Creating a long-term diabetic rabbit model

Abstract

This study was to create a long-term rabbit model of diabetes mellitus for medical studies of up to one year or longer and to evaluate the effects of chronic hyperglycemia on damage of major organs. A single dose of alloxan monohydrate (100 mg/kg) was given intravenously to 20 young New Zealand White rabbits. Another 12 age-matched normal rabbits were used as controls. Hyperglycemia developed within 48 hours after treatment with alloxan. Insulin was given daily after diabetes developed. All animals gained some body weight, but the gain was much less than the age-matched nondiabetic rabbits. Hyperlipidemia, higher blood urea nitrogen and creatinine were found in the diabetic animals. Histologically, the pancreas showed marked beta cell damage. The kidneys showed significantly thickened afferent glomerular arterioles with narrowed lumens along with glomerular atrophy. Lipid accumulation in the cytoplasm of hepatocytes appeared as vacuoles. Full-thickness skin wound healing was delayed. In summary, with careful management, alloxan-induced diabetic rabbits can be maintained for one year or longer in reasonably good health for diabetic studies.

Figure 1

Changes in renal function. (a) and (b) there was a significant increase in urine and urine protein in diabetic rabbits as compared with baseline; (c) and (d) there was a statistically significant difference in blood urea nitrogen (BUN) and serum creatinine levels between the diabetic and age-matched nondiabetic rabbits at 9 and 12 months. (a) and (b) *P < .05  compared with baseline; (c) and (d) *P < .05 between diabetic and age-matched nondiabetic animals.

Figure 2

Hyperlipidemia: there were statistically significant differences in plasma cholesterol (a) and triglyceride (b) levels between the diabetic and age-matched nondiabetic rabbits at 9 and 12 months. *P < .0001 between the diabetic and age-matched nondiabetic rabbits.

Figure 3

The relationship between blood beta-hydroxybutyrate (BHBA) and blood glucose concentrations. When the glucose levels increased above 500 mg/dl, the BHBA levels increased up to10 mg/dl (increase in ketone bodies) or greater than 40 mg/dl (ketoacidosis).

Figure 4

There were significant differences in closure times between one-year diabetic and age-matched nondiabetic wounds (P < .01). Healing times in 2-week diabetic rabbits were longer than the age-matched nondiabetic rabbits, however the difference was not statistically significant (P = .3865).

Figure 5

The pathological changes of a 12-month diabetic rabbit. (a) and (b) There is marked damage to beta-cells (arrow); (c) and (d) the microscopic cross-section of the artery in the pancreas shows a thickened vessel wall (arrow); (e) and (f) Hyaline arteriolosclerosis. The amorphous, homogeneous eosinophilic material is seen in the thickened vascular wall of afferent glomerular arteriole and the lumen is narrowed markedly (arrow). Glomerular atrophy is also present; (g) and (h) lipid accumulation in the cytoplasm of the hepatocytes appearing as vacuoles (hepatic fatty degeneration); (i) and (j) the microscopic section of the aortic media showing mild spot calcifications (arrow).