Insulin replacement therapy in diabetic rats using an osmotic pump normalizes expression of enzymes key to hepatic carbohydrate metabolism

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.