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 [+ or -] 1.4 vs. 29.7 [+ or -] 7.0 mM * [mg.sup.-1] [kg.sup.-1], P < 0.0001]. Intermediate NIA doses induced moderate changes of glucose tolerance [glucose area under the curve increased from 940 [+ or -] 175 to 1,598 [+ or -] 462 mM * min, P < 0.001 (100 mg/kg) and from 890 [+ or -] 109 to 1,669 [+ or -] 691 mM * min, P = 0.003 (67 mg/kg)] with reduced insulin secretion [1,248 [+ or -] 602 pM * min after 16 days and 1,566 [+ or -] 190 pM * min after 60 days vs. 3,251 [+ or -] 804 pM * min in normal animals (P < 0.001)] and [beta]-cell mass [5.5 [+ or -] 1.4 mg/kg after 27 days and 7.9 [+ or -] 4.1 mg/kg after 60 days vs. 17.7 [+ or -] 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 [beta]-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. in vivo pharmacology; large-animal model; glucose tolerance; [beta]-cell reduction; glucose-stimulated insulin secretion.