Influence of Cycloheximide on Acute Diabetogenic Effects of S-Carboxymethylated Human Growth Hormone in Obese (ob/ob) Mice

Acute treatment of ob/ob mice with S-carboxymethylated hGH (RCM-hGH), a diabetogenic derivative of GH which lacks significant insulin-like and growth-promoting activities, results in an increase in fasting plasma insulin and blood glucose levels and enhanced peripheral tissue insulin resistance. Plasma insulin level increases within 3 h after RCM-hGH is administered, whereas increased blood glucose concentration and enhanced peripheral tissue insulin resistance became evident 6 h after the hormone derivative is given. The lag period seen in the manifestation of these diabetogenic effects of RCM-hGH is consistent with the time required for gene expression. Therefore, the present study was undertaken to determine whether the above acute responses to the diabetogenic action of RCM-hGH would be expressed in ob/ob mice in which protein synthesis was blocked with cycloheximide. Female ob/ob mice were given either saline or cycloheximide (0.1 mg/g BW) ip and 1 h later were fasted and treated with either saline or 200 μg RCM-hGH ip. The mice were given a second injection of cycloheximide during the middle of the hormone treatment period to insure that protein synthesis remained blocked for the entire 6 h. In the animals not receiving cycloheximide, fasting plasma insulin level and blood glucose concentration were markedly elevated 6 h after the injection of RCM-hGH. Also, the GH derivative attenuated the ability of insulin added in vitro to stimulate glucose oxidation by adipose tissue segments isolated from the animals. In the cycloheximide treated animals, the RCM-hGH did not increase plasma insulin level or enhance insulin resistance in adipose tissue, whereas it still produced some increase in fasting blood glucose concentration. These findings are consistent with the hypothesis that RCM-hGH-induced insulin resistance may require the expression of a gene for a protein involved in exerting its action on insulin resistance. Key-Words Cycloheximide - S-Carboxymethylated Human Growth Hormone - Insulin Resistance - ob/ob Mouse