Glucocorticoid Ablation Attenuates Insulin Resistance and Improves Glucose Tolerance in the Obese LA/Ntul//-cp RAT

The counterregulatory effects of glucocorticoids and insulin that commonly occur in obesity result in the development of insulin resistance and impaired glycemic responses to dietary carbohydrates. Both adipose tissue and skeletal muscle are dependent on insulin actions to bring about glucose uptake, and the combined hormonal effects contribute to disordered processes of energy metabolism in insulin dependent tissues that generally correspond to the magnitude of insulin resistance. To determine the effects of glucocorticoid inhibition on typical insulin-mediated glycemic processes in obese rats, groups (n=6 -12 rats/phenotype) of normally reared longevity-prone congenic lean and obese animals were fed a Purina chow diet from 6 to 9 weeks of age, and overfed with the Chow diet plus a highly palatable cafeteria diet from 9 to 12 weeks of age. The congenic LA/Ntul//-cp rat strain expresses the obese trait soon after weaning but remains glucose intolerant but non-diabetic thereafter. Subgroups of obese animals were subjected to bilateral adrenalectomy (ADX) at 6 weeks of age to remove glucocorticoid contributions to glycemic parameters. At 6, 9, and 12 weeks of age, each treatment group achieved weight gain (WG) and glucose tolerance (OGT). At 6 and 9 weeks of age on the chow diet, WG on ADX-obese rats was equivalent to that of their lean littermates, but was twice that of their lean littermates from 9 to 12 weeks of age. following 30 to 60 minutes, OGT responses and the area under the OGT curve were impaired but not diabetic in obese animals of all ages, and reverted to those of lean rats following ADX. At 12 weeks of age, the insulin to glucose ratio (I:G) was consistent with insulin resistance in obese rats but not in ADX-obesity or lean rats. At 9 and 12 weeks of age, ADX led to the normalization of OGT and glycemic indices in the obese phenotype. These findings support normalizationof typical insulin-mediated components of glycemic parameters and glucose uptake in peripheral tissues following glucocorticoid ablation of congenic obese rats, and suggest that the counterregulatory effects of insulin and glucocorticoid hormones may be contributory to the impaired glycemic responses in the obese phenotype of the LA/N//-cp (corpulent) rat and are consistent with a receptor-mediated element in the development of insulin resistance and glucose uptake in peripheral tissues commonly associated with the early development of obesity in this strain.