Mild streptozotocin diabetes in the Gottingen minipig. A novel model of moderate insulin deficiency and diabetes

Nonrodent models of diabetes are needed for practical and physiological reasons. Induction of mild insulin-deficient diabetes was investigated in male Gottingen minipigs by use of streptozotocin (STZ) alone (75, 100, and 125 mg/kg) or 125 mg/kg combined with pretreatment with nicotinamide (NIA; 0, 20, 67, 100, 150, and 230 mg/kg). Use of NIA resulted in a less steep slope of the regression line between fasting plasma glucose and changing doses compared with STZ [-7.0+/-1.4 vs. 29.7+/-7.0 mM.mg(-1).kg(-1), P<0.0001]. Intermediate NIA doses induced moderate changes of glucose tolerance [glucose area under the curve increased from 940±175 to 1,598±462 mM.min, P<0.001 (100 mg/kg) and from 890+/-109 to 1,669+/-691 mM.min, P=0.003 (67 mg/kg)] with reduced insulin secretion [1,248+/-602 pM.min after 16 days and 1,566+/-190 pM.min after 60 days vs. 3,251+/-804 pM.min in normal animals (P<0.001)] and β-cell mass [5.5±1.4 mg/kg after 27 days and 7.9±4.1 mg/kg after 60 days vs. 17.7±4.7 mg/kg in normal animals (P=0.009)]. The combination of NIA and STZ provided a model characterized by fasting and especially postprandial hyperglycemia and reduced, but maintained, insulin secretion and β-cell mass. This model holds promise as an important tool for studying the pathophysiology of diabetes and development of new pharmacological agents for treatment of the disease.