African-American women (AAW) exhibit more than a two-fold greater risk of developing type 2 diabetes (T2DM) compared to Caucasian women (CW). Reasons behind this racial disparity are not understood, but lower insulin sensitivity (IS), a major risk factor for development of T2DM, is observed in lean, overweight and obese AAW compared to matched CW. We recently demonstrated a 26% lower IS in young, healthy, non- obese AAW compared to matched CW. Specifically, this difference was due exclusively to lower peripheral glucose uptake (GU), which occurs primarily in skeletal muscle, but also in adipose tissue, with the liver showing comparable IS. The lower peripheral GU could have potentially serious clinical consequences for AAW as this may lead to a strain on the ?-cells due to the long term need for compensatory insulin secretion, resulting in greater risk for development of T2DM. The identification of specific tissue and biochemical pathways that underlie reduced insulin-stimulated GU in AAW would have important positive clinical relevance; that is, interventions that target the specific mechanism(s) of the decreased GU in lean AAW could decrease subsequent IR in obese AAW, and thus lessen the risk for the development of T2DM.
Our specific aims will address two hypotheses: 1) a lower rate of insulin-stimulated glucose transport underlies the reduction in insulin-stimulated GU in AAW; and 2) insulin-stimulated GU into adipose tissue is an important site of decreased insulin sensitivity in AAW. Furthermore, we will explore whether racial differences in skeletal muscle (e.g. fiber type, levels of Glut4 and Hexokinase) and adipokines (e.g. Adiponectin and RBP4), are associated with racial differences in GU.
Aim 1. To examine the specific steps of GU responsible for the reduced insulin stimulated peripheral GU in non-obese AAW compared to CW. We will perform dynamic PET imaging during a hyperinsulinemic euglycemic clamp and apply kinetic modeling to quantify in vivo rates of glucose delivery, transport and phosphorylation within skeletal muscle and adipose tissue, and how control of GU is distributed between these steps. Glucose transport is the major control step for insulin-stimulated GU, but glucose delivery and phosphorylation are also involved. We focus this study in non-obese women to better understand in vivo factors that contribute to the lower insulin-stimulated GU we recently observed in non-obese AAW compared to CW. We expect that lower glucose transport is the primary mechanism underlying the lower GU in AAW.
Aim 2. To characterize the contribution of skeletal muscle (biceps femoris and vastus lateralis) and adipose tissue (visceral, abdominal and mid-thigh subcutaneous) to the lower insulin stimulated GU in AAW compared to CW. In addition to mid-thigh PET imaging described in Aim 1, we will also perform abdominal imaging to measure overall GU in different skeletal muscles and adipose tissues. We will also perform a muscle biopsy to measure the proportion of Type I fibers, and levels of GLUT4 and hexokinase in vastus lateralis. In addition, we will measure plasma levels of adipokines secreted by adipose tissue.
African-American women have more than twice the risk of developing type 2 diabetes compared to Caucasian women, but the reasons behind this racial disparity are unknown. We recently demonstrated that young, non-obese African American women have a distinct form of lower insulin sensitivity (a major risk factor for development of diabetes) compared to Caucasian women, with lower tissue glucose uptake, but similar insulin sensitivity in the liver. We propose to apply advanced imaging techniques to examine the process of glucose uptake in muscle and fat tissues that may explain the lower glucose uptake in African American women. This knowledge will provide important insights into potential therapeutic targets for treatment and prevention of diabetes, which may be specific to African American women.