Leptin‐deficient (ob/ob) mouse‐ a new animal model of peripheral neuropathy of Type 2 diabetes and obesity

Abstract

Whereas peripheral diabetic neuropathy (PDN) has extensively been explored in streptozotocin‐diabetic rodents (Type 1 diabetes), insufficient information is available on PDN in Type 2 diabetic models. The latter represents a problem for clinical trial design, because the vast majority of diabetic patients have Type 2 (non‐insulin‐dependent) diabetes. We characterized PDN in leptin‐deficient ( ob/ob ) mouse, a model of Type 2 diabetes with mild hyperglycemia and obesity. ~11‐wk old ob/ob mice developed motor (MNCV) and sensory nerve conduction velocity (SNCV) deficits, thermal hypolagesia, tactile allodynia, and ~78% loss of intraepidermal nerve fibers. They also had increased sorbitol pathway activity in peripheral nerve, and increased nitrotyrosine and poly(ADP‐ribose) immunofluorescence in nerve, spinal cord and dorsal root ganglia. Aldose reductase inhibition with fidarestat (16 mgkg −1 d −1 , for 6 wks, from 5 wks of age) preserved normal MNCV and SNCV, and alleviated thermal hypoalgesia and intraepidermal nerve fiber loss, but not tactile allodynia. Nitrotyrosine immunofluorescence and the number of poly(ADP‐ribose) positive nuclei in nerve, spinal cord and DRGs of fidarestat‐treated ob/ob mice did not differ from controls. In conclusion, ob/ob mouse is a new model that develops both large motor and sensory fiber and small sensory fiber PDN and responds to pathogenetic treatment.