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 (40 kg) were meal-fed with a low-fat (5%) diet. Hyperinsulinemic (1, 2, and 8 mU kg¿1 min¿1) clamps and/or 6,6-2H-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 (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 weight0.75) 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 (250 vs 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