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Am J Physiol Endocrinol Metab 282: E1342-E1351, 2002. First published February 19, 2002; doi:10.1152/ajpendo.00564.2001
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Vol. 282, Issue 6, E1342-E1351, June 2002

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

Marianne O. Larsen1,4, Michael Wilken2, Carsten F. Gotfredsen3, Richard D. Carr1, Ove Svendsen4, and Bidda Rolin1

Departments of 1 Pharmacological Research I, 2 Assay and Cell Technology, and 3 Histology, Novo Nordisk, DK-2880 Bagsvaerd, Denmark; and 4 Department of Pharmacology and Pathobiology, Royal Veterinary and Agricultural University, DK-1870 Copenhagen, Denmark

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 beta -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 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.


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