Selective insulinization of liver in conscious diabetic dogs

Abstract

Insulin encapsulated in lipid vesicles and targeted to hepatocytes by means of a digalactosyl diglyceride moiety [(designated vesicle encapsulated insulin (VEI)] was administered intravenously to conscious catheterized diabetic dogs to determine the effects of hepatic and extrahepatic glucose utilization. Our results indicate that VEI administered intravenously to diabetic dogs over a dose range of 0.5 to 2.0 mU X kg-1 X min-1 reduces hepatic glucose output or induces hepatic glucose uptake without causing any significant alteration in the rate of extrahepatic glucose utilization. Steady-state comparisons of 1.0 mU X kg-1 X min-1 VEI with intraportal and peripherally administered insulin revealed that VEI and intraportal insulin result in significantly less extrahepatic glucose utilization than does an equivalent dose of peripherally administered insulin (6.36 +/- 1.21 and 5.08 +/- 0.97 vs. 8.82 +/- 1.61 mg X kg-1 X min-1; P less than 0.03). Through the use of VEI, we were able to significantly alter the deposition of intravenously administered glucose from 11% hepatic and 89% extrahepatic noted with peripheral insulin to 35% hepatic and 65% extrahepatic with VEI (P less than 0.03). Thus, by encapsulating insulin into a lipid carrier specifically targeted to the liver, selective hepatic insulinization can be achieved. As a result of this approach, one can alter the distribution of a glucose load to favor hepatic deposition.