Type 1 diabetes mellitus is caused by a lack of
insulin that results from the autoimmune destruction of the pancreatic beta-cells. Severe diabetes, if not controlled by periodic
insulin injections, can lead to
ketoacidosis and death. We have previously shown that sustained low level production of
insulin in the liver of diabetic rats prevented their death from complications of diabetes. To test the hypothesis that there is a window of serum
insulin concentrations that can prevent
ketoacidosis without significant risk of
hypoglycemia secondary to
hyperinsulinemia, rats were infused with various doses of a recombinant retrovirus encoding an engineered rat preproinsulin-1 gene. The gene was engineered to allow processing into mature
insulin by the
protease furin. At the lower doses tested, fatal
ketoacidosis was prevented, but the rats exhibited nonfasting
hyperglycemia. At intermediate doses, which resulted in serum
insulin concentrations of 1.6 mg/ml, the rats achieved near-normoglycemia and no serum
ketones. These rats did not exhibit
hypoglycemia even during a 24-h fast. At high virus doses, the animals achieved nonfasting normoglycemia but exhibited
hypoglycemia during the fast. In conclusion, we have defined a therapeutic window of hepatic
insulin expression that provides protection against
ketoacidosis without significant risk of
hypoglycemia. This window of sustained hepatic
insulin expression might permit its development into a novel treatment modality for the prevention of
ketoacidosis in patients with severe
insulin-dependent diabetes mellitus.