Immunocompromised rodents are essential for pre-clinical testing of cell-based therapies. The SRG rat (Sprague Dawley Rag2-/-, Il2rg-/-) lacks mature B, T, and NK cells, and is normoglycemic under standard conditions. Compared to mice, the SRG rat offers more human-like metabolism, easier surgical manipulations, and greater volume and frequency of blood collection. Compared to nude rats, the SRG is more permissive to a wider range of human xenografts. Given the advantages of the SRG rat, we determined whether it could serve as a model of streptozotocin-induced (STZ) Type 1 Diabetes or diet-induced obesity (DIO) as a model of Type 2 Diabetes. We compared the effects of STZ on blood glucose levels in SRG versus wild-type Sprague Dawley (SD) male rats. Rats were given vehicle, STZ 40 mg/kg, or STZ 65 mg/kg. After low dose STZ, day 6 non-fasting glucose was 262 ± 41 (SEM) mg/dL in SD rats and 565 ± 64 (SEM) mg/dL in SRG rats. After high dose STZ, day 6 non-fasting glucose was 679 ± 23 (SEM) mg/dL in SD rats and 505 ± 72 mg/dL in SRG rats. Weight loss associated with hyperglycemia was more pronounced in SRG rats compared to SD rats. To induce T2D, obesity, and insulin resistance, SRG rats were fed control or high fat diet (60% kcal from fat). Food intake and body weight were measured weekly. SRG rats underwent IPGTT (after 10 and 24 weeks of high fat diet) and ITT (after 11 weeks of high fat diet). Compared to low fat diet, DIO rats had increased caloric intake and body weight throughout the study. After 10 weeks, DIO rats had impaired glucose tolerance without elevated fasting insulin. Insulin tolerance did not differ at 11 weeks. At 24 weeks, glucose tolerance did not differ between diet groups, but DIO SRG rats displayed elevated fasting insulin (P < 0.01).

In conclusion, SRG rats display increased sensitivity to 40 mg/kg STZ when compared to SD rats, with rapid induction of weight loss and hyperglycemia. The SRG glycemic response to chronic DIO is complex and changes over time, likely due to compensatory hyperinsulinemia.

Disclosure

G. Walton: None.

© 2024 by the American Diabetes Association
2024
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.