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−1d−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.