Hepatic insulin expression improves glycemic control in type 1 diabetes rats

Low levels of hepatic insulin production have been shown to prevent lethal ketoacidosis associated with type 1 diabetes. To assess the beneficial effe cts of sustained hepatic production of insulin on glycemic control in type 1 diabetes, we have employed the adenovirus-mediated gene delivery system t o transfer an engineered rat preproinsulin gene to the livers of streptozot ocin-induced diabetic nude rats. Hepatic insulin production resulted in the reduction of blood glucose in treated diabetic rats, the degree of blood g lucose reduction correlated with both the vector dose and the level of hepa tic insulin expression. At moderate vector doses, 0.3-0.7 ng/ml of plasma i nsulin was produced in treated diabetic animals, resulting in significant r eduction of nonfasting hyperglycemia and improvement in glucose tolerance. Furthermore, these animals maintained euglycemia after 12-h fast. Al higher vector doses, greater than 1 ng/ml of plasma insulin was produced, complet ely reversing nonfasting hyperglycemia in treated rats. However, all of the treated animals developed severe hypoglycemia upon fasting. This study has defined the maximal tolerable level of hepatic insulin production that is sufficient to reduce the degree and ameliorate the adverse effects of nonfa sting hyperglycemia without risk of fasting hypoglycemia in type 1 diabetic rats. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.