Diabetogenic activity of 20 kDa human growth hormone (20K-hGH) and 22K-hGH in rats.
To compare the diabetogenic activity of 20 kDa human growth hormone (20K-hGH) with that of 22K-hGH, we evaluated insulin sensitivity with a euglycaemic clamp in rats. The glucose infusion rate (GIR) in euglycaemic clamp studies was measured as an indicator of insulin sensitivity. [(14)C]glucose and 2-[(3)H] deoxy- D -glucose injection were used to calculate the rate of glucose utilization (R(d)), the hepatic glucose output (HGO), and the glucose metabolic index (R(g)'). Both 20K- and 22K-hGH were infused at equivalent rates (1.0 (mg/kg)/day). A 24 h infusion of 20K-hGH had no significant effects on the GIR, R(d), HGO and R(g)(')except for in gastrocnemius muscle. In contrast, 22K-hGH significantly lowered the GIR compared with the control (P< 0.001) and 20K-hGH groups (P< 0.01). The infusion of 22K-hGH also reduced R(d)compared with the controls and the 20K-hGH rats by 46.6% (P< 0.001) and 39.6% (P< 0.05) respectively, while no differences were observed in the HGO. Moreover, 22K-hGH inhibited glucose uptake, which was estimated from the insulin-stimulated R(g)' in some tissues. These results suggest that 22K-hGH inhibits the uptake and use of glucose in various tissues, which then leads to insulin resistance. In conclusion, the diabetogenicity of 20K-hGH is much weaker than that of 22K-hGH, and the reduced insulin-antagonizing action of 20K-hGH could have important clinical benefits.
Takahashi
S
S
Drug Discovery Institute, Nihon Shering KK, Mobara, Chiba, 297-0017, Japan. shuntakashashi@schering.co.jp
Shiga
Y
Y
Satozawa
N
N
Hayakawa
M
M
D000273:Adipose Tissue / Q000187:drug effects; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D006321:Heart / Q000187:drug effects; D019382:Human Growth Hormone / Q000494:pharmacology*; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D010446:Peptide Fragments; C404802:human growth hormone 22K; C039519:somatotropin 20K; D019382:Human Growth Hormone; D005947:Glucose