populations. The situation may be analogous to Asian populations, as the WC of risk is different in Chinese, Japanese and Asian Indians. In African American women we found that a WC of 98 cm predicted both insulin resistance and obesity and this WC of risk was similar in African-American, African immigrant, Black South African and West African women. Therefore among populations of African descent, there may be less variation in women than men. However, as the WC of risk is 88 cm in white women, there is a large race difference and guidelines which screen for disease might be more effective if this was better recognized and understood. Another key component of this program is the development of an index of free fatty acid sensitivity to insulin. Free fatty acids are the building blocks used by the body to build TG. There are 3 fatty acids in each TG particle. In this initiative we are working with mathematicians. The modeling is underway. Due to the multiplicity of hormones that affect free fatty acid levels as well as the wide range of biological variation in free fatty acids, achieving a model of the effect of insulin on free fatty acids is a great challenge. Our preliminary findings are that the rate of clearance of free fatty acids from the circulation is related to insulin concentration rather than insulin resistance. If confirmed this will represent a paradigm change. We currently believe that free fatty acid clearance, high peripheral fat, obesity and low normal TG may be linked by high insulin concentrations. If this is confirmed in future studies we would have made a big step forward in understanding both race and ethnic differences in TG metabolism as well. Elevated TG and low HDL are considered lipid hallmarks of insulin resistance. However while elevated TG is a marker of insulin resistance in whites, we have shown that TG is not a marker of insulin resistance in African Americans. The investigation of the relationship of TG to insulin resistance is such an important component of this research program, that the cohort of African-Americans participating in this protocol are known as TARA which stands for Triglyceride and Cardiovascular Risk in African Americans. Results from TARA were so impressive that the hypothesis that TG was not a marker of insulin resistance in African Americans was subsequently tested in NHANES data collected from 1999-2001. In this NHANES data set of whites, African-Americans and Mexican Americans, the fact that TG was not a marker of insulin resistance was confirmed. However, TG was a powerful marker of insulin resistance in whites and Mexican Americans. Altogether this research on race differences in the relationship of TG to insulin resistance again demonstrates that to detect disease at time when intervention can affect outcome, there is a need to develop ethnic-specific guidelines. More recently the TG/HDL ratio at a level of >3.0 has been suggested to be a marker of insulin resistance. This is well established in whites. But we have shown using TARA data that this did not work in African Americans. Therefore, we were asked to examine the efficacy of TG/HDL ratio in the Jackson Heart Study, a cohort of 2000 African Americans living in Jackson, Mississippi. This larger dataset was a sufficient size to examine men and women separately. We found, that the ratio at the ethnic-specific level of 2.5 actually worked in African-American men to predict insulin resistance, but did not work in African-American women. In fact, in women the ratio would give incorrect results >50% of the time. Therefore to identify and prevent diseases related to insulin resistance in African American women, we have to identify which tests do work. Best health will only be achieved with accurate and correct early screening. Having found that the TG/HDL ratio was not effective predictor of insulin resistance in African-American women, we tested the ratio in white South African women, Black South African women, West African women from Ghana and Nigeria and African-American women. We found that while the ratio effectively predicted insulin resistance in the white women, it did not work in any group of women of African descent. Again demonstrating that findings related to ins

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