Pre-clinical studies show anti-diabetic effect of INSPARIN, a protein derived from the E4orf1 gene of a human adenovirus.

BACKGROUND

Human adenovirus Ad36-derived protein, termed INSPARIN, up-regulates cellular glucose uptake through insulin-independent cell signaling. Transgenic or viral vector mediated delivery of INSPARIN exhibits significant anti-diabetic potential in mice. To translate these findings for clinical use, this preclinical study determined the short- and long-term effectiveness of nano-liposome-mediated delivery of INSPARIN to improve glucose metabolism in cell and animal models.

METHODS

Void or INSPARIN Nanoparticles (NP) composed of soy-phosphatidylcholine were prepared freshly before use. Glucose uptake was measured in 3T3-L1, C2C12, and HepG2 cells following 72 h treatment with void or INSPARIN NP using a [³H]-2-deoxyglucose uptake assay. Male C57BL/6J mice fed a 45% high-fat diet received single or repeated subcutaneous injections of INSPARIN NP, followed by oral glucose tolerance tests, serum insulin, and HbA1c measurements. Biodistribution was assessed by DiD-labeled nanoparticle imaging, and long-term safety was evaluated by histopathology of major organs.

RESULTS

INSPARIN NP upregulated glucose uptake in preadipocytes, hepatocytes, and myoblasts. In mice, INSPARIN NP delivered the drug to the liver when administered intravenously and to inguinal adipose tissue when administered subcutaneously. Single subcutaneous administration of INSPARIN NP promoted faster blood glucose clearance in a dose-dependent manner, but without leading to hypoglycemia. Daily subcutaneous administration of INSPARIN NP for seven weeks significantly reduced HbA1c levels despite continued high fat diet, and without any adverse effects on major organs studied.

CONCLUSIONS

These findings support suitability of nano-liposome mediated subcutaneous delivery of INSPARIN in clinical trials for treating diabetes.