Reversal of tumor-associated hyperglucagonemia as treatment for cancer cachexia.

Abstract

The tumor-bearing state is associated with increased circulating glucagon levels that may play an etiologic role in cancer cachexia. The secretion of glucagon can be inhibited with long-term somatostatin analogs, and, in combination with insulin, should maximally reverse the low insulin/glucagon ratio seen in cancer cachexia. The goal of this study is to examine the effect of somatostatin (octreotide) and insulin in a model of cancer cachexia and to determine whether inhibition of glucagon secretion will reverse some of the abnormalities in carbohydrate metabolism to selectively benefit host versus tumor metabolism. Sixty-seven female Lewis rats were subcutaneously inoculated with 1 x 10(6) metastasizing mammary adenocarcinoma tumor cells. On day 30 the animals were randomized into four groups to receive (1) tumor-bearing control (saline injections); (2) octreotide, 150 microgram/kg intraperitoneally twice a day; (3) neutral protamine Hagedorn insulin, 5 units/kg subcutaneously twice a day; or (4) both insulin and octreotide injections. A fifth group of non-tumor-bearing controls was included. The animals received treatment for 5 days and were then killed. The tumor-bearing state was found to be associated with an increase in glucagon levels and a significant decrease in the insulin/glucagon ratio. The combination of somatostatin+insulin resulted in a 23-fold increase in the insulin/glucagon ratio without causing significant host morbidity from hypoglycemia. This increased insulin/glucagon ratio was associated with increased carcass weight, increased muscle weight, increased muscle protein, increased liver cellular protein, increased liver microsomal P-450 content, and decreased tumor protein content compared with the tumor-bearing controls. These results were not seen with insulin or somatostatin alone. Hepatic lactate dehydrogenase, glucose-6-phosphatase, and fructose-1, 6-diphosphatase activities were increased as a result of combination hormone treatment. Combination hormone treatment with somatostatin and insulin results in a marked increase in the insulin/glucagon ratio and a selective nutritional benefit to the host. The inhibition of tumor-associated hyperglucagonemia should be considered in the treatment of cancer cachexia.