Muscle biomarkers of type 2 diabetes disease progression in Goto-Kakizaki rats
Muscle is an important component of systemic glucose homeostasis, and insulin resistance is a common feature of most human type 2 diabetics. This thesis aims at characterizing some aspects of disease progression in type 2 diabetes along with the effects of a high fat diet on skeletal muscle of Goto-Kakizaki rats using microarray data analysis and population modeling. Dynamics of differential mRNA expression along with physiological indices relevant to diabetes were quantitated. A population disease progression model was applied to examine disease and diet effects on a muscle biomarker, Pyruvate dehydrogenase kinase 4 (PDK4). This model incorporated both muscle PDK4 mRNA dynamics and various plasma factor contributions to the PDK4 dynamics. The polygenetic, spontaneous, non-obese diabetic Goto-Kakizaki (GK) rat is a useful animal model for studies of type 2 diabetes. The Taconic subline of GK rats was used as the animal model to study the muscle dynamics in diabetes independent of obesity-related factors. Groups of GK rats along with control WKY rats were sacrificed at various ages from 4 weeks old up to 20 weeks old. Physiological measurements including plasma glucose and insulin were obtained. Muscle gene expression was evaluated using Affymetrix 230-2 chips. Hyperglycemia at early ages and potential beta cell failure at late ages were observed in GK rats. In addition, the musculature of GK animals has higher oxidative capacity than the WKY population. Chronic inflammation is also present in the GK musculature. Rodents fed with a high fat diet (approximately 50% energy from fat) rapidly develop severe whole body and skeletal muscle insulin resistance. High fat diet-fed GK and WKY rats were studied to examine mechanisms underlying insulin resistance in obese individuals. Similar increases in body weight were observed in both strains. High fat feeding had no significant influence on plasma glucose and insulin but elevated muscle triglyceride content in GK rats. Microarray data analysis indicated higher lipid use in muscle in both strains after high fat feeding. High fat feeding elevated lipolysis and decreased lipogenesis in WKY muscle, while GK muscle maladapts to the high fat diet possibly due to inappropriate activation of PPARα and hyper-oxidation of lipids. A population disease progression model was applied to the PDK4 mRNA profile from these animals. PDK4 is a key enzyme regulating the balance between oxidation of carbohydrate and lipid fuels. Higher PDK4 mRNA expression was observed in GK muscles compared with WKY muscles. In addition, high fat feeding increased the baseline in GK muscle and elevated the PDK4 mRNA level in both strains. The proposed mechanism-based disease progression model successfully described the age, disease and diet effects as well as the relative contribution of plasma regulators on PDK4 mRNA expression. In summary, this dissertation provides insights regarding the physiologic and molecular mechanisms underlying type 2 diabetes disease progression and diet effects on skeletal muscle. Population modeling describing the quantitative relationships for disease markers may assist in predicting the time course of this disease.