Increased Urea Synthesis in Insulin-Dependent Diabetic Dogs Maintained Normoglycemic: Effect of Portal Insulin Administration and Food Protein Content

In IDDM, the gluconeogenic turnover of amino acids is increased even if glycemia is well controlled and may be restored to normal by means of prehepatic insulin substitution. Therefore, the present study was designed 1) to investigate the influence of route of insulin administration (portal versus peripheral) on the urea production rate, which is considered to measure amino acid catabolism, and 2) to elucidate the impact of different food-protein intake. Paired studies were conducted in chronic insulin-dependent diabetic dogs maintained normoglycemic. Diabetic animals and nondiabetic controls were fed either a high-protein diet (46% of energy intake provided by proteins; study 1) or a low-protein carbohydrate-supplemented diet (20% of energy intake provided by protein; study 2) for 2 days, and flux rates of glucose and urea were measured using isotope dilution techniques. In both studies, the diabetic animals were maintained normoglycemic by glucose-controlled insulin infusion delivered either systemically or portally. In study 1 versus study 2, the animals showed lower α-amino nitrogen levels and concentrations of gluconeogenic amino acids, predominantly alanine. There were no significant differences in plasma glucose and glucose turnover between the experimental groups on either systemic or portal insulin infusion versus controls; however, peripheral insulin levels were higher for diabetic animals maintained with systemic versus portal insulin delivery (P < 0.05). No significant differences in glucagon, lactate, pyruvate, nonesterified fatty acids, or β-hydroxybutyrate were observed. Urea production was significantly higher in study 1 compared with study 2: 7.48 ± 0.83 vs. 5.97 ± 0.59 μmol · kg⁻¹ · min⁻¹ (normal dogs); 12.97 ± 1.86 vs. 5.54 ± 0.60 μmol · kg⁻¹ · min⁻¹ (diabetic dogs on portal insulin); 16.11 ± 2.59 vs. 6.82 ± 0.70 μmol · kg⁻¹ · min⁻¹ (diabetic dogs on systemic insulin infusion); P < 0.05 for all. The diabetic dogs maintained normoglycemic with systemic insulin infusions had significantly higher rates of urea synthesis than those with portal insulin infusion (P < 0.05). It is concluded that in IDDM, even if normoglycemia is managed, there is significantly increased amino acid catabolism with posthepatic systemic insulin treatment. This increased catabolic rate is more pronounced during high-protein nourishment.