The Effects of Aging, Epigenetic Expression, and Obese Phenotype on Parameters of Glycemic Status, Glucose Oxidation, Insulin Resistance and Adiposity in the Congenic LA/Ntul//-cp Rat

Pathophysiologic manifestations of systemic Insulin resistance (IR) in association with obesity and overweight conditions are a common observation in man and animals. The purpose of the current investigation was to determine the characteristics of adiposity, IR, and insulin-stimulated glucose oxidation (ISGOX) in diaphragm muscle in normally reared and fed aging female congenic, lean and obese LA/Ntul//-cp rats from 4 to 24 months of age. Insulin resistance (IR) in the diaphragm muscle is a condition where the muscle under fixed glucose concentrations may become less responsive to insulin, thereby impairing glucose uptake and potentially contributing to progressive diaphragmatic weakness and respiratory dysfunction. Thus, IR may become a contributor to insulin resistance in muscle and adipose tissue depots particularly in conditions like obesity and obesity linked comorbidities including type 2 diabetes (T2DM/NIDDM). While peripheral skeletal musculature groups often represent a primary locale of IR in man and animals, the ongoing physiologic contractile activity of the diaphragm muscle may escape much of the early impact of IR since it remains a more physiologically active muscle group than skeletal muscle groups throughout the lifespan in man and animals, and thus may confer a measure of metabolic protection from more extensive features of IR. Groups of lean and obese female littermate LA/Ntul//-cp rats, a rodent model where epigenetic obesity occurs independently of NIDDM were studied at 4, 14, and 24 months of age. Parameters of adiposity, IR and ISGOX in diaphragm muscle were determined in the presence or absence of insulin (100 µU/ml; medium glucose 10 mM). Relative adiposity was computed by the addition of the sum of dorsal and retroperitoneal adipose tissue depots as a proportion of final body weight. Body weight of lean animals was similar at all ages studied, while body weight of obese rats increased further at each successive age studied. Fasting plasma glucose concentrations were similar in both phenotypes at all ages studied, but plasma insulin concentrations and the insulin:glucose ratios, established biomarkers of IR, were markedly elevated in the obese phenotype, with only modest age-related improvement. Measures of basal and ISGOX in diaphragm were consistent with age related decreases in baseline and insulin-stimulated glucose oxidation in the lean phenotype. In contrast, baseline and ISGOX in the obese phenotype were consistent with IR. These results suggest that the capacity for insulin-stimulated glucose oxidation and energy metabolism decreased by advances in aging in this muscle group in concert with progressive increases in adiposity with aging.