Interaction Between Insulin and Glucose-Delivery Route in Regulation of Net Hepatic Glucose Uptake in Conscious Dogs

In the presence of fixed basal levels of insulin, the route of intravenous glucose delivery (portal vs. peripheral) determines whether net hepatic glucose uptake (NHGU) occurs. Our aims were to determine if the route of intravenous glucose delivery also plays a role in regulating NHGU in the presence of hyperinsulinemia and to determine if length of fast (18 vs. 36 h) influences regulation of NHGU. Five conscious dogs fasted 18 h were given somatostatin and replacement insulin (245 ± 34 μU · kg⁻¹ · min⁻¹) and glucagon (0.65 ng · kg⁻¹ · min⁻¹) infusions intraportally. After a 40-min control period, the insulin infusion rate was increased fourfold, and glucose was infused for 3 h. Glucose was given either through a peripheral vein or the portal vein for 90 min to double the glucose load reaching the liver. The order of infusions was randomized. NHGU was measured with the arterial – venous difference technique. Insulin and glucagon levels were 12 ± 2, 35 ± 6, and 36 ± 5 μU/ml and 55 ± 12, 61 ± 13, and 59 ± 7 pg/ml during the control, peripheral, and portal infusions, respectively. The glucose infusion rate, the load of glucose reaching the liver, and the arterial-portal plasma glucose gradient were 0, 9.58 ± 2.28, and 10.44 ± 2.94 mg · kg⁻¹ · min⁻¹; 29.4 ± 3.6, 56.8 ± 3.4, and 56.8 ± 2.8 mg · kg⁻¹ · min⁻¹; and 2 ± 1, 5 ± 1, and −51 ± 15 mg/dl during the same periods. The liver switched from net glucose output (2.5 ± 0.4 mg · kg⁻¹ · min⁻¹) to uptake of 1.4 ± 0.7 and 3.5 ± 0.8 mg · kg⁻¹ · min⁻¹ during peripheral and portal glucose delivery, respectively. Despite a similar hormonal milieu and indistinguishable glucose loads, there was significantly (P < 0.01) more NHGU when glucose was infused intraportally. Identical studies in five conscious dogs fasted 36 h gave results similar to those of dogs fasted 18 h. After 36 h of fasting, NHGU was 1.6 ± 0.4 and 4.0 ± 0.4 mg · kg⁻¹ · min⁻¹ during the peripheral and portal glucose infusions, respectively (P < 0.005). In conclusion, the route of intravenous glucose administration plays an important role in regulating NHGU even in the presence of hyperinsulinemia in conscious dogs fasted 18 and 36 h.