Human growth hormone fragment (hGH44-91) produces insulin resistance and hyperinsulinemia but is less potent than 22 kDa hGH in the rat.
A 17 kDa fragment of human growth hormone (22 kDa hGH), identified as hGH44-191, 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. Out aim was to investigate this anomaly by comparing acute development of hyperinsulinemia and insulin resistance ("diabetogenic activity") during hGH44-191 or 22 kDa hGH infusion in normal rats. Fasted awake make rats (350-370 g) were infused via a carotid cannula with saline (CON), 22 kDa hGH (at 0.125 micrograms/min), or hGH44-191 (at 0.64 or 0.32 micrograms/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 hGH44-191 at 0.64 micrograms/min produced basal (preclamp) hyperinsulinemia compared to CON. During the clamp, insulin resistance was consistently produced by 22 kDa hGH at 0.125 and hGH44-191, at 0.64 micrograms/min compared to CON. Using specific radioimmunoassays for 22 kDa hGH and hGH44-191, we determined that under conditions of equivalent diabetogenic activity, molar circulating levels of hGH44-191 were 50-60-fold higher than 22 kDa hGH. It was concluded that whereas 22 kDA hGH and hGH44-191 are both capable of generating acute hyperinsulinemia and insulin resistance in the normal rat, the diabetogenic potency of hGH44-191 is not enhanced compared to 22 kDa hGH, and that diabetogenic potency is in accord with the reported lower binding affinity of hGH44-191 to the GHR.
Hettiarachchi
M
M
Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, NSW Australia.
Watkinson
A
A
Leung
K C
KC
Sinha
Y N
YN
Ho
K K
KK
Kraegen
E W
EW
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D013006:Growth Hormone / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D006946:Hyperinsulinism / Q000139:chemically induced*; D007262:Infusions, Intravenous; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D011863:Radioimmunoassay; D051381:Rats
D001786:Blood Glucose; D010446:Peptide Fragments; D013006:Growth Hormone