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OBJECTIVE- We hypothesized that intranasal insulin (I-I) delivery targets the nervous system while avoiding potential adverse systemic effects when compared with subcutaneous insulin (S-I) for experimental streptozotocin-induced diabetic peripheral neuropathy (DPN).
RESEARCH DESIGN AND METHODS- II or S-I at 0.87 IU daily or placebo were delivered in separate cohorts of diabetic and nondiabetic CDl 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 before end point, 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 with 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/Akt, cyclic AMP response element- binding protein, and glycogen synthase kinase 3β to near normal levels within diabetic DRGs.
CONCLUSIONS - I-I slows the progression of experimental DPN in streptozotocin mice, avoids adverse effects associated with S-I treatment, and prolongs lifespan when compared with S-I. I-I may be a promising approach for the treatment of DPN. Diabetes 58:934-945, 2009
The most common form of peripheral nervous system (PNS) disease complicating diabetes mellitus is diabetic symmetric sensorimotor polyneuropathy (DPN) (1,2). Diabetic PNS is subject to behavioral, electrophysiological, and morphological changes within peripheral nerve axons, the dorsal root ganglion (DRG), and epidermal nerve fibers (2-4). Although considered an "end-stage" complication, DPN may occur early and may involve children with diabetes (5).
Clinical intervention trials in both type 1 and type 2 diabetes have demonstrated that chronic hyperglycemia has a strong association with the prevalence of complications (6,7). Beyond chronic hyperglycemia, other commonly hypothesized mechanisms relevant for pathogenesis of DPN include excessive sorbitol-aldose reductase pathway flux (8), protein kinase C isoform(s) overactivity (9), increased oxidative and nitrative stress (10), microangiopathy (11), and advanced glycation end products and their receptor (12,13). An important mechanism of DPN may also relate to impaired availability, action, or uptake of growth factors necessary to support peripheral neurons (3,4,14,15). For diabetic...