Recombinant deoxyribonucleic acid-derived 22K- and 20K-human growth hormone generate equivalent diabetogenic effects during chronic infusion in dogs.

Chronic administration of human GH (mol wt, 22,000; 22K-hGH) is known to generate insulin resistance in dogs. However, recent hypotheses claim that diabetogenicity may be attributable to smaller weight contaminants or fragments not found in purified lower weight hGH (mol wt, 20,000; 20K-hGH) also secreted by the pituitary. In this study, we examined the effects of chronic (12-day) low dose (0.02 mg/kg X day) infusion of recombinant DNA-derived methionyl 22K- and 20K-hGH on glucose tolerance in conscious dogs. Minimal model analysis of the frequently sampled iv glucose tolerance tests quantified insulin sensitivity and glucose effectiveness, the ability of glucose per se to normalize its own concentration. Infusion of 22K-hGH, raising plasma hGH levels to 3.8 +/- 0.6 ng/ml, resulted in an elevation in fasting glucose levels after 2 days of infusion (104 +/- 1 vs. pre-hGH 97 +/- 2 mg/dl; P less than 0.01), but the effect was transient. No change was noted during 20K-hGH treatment (P greater than 0.2). Mildly elevated fasting insulin levels were observed in both 22K- and 20K-hGH-treated dogs (P less than 0.04 and 0.03, respectively). However, despite maintenance of adequate glucose tolerance during both infusions (P greater than 0.07), marked insulin resistance was apparent; insulin sensitivity dropped from 9.7 +/- 2.4 and 11.2 +/- 2.1 X 10(-4) min-1/(microU/ml) in 22K- and 20K-hGH-treated dogs, to 2.5 and 2.8 X 10(-4) min-1/(microU/ml), a drop of 75% (P less than 0.01 and 0.001). Insulin resistance persisted throughout the infusion period, slowly returning to pre-hGH treatment levels in 22K-hGH-treated dogs during recovery. Insulin resistance persisted 3 days after cessation of 20K-hGH treatment (day 15), but returned to pre-hGH levels by day 25. Integrated glucose-stimulated insulin release was enhanced after 2 days of 22K- or 20K-hGH treatment (P less than 0.03 and less than 0.05), but the effect was transient. Maintenance of normal glucose tolerance in the face of severe insulin resistance and only transiently elevated insulin response was possible because glucose effectiveness remained unchanged. In conclusion, despite minimal effects of low dose hGH infusion on glucose tolerance and fasting glucose and insulin levels, 22K- and 20K-hGH are equipotent in generating severe insulin resistance and potentiating glucose-stimulated insulin release.