Mitochondrial Function and Insulin Sensitivity in African American Women

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

Linked publications, trials & patents

Abstract

DESCRIPTION (provided by applicant): African-American women (AAW) are at greater risk for type 2 diabetes compared to Caucasian women (CW). Reasons for this increased risk are not understood, but lower insulin sensitivity (IS) is observed in AAW. Our goal during the initial funding period was to gain a better understanding of IS in lean AAW to help elucidate their increased risk for diabetes. Despite lower adiposity, smaller waist circumference, and similar physical activity levels, IS was lower in AAW. A novel finding was that this difference was due exclusively to lower peripheral IS. This pattern diverges from the typical pattern of insulin resistance (IR) in both liver and skeletal muscle observed with obesity. Mitochondrial capacity was lower in AAW and was correlated with muscle IS. We conclude that lean, AAW have a characteristically distinct form of lower IS that appears to be linked to skeletal muscle. A greate racial difference in IS is seen in obese women than we observed in lean women. We propose that this discrepancy is due to an accumulation of lipid in liver and greater lipid accumulation in muscle in obese AAW, leading to a greater racial difference in IS that is apparent in both liver and muscle. We suggest that although AAW have lower hepatic lipid levels, they are more sensitive to hepatic lipid accumulation. Our initial findings clearly show a muscle phenotype difference in lean AAW that suggests that aerobic exercise may be ideally suited to improve IS. Yet, no chronic exercise interventions with comprehensive gold-standard measures of insulin sensitivity, tissue-specific lipid content, and mitochondrial function have been conducted. We propose to provide the detailed, quality studies needed to advance the field. Mitochondrial dysfunction is one theory of the etiology of IR, and we show that this is a likely factor predisposing AAW to increased IR and diabetes. However, the mechanisms for the racial differences, and the nature of the link between mitochondrial function and IS in is not known. One aspect of mitochondrial function that has been shown to result in IR is increased reactive oxygen species (ROS) production. To address these issues we have developed 3 aims: 1) Comprehensive characterization of IR in obese AAW compared to obese CW; 2) Examine the physiological impact of exercise intervention on IS, mitochondrial function and factors related to IR in these obese AAW and CW; and 3) Mechanistic studies using myotubes generated from myoblasts to conduct specific studies that examine intrinsic mitochondrial function and glucose uptake, and directly target glucose transport and insulin signaling, assess ROS production by measuring skeletal muscle mitochondrial hydrogen peroxide emission, and examine differences in proteins involved in mitochondrial maintenance, that may be related to differences in mitochondrial function and IS. The goal of this project is to gain essential information to fill gas in our knowledge of the lower IS in obese AAW, provide translational insight into the response of AAW to aerobic exercise, with novel mechanistic studies to expand our understanding of the relationship between mitochondrial function and IR in muscle.