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

Abstract

Nonrodent models of diabetes are needed for practical and physiological reasons. Induction of mild insulin-deficient diabetes was investigated in male Göttingen 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.