Caveolin-1 and Altered Neuregulin Signaling Contribute to the Pathophysiological Progression of Diabetic Peripheral Neuropathy

Objective: Diabetes is heterogeneous group of disorders characterized by aberrant insulin signaling and hyperglycmia. Chronic hypergylcemia leads to the development of complications including diabetic peripheral neuropathy (DPN). DPN is a pervasive complication associated with diabetes and its development is not completely understood. Research Design and Methods: We aimed to determine if ErbB2 activation and the absence of Caveolin-1 (Cav-1) contribute to the development of DPN. We induced diabetes in Cav-1 knockout and wild-type mice and assessed thermal and mechanical sensitivity, motor and sensory nerve conduction velocity (MNCV/SNCV), ErbB2 activation, g-ratio, and epidermal nerve fiber density. The contribution of ErbB2 activation to DPN was evaluated using two ErbB2 inhibitors and a conditional double transgenic mouse line that expressed a constitutively active ErbB2 in myelinated Schwann cells. Results: Diabetic mice exhibited decreased MNCV and thermal and mechanical sensitivity after acute diabetes, and these deficits were more severe and developed earlier in Cav-1 knockout mice. Hyperglycemia increased ErbB2 activity, which was amplified in Cav-1 knockout mice. Chronic hyperglycemia resulted in the additional development of reductions in SNCV and epidermal nerve fiber density. Treating diabetic mice with either ErbB2 inhibitor completely restored deficits after acute hyperglycemia and partially reduced deficits after chronic hyperglycemia. Additionally, induction of constitutively active ErbB2 in myelinated Schann cells in the absence of hyperglycemia was sufficient to induce a deficit in MNCV and mechanical sensitivity. Conclusions: Cav-1 may be an endogenous regulator of ErbB2 activity, which when increased contributes to the pathophysiological development of diabetic peripheral neuropathy. Altered ErbB2 signaling is a novel mechanism that contributes to Schwann cell dysfunction in diabetes, and inhibiting ErbB2 may alleviate nerve dysfunction associated with diabetes