Kl. Kramer et al., Insulin replacement therapy in diabetic rats using an osmotic pump normalizes expression of enzymes key to hepatic carbohydrate metabolism, ARCH BIOCH, 368(2), 1999, pp. 291-297
Intensively treating type I diabetics with continuous subcutaneous insulin
infusions or multiple daily insulin injections to normalize mean blood gluc
ose concentrations significantly reduces the onset of secondary diabetic co
mplications when compared to conventionally treated diabetics. Our studies
focused on characterizing hepatic enzyme expression in intensively and conv
entionally treated diabetic rats. Alloxan-induced diabetic rats were conven
tionally treated with insulin injected twice daily or intensively treated w
ith similar daily dosages of insulin administered via a surgically implante
d osmotic pump. Our results demonstrate a significant difference in hepatic
enzyme expression when these treatment regimes are compared. In convention
ally treated diabetic rats, phosphoenolpyruvate carboxykinase (PEPCK) prote
in and mRNA levels remained slightly elevated when compared to normal anima
ls, glycogen phosphorylase (GP) protein levels were still slightly decrease
d, and glycogen synthase (GS) protein and mRNA levels remained at the eleva
ted levels observed in untreated diabetics. In contrast, the protein and mR
NA levels of all three enzymes were normalized in the insulin pump-treated
animals. These results suggest that intensive insulin therapy improves glyc
emia directly by normalizing hepatic gene expression while conventional ins
ulin therapy normalizes plasma glucose concentrations indirectly. (C) 1999
Academic Press.