African-American (AA) individuals are less sensitive to insulin than Caucasian (C) individuals, a difference that may bear upon the greater prevalence of type 2 diabetes among AA, both adults and children. The ethnic/racial difference in insulin sensitivity (SI) is established early in life, and is apparent among prepubertal children, suggesting an inherent physiological basis. To date, no explanation has been uncovered for lower SI among AA. Preliminary data from the Pi's laboratory indicate that muscle lipid content (ML), as estimated from both computed tomography scanning and magnetic resonance spectroscopy, is higher among AA vs C women. Research has indicated that greater ML is associated with lower SI. The PI also has shown that AA have relatively lower adiponectin, a hormone that stimulates intramuscular lipid oxidation and improves Si. Preliminary data indicate that lower adiponectin among AA may be due to greater post-challenge insulin concentration.
The Specific Aims of this proposal are to: 1. Determine whether greater ML among AA explains lower SI. 2. Determine whether greater ML among AA is associated with, and potentially due to, lower oxidative capacity, as reflected in the ADP time constant from 31P-MRS. 3. Using low- and moderate-fat dietary interventions, determine if experimental manipulation of ML alters Si in healthy AA and C subjects; and, using low- and high-carbohydrate dietary interventions, determine if experimental manipulation of insulin secretion alters insulin, adiponectin, and ML in healthy AA and C subjects. Secondary Aims are to determine whether higher GLP-1 among AA is responsible for greater insulin secretion, and whether experimental manipulation of ML is associated with changes in 5'-AMP-activated protein kinase (AMPK), and/or other factors involved in the regulation of substrate metabolism. Because lifestyle and pharmacologic interventions that deplete ML have been reported, demonstration that greater ML is responsible for ethnic/racial differences in SI is likely to lead to means of reducing risk for type 2 diabetes among AA.
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