Human growth hormone fragment (hGH_44–191) produces insulin resistance and hyperinsulinemia but is less potent than the 22 kDa hGH in the rat

Abstract

A 17 kDa fragment of human growth hormone (22 kDa hGH), identified as hGH_44–191, has lower binding affinity for growth hormone receptors (GHRs), but has been reported to be more potent in producing glucose intolerance in yellow obese mice. Our aim was to investigate this anomaly by comparing acute development of hyperinsulinemia and insulin resistance (“diabetogenic activity”) during hGH_44–191 or 22 kDa hGH infusion in normal rats. Fasted awake male rats (350–370 g) were infused via a carotid cannula with saline (CON), 22 kDa hGH (at 0.125 μg/min), or hGH_44–191 (at 0.64 or 0.32 μg/min) for 5.75 h. Over the last 2 h, a euglycemic hyperinsulinemic clamp (insulin infusion rate 0.25 U/kg/h) was performed. After 3.75 h infusion, 22 kDa hGH at 0.125 and hGH_44–191) at 0.64 μg/min produced basal (preclamp) hyperinsulinemia compared to CON. During the clamp, insulin resistance was consistently produced by 22 kDa hGH at 0.125 and hGH_44–191 at 0.64 μg/min compared to CON. Using specific radio-immunoassays for 22 kDa hGH and hGH_44–191 we determined that under conditions of equivalent diabetogenic activity, molar circulating levels of hGH_44–191 were 50–60-fold higher than 22 kDa hGH. It was concluded that whereas 22 kDa hGH and hGH_44–191 are both capable of generating acute hyperinsulinemia and insulin resistance in the normal rat, the diabetogenic potency of hGH_44–191 is not enhanced compared to 22 kDa hGH, and that diabetogenic potency is in accord with the reported lower binding affinity of hGH_44–191 to the GHR.