Koopmans Sietse Jan, Mroz Zdzislaw, Dekker Ruud, Corbijn Henk, Ackermans Mariette, Sauerwein Hans
Department of Nutrition and Food, Animal Sciences Group, Wageningen UR., P.O. Box 65, 8200 AB Lelystad, The Netherlands.
Metabolism. 2006 Jul;55(7):960-71. doi: 10.1016/j.metabol.2006.03.004.
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.
在链脲佐菌素（STZ）处理的糖尿病猪中研究胰岛素介导的葡萄糖代谢，以探讨STZ诱导的糖尿病猪是否可作为胰岛素抵抗型2型糖尿病的合适模型。猪（约40千克）用低脂（5%）饮食进行分餐喂养。对36头猪进行了高胰岛素血症（1、2和8 mU kg⁻¹ min⁻¹）钳夹试验和/或6,6-(²)H-葡萄糖输注研究。糖尿病猪（缓慢静脉输注130 mg STZ/kg，持续30分钟）与正常猪相比，无酮血症，空腹血糖升高（21.7±1.1 vs 5.3±0.2 mmol/L），血浆胰岛素水平相当（9±7 vs 5±1 mU/L），甘油三酯浓度升高（1.0±0.3 vs 0.2±0.1 mmol/L）。标准餐后，糖尿病猪的血浆甘油三酯、胆固醇和非酯化脂肪酸浓度显著高于正常猪（分别为1.2±0.3 vs 0.3±0.1、2.3±0.2 vs 1.7±0.1和1.5±0.5 vs 0.2±0.1 mmol/L，P <.05）。与正常猪相比，糖尿病猪的空腹全身葡萄糖摄取、肝脏葡萄糖生成和尿糖排泄增加（P <.01）（9.1±0.6 vs 4.8±0.4、11.4±0.6 vs 4.8±0.4和2.3±0.2 vs 0.0±0.0 mg kg⁻¹ min⁻¹）。在高胰岛素血症性血糖正常（约6 mmol/L）期间，与正常猪相比，糖尿病猪的全身葡萄糖摄取严重减少（P <.01），肝脏葡萄糖生成中度增加（P <.05）（6.7±1.3 vs 21.1±2.2和1.7±0.5 vs 0.8±0.3 mg kg⁻¹ min⁻¹），尽管血浆胰岛素浓度分别为45±5 vs 24±5 mU/L。在等能量喂养（1045 kJ/kg体重⁰.⁷⁵）期间，用二甲双胍与安慰剂对糖尿病猪进行治疗（每日两次，每次1.5 g），持续2周，结果空腹和餐后高血糖均降低（14.7±1.5 vs 19.4±0.6和24.9±2.2 vs 35.5±4.9 mmol/L），每日尿糖排泄减少（约250 vs约350 g/kg食物），胰岛素刺激的葡萄糖处置增加（9.4±2.2 vs 5.8±1.7 mg kg⁻¹ min⁻¹；P <.05）。总之，在低脂饮食的猪中缓慢输注STZ（130 mg/kg）可诱导2型糖尿病的特征性代谢异常及其对口服二甲双胍治疗的敏感性。因此，它是研究2型糖尿病代谢变化不同方面的合适的类人动物模型。STZ诱导的糖尿病猪的胰岛素抵抗很可能继发于高血糖和/或高脂血症，因此是代谢性的。
