(P07-006-24) Optimal Timing for Administering Anti-Diabetic Agent Insparin

Objectives: We reported that transgenic or vector-mediated expression of adenovirus36-derived E4orf1 protein (Insparin) upregulates cellular glucose uptake and promotes glucose clearance in rodents. Next, as a clinically relevant approach, we used nanoliposome (NP) mediated subcutaneous (SC) delivery of Insparin to improve glycemic control, and to reduce HbA1c levels in high fat diet (HFD) fed mice. This therapeutic effect of Insparin requires daily injections, as alternate day injections are not efficacious in reducing HbA1c levels. The current study determined optimal timing of Insparin injection within a day, in relation to feeding, that will efficiently clear postprandial glucose from the blood and thus reduce glycosylation of Hb.

Methods: NP encapsulating Insparin or void NP were prepared using soy phosphatidylcholine. 12-16 week old C57BL/6J mice on 45% HFD for 8-weeks were divided into 4 groups of 8 mice each. The 4 groups of mice received SC injections of void-NP (n = 4) or 145 ug Insparin-NP (n=4) at 12 noon, 6pm, 12 am or 6am. Two hours after the last injection, all 32 mice were fasted for 4h, followed by an oral glucose tolerance test (GTT).

Results: Mice receiving Insparin 18h and 12h prior to GTT showed about 15% and 19% respectively faster blood glucose clearance compared with mice injected with Insparin-NP 6 h or 24 h before GTT, as determined by area under the glucose curve. Within the group, the mice injected with Insparin-NP 18h and 12h prior to GTT showed significantly faster blood glucose clearance following the glycemic load.

Conclusions: It appears that the therapeutic effect of Insparin starts increasing at 6 h post injection, reaches maximizes in 12 – 18 h and reduces by 24 h post injection. These observations suggest that administration of Insparin-NP 6 h before onset of the feeding cycle in mice will provide maximum anti-diabetic effect of Insparin. Further studies are warranted to test long term efficacy of Insparin administered at optimal times in relation to food intake to maximize its therapeutic effect.

Funding Sources: Insparin Therapeutics