brl-26830a and Insulin-Resistance

BRL 26830A, a beta adrenoceptor agonist, has been shown to have antiobesity and antidiabetic properties in rodents. The aim of this study was to study the effects of chronic BRL 26830A treatment (20 mg/kg/day for 9 weeks) on weight gain and the development of insulin resistance in gold-thioglucose-injected mice (GTG). BRL 26830A slowed the rate of weight gain in GTG such that mice weighed significantly less between 2 w and 7 w of treatment. However, at the time of sacrifice (9 w), there was no difference in body weight between treated and untreated GTG. The obesity-induced reduction in lipogenesis in brown adipose tissue (BAT) was increased 9 fold to greater than CON levels. However, weight and fatty acid (FA) content of BAT were reduced, suggesting increased lipid turnover and thermogenesis. Lipogenesis, FA content and fat pad weight were unchanged in white adipose tissue (WAT) and decreased in liver of GTG. Glucose tolerance was improved in both CON and GTG. Hyperglycemia, hyperinsulinemia and changes in cardiac and hepatic glucose oxidation as indicated by PDHC activity were normalized. Serum triglycerides and non-esterified fatty acids were reduced. Thus, chronic BRL 26830A treatment prevented the development of insulin resistance and attenuated weight gain, but did not prevent the development of obesity in this model.

Topics: Adipose Tissue; Adipose Tissue, Brown; Adrenergic beta-Agonists; Animals; Aurothioglucose; Blood Glucose; Body Composition; Ethanolamines; Fatty Acids; Glycogen; Insulin; Insulin Resistance; Lipid Metabolism; Lipids; Male; Mice; Mice, Inbred CBA; Obesity; Pyruvate Dehydrogenase Complex; Weight Gain

The size and morphological characteristics of muscles from diabetic obese (db/db) mice and their normal lean littermates were investigated. The soleus muscles were similar in size in diabetic and normal mice but the biceps brachii and gastrocnemius were significantly lighter in the diabetic animals. In the biceps brachii the small size resulted from an overall reduction in fibre diameter, which was most acute in the fast white fibres, and an increase in the proportion of smaller fast intermediate fibres. Treatment of diabetic mice with BRL 26830 a thermogenic, beta-adrenoceptor agonist, restored the weight, fibre diameter and fibre type composition of the biceps brachii to that of lean littermates. This treatment also increased the weight of the gastrocnemius, together with its protein content. Since BRL 26830 restored normoglycaemia in the diabetic mice, without decreasing their body weight, we suppose that it improved insulin action in their muscles and this, in turn, stimulated muscle growth.

Topics: Adrenergic beta-Agonists; Animals; Body Temperature Regulation; Diabetes Mellitus; Diabetes Mellitus, Experimental; Ethanolamines; Female; Insulin Resistance; Mice; Mice, Inbred C57BL; Muscles; Obesity

Zucker fa/fa rats exhibit glucose intolerance in comparison with lean Fa/? littermates. A single acute dose of BRL 26830 (2.9 mg/kg p.o.) improved glucose tolerance in Fa/? littermates but exacerbated glucose intolerance in the fa/fa rats. This latter effect occurred in spite of an increase in the plasma insulin concentration. Chronic treatment of Zucker fa/fa rats with BRL 26830 (2.9 mg/kg) for 24 days or more produced a significant reduction in the area under the glucose tolerance curve. In addition, the glucose decay rate (k%) following the administration of insulin intravenously was significantly increased in the BRL 26830-treated rats suggesting that tissue insulin sensitivity was increased. Glucose turnover measurements show that chronic treatment of Zucker fa/fa rats with BRL 26830 produced a significant increase in the rate of glucose utilization integrated over a 3 hr period, but this increase was, in part, off-set by an increase in the endogenous rate of glucose production. The ultimate fate of the extra glucose that is metabolized is not known but it is suggested that it might be used to support the thermogenic response that is also activated by BRL 26830.

Topics: Adrenergic beta-Agonists; Animals; Blood Glucose; Ethanolamines; Glucose; Glucose Tolerance Test; Insulin; Insulin Resistance; Insulin Secretion; Male; Rats; Rats, Zucker

Obese (ob/ob) mice were treated with the thermogenic beta-adrenoceptor agonist BRL 26830 for 14 days. White adipocytes prepared from these animals showed significant increases in insulin receptor number, with no change in the affinity for these receptors. Increased receptor number was accompanied by increased glucose transport, as measured by 2-deoxyglucose uptake in vitro.

Topics: Adipose Tissue; Adrenergic beta-Agonists; Animals; Biological Transport; Ethanolamines; Glucose; In Vitro Techniques; Insulin; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Receptor, Insulin

Young lean (Fa/?) and obese (fa/fa) rats were treated with the thermogenic beta-adrenoceptor agonist, BRL 26830, for 3 weeks. In lean rats this treatment had no effect on body weight but there was a marked increase in the insulin sensitivity of soleus muscle strips with respect to glycolytic rate. Treatment of obese rats with BRL 26830 produced a small but not significant decrease in body weight but the sensitivity of both glycolysis and glycogen synthesis to insulin was increased so that muscles of treated obese rats showed similar insulin sensitivity to untreated lean rats. It is suggested that such changes are unlikely to be merely a secondary consequence of an anti-obesity action.

Topics: Animals; Blood Glucose; Ethanolamines; Glycogen; Insulin Resistance; Lactates; Lactic Acid; Male; Muscles; Obesity; Rats; Rats, Zucker; Receptors, Adrenergic, beta