The existence of an insulin-stimulated glucose and non-essential but not essential amino acid substrate interaction in diabetic pigs.

BACKGROUND: The generation of energy from glucose is impaired in diabetes and can be compensated by other substrates like fatty acids (Randle cycle). Little information is available on amino acids (AA) as alternative energy-source in diabetes. To study the interaction between insulin-stimulated glucose and AA utilization in normal and diabetic subjects, intraportal hyperinsulinaemic euglycaemic euaminoacidaemic clamp studies were performed in normal (n=8) and streptozotocin (120 mg/kg) induced diabetic (n=7) pigs of ~40-45 kg. RESULTS: Diabetic vs normal pigs showed basal hyperglycaemia (19.0±2.0 vs 4.7±0.1 mmol/L, P<.001) and at the level of individual AA, basal concentrations of valine and histidine were increased (P<.05) whereas tyrosine, alanine, asparagine, glutamine, glutamate, glycine and serine were decreased (P<.05). During the clamp, diabetic vs normal pigs showed reduced insulin-stimulated glucose clearance (4.4±1.6 vs 16.0±3.0 mL/kg·min, P<.001) but increased AA clearance (166±22 vs 110±13 mL/kg· min, P<.05) at matched arterial euglycaemia (5-7 mmol/L) and euaminoacidaemia (2.8-3.5 mmol/L). The increase in AA clearance was mainly caused by an increase in non-essential AA clearance (93.6±13.8 vs 46.6±5.4 mL/kg·min, P<.01), in particular alanine (14.2±2.4 vs 3.2±0.4 mL/kg·min, P<.001). Essential AA clearance was largely unchanged (72.9±8.5 vs 63.3±8.5 mL/kg· min), however clearances of threonine (P<.05) and tyrosine (P<.01) were increased in diabetic vs normal pigs (8.1±1.3 vs 5.2±0.5, and 14.3±2.5 vs 6.4±0.7 mL/kg· min, respectively). CONCLUSIONS: The ratio of insulin-stimulated glucose versus AA clearance was decreased 5.4-fold in diabetic pigs, which was caused by a 3.6-fold decrease in glucose clearance and a 2.0-fold increase in non-essential AA clearance. In parallel with the Randle concept (glucose-fatty acid cycle), the present data suggest the existence of a glucose and non-essential AA substrate interaction in diabetic pigs whereby reduced insulin-stimulated glucose clearance seems to be partly compensated by an increase in non-essential AA clearance whereas essential AA are preferentially spared from an increase in clearance.

Association of insulin resistance with hyperglycemia in streptozotocin-diabetic pigs: effects of metformin at isoenergetic feeding in a type 2-like diabetic pig model.

Insulin-mediated glucose metabolism was investigated in streptozotocin (STZ)-treated diabetic pigs to explore if the STZ-diabetic pig can be a suitable model for insulin-resistant, type 2 diabetes mellitus. Pigs (approximately 40 kg) were meal-fed with a low-fat (5%) diet. Hyperinsulinemic (1, 2, and 8 mU kg(-1) min(-1)) clamps and/or 6,6-(2)H-glucose infusion studies were performed in 36 pigs. Diabetic (slow, 30-minute infusion of 130 mg STZ/kg) vs normal pigs were nonketotic, showed fasting hyperglycemia (21.7 +/- 1.1 vs 5.3 +/- 0.2 mmol/L), comparable plasma insulin (9 +/- 7 vs 5 +/- 1 mU/L), and elevated triglyceride concentrations (1.0 +/- 0.3 vs 0.2 +/- 0.1 mmol/L). After a standard meal, plasma triglycerides, cholesterol, and nonesterified fatty acid concentrations were significantly higher in diabetic vs normal pigs (1.2 +/- 0.3 vs 0.3 +/- 0.1, 2.3 +/- 0.2 vs 1.7 +/- 0.1, and 1.5 +/- 0.5 vs 0.2 +/- 0.1 mmol/L, respectively, P < .05). Fasting whole-body glucose uptake, hepatic glucose production, and urinary glucose excretion were increased (P < .01) in diabetic vs normal pigs (9.1 +/- 0.6 vs 4.8 +/- 0.4, 11.4 +/- 0.6 vs 4.8 +/- 0.4, and 2.3 +/- 0.2 vs 0.0 +/- 0.0 mg kg(-1) min(-1)). During hyperinsulinemic euglycemia (approximately 6 mmol/L), whole-body glucose uptake was severely reduced (P < .01) and hepatic glucose production was moderately increased (P < .05) in diabetic vs normal pigs (6.7 +/- 1.3 vs 21.1 +/- 2.2 and 1.7 +/- 0.5 vs 0.8 +/- 0.3 mg kg(-1) min(-1)) despite plasma insulin concentrations of 45 +/- 5 vs 24 +/- 5 mU/L, respectively. Metformin vs placebo treatment of diabetic pigs (twice 1.5 g/d) for 2 weeks during isoenergetic feeding (1045 kJ/kg body weight(0.75)) resulted in a reduction in both fasting and postprandial hyperglycemia (14.7 +/- 1.5 vs 19.4 +/- 0.6 and 24.9 +/- 2.2 vs 35.5 +/- 4.9 mmol/L), a reduction in daily urinary glucose excretion (approximately 250 vs approximately 350 g/kg food), and an increase in insulin-stimulated glucose disposal (9.4 +/- 2.2 vs 5.8 +/- 1.7 mg kg(-1) min(-1); P < .05), respectively. In conclusion, a slow infusion of STZ (130 mg/kg) in pigs on a low-fat diet induces the characteristic metabolic abnormalities of type 2 diabetes mellitus and its sensitivity to oral metformin therapy. It is therefore a suitable humanoid animal model for studying different aspects of metabolic changes in type 2 diabetes mellitus. Insulin resistance in STZ-diabetic pigs is most likely secondary to hyperglycemia and/or hyperlipidemia and therefore of metabolic origin.

Diurnal rhythms in plasma cortisol, insulin, glucose, lactate and urea in pigs fed identical meals at 12-hourly intervals.

Diurnal rhythms in plasma cortisol, insulin, glucose, lactate and urea concentrations were investigated in eight catheterized pigs of approximately 35 kg BW. Pigs were fed isoenergetic/isoproteinic diets at a restricted level (2.5 x maintenance requirement for energy) in two daily rations (06:00 and 18:00 hours) in order to obtain equal intervals between feed intake. Preprandial plasma cortisol concentration was 22+/-3 ng/mL in the morning and 14+/-2 ng/mL in the evening (p<0.025), whereas the concentrations of insulin, glucose, lactate, and urea were similar. In the postprandial period in the morning (06:00-09:00 hours) plasma cortisol, insulin and lactate concentrations (expressed as the total area under the curve) were greater (p<0.001) compared to the evening (18:00-21:00 hours) by 100%, 42%, and 24%, respectively, while postprandial plasma glucose and urea concentrations were not affected by time of the meal. When postprandial plasma concentrations were expressed as a response over preprandial concentrations (decremental or incremental area under the curve), the diurnal rhythm was not observed for cortisol and glucose, persisted for insulin and lactate, and appeared for urea with a smaller postprandial urea response (p<0.05) in the morning compared to the evening. We conclude that the diurnal rhythm in plasma cortisol is independent of feeding whereas the diurnal rhythms in plasma insulin, lactate and urea are unveiled by the morning/evening meals in pigs. At equal 12-h intervals between meals, the postprandial responses of lactate and urea show diurnal variations, each in a specific manner, which suggest decreased postprandial efficiency of carbohydrate metabolism and increased postprandial efficiency of protein metabolism in the morning compared to the evening.