Type 2 diabetes (T2DM) is a prevalent, costly and growing world-wide health concern. T2DM is a condition of impaired glucose homeostasis which reflects a disruption in fuel homeostasis that intricately and interdependently involves liver, adipose tissue, and skeletal muscle. Clinically, diabetes is defined by excessive blood glucose concentrations. Maintaining appropriate blood glucose involves a balance between input (exogenous from diet and endogenous from liver glycogenolysis and gluconeogenesis) and output (uptake by peripheral tissues). Insulin is a primary factor controlling glucose homeostasis, decreasing input from endogenous production (gluconeogenesis/glycogenolysis) and increasing output (uptake). Insulin resistance, defined as the inability to dispose of excess glucose in the presence of normal or elevated amounts of circulating insulin, is a common feature of most type 2 diabetics. Both because of its bulk (35–40% of body mass) and its high rate of energy consumption, muscle accounts for about 80 percent of insulin-directed glucose uptake (Koistinen and Zierath, 2002
). As such, skeletal muscle is central to maintaining systemic glucose homeostasis.
The Goto-Kakizaki (GK) rat, which exhibits a spontaneous form of diabetes, is a common animal model for diabetes studies (Goto et al., 1988
; Portha, 2005
). Unlike most other genetic models of type 2 diabetes, diabetes in GK rats is polygenic in origin and in this respect they are a good surrogate for the human disease. While the majority of type 2 diabetes patients in Western countries are overweight or obese, in Asia 60% are non-obese, “lean” diabetics (Brunetti, 2007
). Because of their non-obese phenotype, this model allows for the study of diabetes-related characteristics without the confounding influence of increased obesity-related factors.
Insulin resistance in skeletal muscle is well documented in the GK rat (Portha, 2005
; Steiler et al., 2003
), and defects in signal transduction have also been noted (Dadke et al., 2000
; Kanoh et al., 2001
; Steiler et al., 2003
). In addition, alterations in muscle fiber type composition in GK rats have been reported (Yasuda et al., 2002
). More recently, defects in muscle microvasculature have been documented in GK rats, which may be important to both glucose delivery/uptake by muscle as well as its metabolism and function (Copp et al.; Padilla et al., 2006
; Padilla et al., 2007
The GK rat was originally developed in Japan, and various sublines have been established throughout the world. Recently, a commercial subline was established in the US by Taconic Farms. Elevated blood glucose and a non-obese phenotype are consistently documented characteristics of GK animals. However, many conflicting reports exist in the literature as to other physiological characteristics including body weights, plasma insulin, plasma adipokines, and lipid profiles. Such differences may stem from variations in different GK sub-lines, variations in rat strains used as controls in different studies, ages studied, or experimental variations in methodology between studies. Therefore, we conducted a carefully controlled systems-based study of the US Taconic sub-line from weaning through mid-adulthood (20 weeks). In this study, animals were subjected to only minimal animal manipulation/stress and were fed ad libitum throughout. We chose to maintain our rats in a normal fed state in order to avoid possible variations in physiological measurements induced by fasting. We have previously reported growth characteristics and indices of diabetes along with an analysis of differential gene expression in livers from these animals . Because of the central role of muscle in the etiology of diabetes, we also undertook a comparative analysis of differential gene expression, using Affymetrix 230–2 gene chips, in skeletal muscles of GK rats relative to Wistar Kyoto (WKY) controls as a function of disease progression.