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

• Published in: Metabolism, clinical and experimental clinical and experimental, 2006-07, Vol.55 (7), p.960-971
• Main Authors: KOOPMANS, Sietse Jan, MROZ, Zdzislaw, DEKKER, Ruud, CORBIJN, Henk, ACKERMANS, Mariette, SAUERWEIN, Hans
• Format: Article
• Language: English
• Subjects: Animals; beta-cell; Biological and medical sciences; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Diabetes. Impaired glucose tolerance; Eating; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; food-intake; free fatty-acids; Glucose - metabolism; Glycosuria - etiology; Hyperglycemia - metabolism; Insulin - blood; Insulin Resistance; lipid-metabolism; Medical sciences; Metabolic diseases; Metformin - therapeutic use; miniature pig; niddm; normal rats; obesity; pathogenesis; Streptozocin; Swine; Triglycerides - blood
• ISSN: 0026-0495; 1532-8600
• 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 a