(P04-028-25) Acute and Long-Term Effects of Insparin and Pioglitazone on Tissue Distribution of Glucose Uptake

Objectives: Acute administration of Insparin, a protein derived from human adenovirus Ad36, enhances cellular glucose uptake and promotes rapid blood glucose clearance in mice independent of insulin. Long term administration of Insparin improves glycemic control of diabetic mice. Here we determined if there is a difference in tissue distribution of glucose uptake when facilitated by Insparin, a potential antidiabetic drug, or by pioglitazone (Pio), a known antidiabetic drug.

Methods: C57BL/6J mice on high fat diet (HFD) for 36 wk were matched for body weight and glucose tolerance. Mice (n=6 each) received a SC injection of nanoparticles (NP) containing 0µg (control) or 145µg of Insparin (INSP). In another experiment, C57BL/6J mice on HFD for 14 wk (continued on HFD) were divided into 4 groups (n=4 each) matched for body weight and %fat mass, glucose tolerance, and HbA1c. Mice received 0mg (Control for Pio), or 5mg/kg BW Pio in diet (Pio), SC injections of NP containing 0µg (Control for INSP), or 145µg Insparin (INSP) 5d/wk for 8 wk. In both experiments, after about 4h fast, glucose uptake assay was initiated by injecting 100µCi/kg 2-deoxy glucose (2DG) IP. Mice were euthanized 15 minutes post injection, followed by tissue collection (adipose, muscle, kidney, liver, pancreas, heart, and brain) for scintillation counting, normalized to 2DG dose and tissue mass.

Results: Acute Insparin treatment did not affect glucose uptake in the tissues collected. However, long term Insparin administration reduced 2DG uptake in the heart (p=0.03) and Pio decreased 2DG uptake in brown adipose tissue (BAT) (p=0.04) compared to their respective controls.

Conclusions: It has been suggested that cardioprotectivity of SGLT2-i class of anti-diabetes drugs may be due to reduced cardiac glucose uptake leading to lower glucotoxicity and oxidative stress, and myocardial shift to using ketone bodies for energy. Considering that Insparin increases serum free fatty acids and reduces glucose uptake by heart, we speculate that Insparin may have cardioprotective effect via a similar mechanism. Reduced BAT glucose uptake suggests lower BAT activity, potentially contributing to weight gain associated with Pio treatment. Further research is needed to understand clinical implications of the findings for both antidiabetic agents.

Funding Sources: Partly funded by Insparin Inc, and Helen Devitt Jones Foundation