Diabetogenic activity of native and biosynthetic human growth hormone in obese (ob/ob) mouse

It has been repeatedly suggested that diabetogenic activity is not an intrinsic property of native pituitary growth hormone (GH) and that the diabetogenic effects produced by GH preparations are due to low-molecular-weight contaminants or degradation products of the hormone. This possibility was evaluated in this study by assessing the ability of purified native human GH (hGH) and biosynthetic methionyl-hGH to exacerbate fasting hyperglycemia and glucose intolerance in the obese (ob/ob) mouse. Native hGH that had been purified by DEAE-cellulose chromatography (A-type; 1.8 IU/mg) produced fasting hyperglycemia and glucose intolerance in the ob/ob mouse when injected subcutaneously at doses of 50 micrograms/day or greater for 3 days. It had no effect when a single subcutaneous dose of 200 micrograms was administered 24 h previously. To eliminate possible contamination with smaller peptides, the hGH was gel-filtered on a column of Sephacryl S-200 in 6 M guanidine-HCl. When injected subcutaneously into ob/ob mice at a dose of 50 micrograms/day or greater for 3 days, the guanidine-treated hGH produced glucose intolerance. Also biosynthetic methionyl-hGH produced marked fasting hyperglycemia and glucose intolerance when injected subcutaneously at doses of 50 or 100 micrograms/day for 3 days. These results support the conclusion that hGH itself is indeed diabetogenic but that chronic exposure of the organism to the hormone is required for its effects on glucose metabolism to become clearly manifest.