Background: gp130 receptor ligands represent a therapeutic strategy for the treatment of type 2 diabetes (T2D)1, 2. Accordingly, we have generated a novel chimeric cytokine, termed IC7Fc, and previously demonstrated it improves metabolic homeostasis in diet-induced obesity and insulin resistance. Whether IC7Fc improves glycemia in a mouse model of human T2D is unknown. Accordingly, in this study, we administered IC7Fc to the leptin receptor-deficient (db/db) mouse, which is an appropriate pre-clinical model to study the efficacy of anti-diabetic drugs.
Basic methodologies: Male diabetic db/db mice and their lean controls (db/+) received a single dose of IC7Fc (1 mg/kg i.p.) or saline in the fed state at 7, 13 and 17 wk of age as the animals transitioned from β-cell compensation (7 wk) to β-cell failure (17 wk). Blood glucose, plasma insulin and body composition were measured.
Major findings: The acute administration of IC7Fc reduced (P<0.001) blood glucose in 7 wk old db/db mice within 90 min compared to saline treated db/db mice. The actions of IC7Fc progressively diminished along with the age-dependent progression of the disease such that at 17 wk of age, IC7Fc was ineffective in reducing blood glucose. Remarkably, we observed that a single dose of IC7Fc decreased (P<0.05) total body mass, fat mass and fasting insulin 10 d post injection, effects not observed in age-matched lean (db/+) control mice.
Concluding statement: IC7Fc is an effective and potent therapy in db/db mice with a functional pancreas. Thus, IC7Fc may be a viable new treatment for T2D, provided patients still maintain β-cell function.