Acute effects of S-carboxymethylated human growth hormone on insulin resistance in the obese (ob/ob) mouse

Chronic treatment of ob/ob mice with growth hormone (GH) increases plasma insulin and blood glucose concentrations, and enhances insulin resistance in peripheral tissues. The purpose of the present study was: (1) to determine the length of time required for the development of increased circulating insulin concentration and adipose tissue insulin resistance in response to GH in the ob/ob mouse, (2) to examine the relationship between the rise in insulin concentration and the development of insulin resistance, and (3) to test whether the hormone derivative could enhance insulin resistance in isolated adipose tissue when added in vitro. Female ob/ob mice were injected intraperitoneally (ip) with either saline or 200 micrograms of S-carboxymethylated human GH (RCM-hGH), a diabetogenic GH derivative, which lacks significant insulinlike or growth-promoting activities. A threefold increase in plasma insulin concentration was observed three and six hours after RCM-hGH injection, but increased hyperglycemia was evident only after six hours. The in vitro stimulatory effect of insulin on [14C]glucose oxidation by parametrial adipose tissue was unchanged at three hours but suppressed six hours following administration of RCM-hGH. When the plasma insulin level of ob/ob mice was increased threefold by the administration of neutral protamine Hagedorn (NPH) insulin, the in vitro stimulatory effect of insulin on [14C]glucose oxidation by adipose tissue isolated from these animals was not altered, suggesting that insulin-induced receptor or postreceptor changes do not account for the increased insulin resistance produced by RCM-hGH.(ABSTRACT TRUNCATED AT 250 WORDS)