Intranasal Insulin Ameliorates Experimental Diabetic Neuropathy

Abstract

Objective: We hypothesized that intranasal insulin (I-I) delivery targets the nervous system while avoiding potential adverse systemic effects when compared to subcutaneous insulin (S-I) for experimental streptozotocin (STZ)-induced diabetic peripheral neuropathy (DPN).

Research Design and Methods: I-I or S-I 0.87 IU daily or placebo were delivered in separate cohorts of diabetic and non-diabetic CD1 mice during 8 months of diabetes. Radiolabeled insulin detection was used to compare delivery and biodistribution for I-I and S-I. Biweekly behavioral testing, and monthly electrophysiological and quantitative studies assessed progression of DPN. At and prior to endpoint, morphometric analysis of DRG, peripheral nerve, distal epidermal innervation, and specific molecular markers were evaluated.

Results: Radiolabeled I-I resulted in more rapid and concentrated delivery to the spinal cord and DRG, with less systemic insulin exposure. When compared to S-I or intranasal placebo, I-I reduced overall mouse mortality and sensory loss, while improving neuropathic pain and electrophysiological/morphological abnormalities in diabetic mice. I-I restored mRNA and protein levels of phosphoinositide 3-kinase (PI3K)/Akt, cyclic AMP response element binding protein (CREB), and glycogen synthase kinase 3β (GSK-3β) to near normal levels within diabetic DRGs.

Interpretation: I-I slows the progression of experimental DPN in STZ mice, avoids adverse effects associated with S-I treatment, and prolongs lifespan when compared to S-I. I-I may be a promising approach for the treatment of DPN.