The Diabetogenic Activity of Fragments of Human Growth Hormone in Obese (ob/ob) Mice

Abstract

The genetically obese (ob/ob) mouse was used to investigate the effects of highly purified human growth hormone (hGH), reduced and S-carbamidomethylated hGH (RCAM-hGH), plasmin-digested RCAM-hGH (PD-RCAM-hGH), and peptide fragments isolated from the plasmin digests of RCAM-hGH on fasting blood glucose concentration and glucose tolerance. Mice treated for three days with hGH exhibited both increased fasting blood glucose concentrations and aggravated intolerance to administered glucose. Similar changes in the fasting blood glucose concentration and glucose tolerance were observed after treatment of mice with RCAM-hGH and PD-RCAM-hGH. Moreover, two noncovalent complexes of peptides of RCAM-hGH, one consisting of residues 1-134 bound to 141-191 (Dal) and the other consisting of almost equal amounts of 1-134 and 42-134 bound to 141-191 (Dc2), appeared to retain the full activity of the native hormone in that they increased fasting blood glucose concentrations and aggravated glucose intolerance in the ob/ob mice. A peptide consisting of residues 95-134 of RCAM-hGH appeared to retain some diabetogenic activity, while a peptide consisting of residues 20-41 was devoid of activity. Tolerance tests performed six hours after a single injection of either hGH or fraction Dal indicated that this time interval was not sufficient to elicit the diabetogenic response. Thus, these studies indicate that neither intact disulfide bridges nor intact primary amino acid sequence of the hGH molecule are required for the expression of its diabetogenic activity.