Mild streptozotocin diabetes in the Göttingen 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 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.
Larsen
Marianne O
MO
Department of Pharmacological Research I, Novo Nordisk, DK-2880 Bagsvaerd, Denmark. mmla@novonordisk.com
Wilken
Michael
M
Gotfredsen
Carsten F
CF
Carr
Richard D
RD
Svendsen
Ove
O
Rolin
Bidda
B
D000818:Animals; D001120:Arginine; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D004195:Disease Models, Animal; D005215:Fasting; D005502:Food; D005934:Glucagon / Q000097:blood; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood / Q000172:deficiency* / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009536:Niacinamide / Q000008:administration & dosage; D013311:Streptozocin / Q000008:administration & dosage; D013556:Swine, Miniature; D013997:Time Factors
D001786:Blood Glucose; D007328:Insulin; D009536:Niacinamide; D013311:Streptozocin; D005934:Glucagon; D001120:Arginine