The Leptin-Deficient (ob/ob) Mouse: A New Animal Model of Peripheral Neuropathy of Type 2 Diabetes and Obesity

V. R. Drel, N. Mashtalir, O. Ilnytska, J. Shin, F. Li, V. V. Lyzogubov, I. G. Obrosova
2006 Diabetes  
Whereas functional, metabolic, neurotrophic, and morphological abnormalities of peripheral diabetic neuropathy (PDN) have been extensively explored in streptozotocininduced diabetic rats and mice (models of type 1 diabetes), insufficient information is available on manifestations and pathogenetic mechanisms of PDN in type 2 diabetic models. The latter could constitute a problem for clinical trial design because the vast majority of subjects with diabetes have type 2 (non-insulin dependent)
more » ... tes. This study was aimed at characterization of PDN in leptin-deficient (ob/ob) mice, a model of type 2 diabetes with relatively mild hyperglycemia and obesity. ob/ob mice (ϳ11 weeks old) clearly developed manifest sciatic motor nerve conduction velocity (MNCV) and hind-limb digital sensory nerve conduction velocity (SNCV) deficits, thermal hypoalgesia, tactile allodynia, and a remarkable (ϳ78%) loss of intraepidermal nerve fibers. They also had increased sorbitol pathway activity in the sciatic nerve and increased nitrotyrosine and poly(ADP-ribose) immunofluorescence in the sciatic nerve, spinal cord, and dorsal root ganglion (DRG). Aldose reductase inhibition with fidarestat (16 mg ⅐ kg ؊1 ⅐ d ؊1 ), administered to ob/ob mice for 6 weeks starting from 5 weeks of age, was associated with preservation of normal MNCV and SNCV and alleviation of thermal hypoalgesia and intraepidermal nerve fiber loss but not tactile allodynia. Sciatic nerve nitrotyrosine immunofluorescence and the number of poly(ADP-ribose)-positive nuclei in sciatic nerve, spinal cord, and DRGs of fidarestattreated ob/ob mice did not differ from those in nondiabetic controls. In conclusion, the leptin-deficient ob/ob mouse is a new animal model that develops both large motor and sensory fiber and small sensory fiber PDN and responds to pathogenetic treatment. The results support the role for increased aldose reductase activity in functional and structural changes of PDN in type 2 diabetes. Diabetes 55: 3335-3343, 2006 P eripheral diabetic neuropathy (PDN) is a devastating complication of diabetes and a leading cause of foot amputation (1,2). Clinical indications of PDN include increased vibration and thermal perception thresholds that progress to sensory loss, occurring in conjunction with degeneration of all fiber types in the peripheral nerve. A proportion of patients with PDN also describe abnormal sensations such as paresthesias, allodynia, hyperalgesia, and spontaneous pain that sometimes coexist with loss of normal sensory function (3). Functional, metabolic, neurotrophic, and morphological abnormalities of PDN have extensively been explored in animal models of type 1 diabetes and, in particular, in streptozotocin-induced diabetic rats (4 -8) and mice (9,10). In contrast, manifestations and pathogenetic mechanisms of PDN in type 2 diabetic models remain remarkably understudied despite the fact that the vast majority of subjects with diabetes have type 2 (non-insulin dependent) diabetes. The epidemic of obesity in the developed countries is driving a large increase in type 2 diabetes and consequentially setting the scene for an impending wave of morbidity and mortality associated with diabetes complications including PDN (11). The latter dictates a necessity for detailed studies of neuropathic changes in animal models of PDN resulting from obesity and type 2 diabetes. Important information on neurological and neurovascular deficits characteristic for PDN has been obtained in studies in Zucker obese and Zucker diabetic fatty rats (12,13) and other models of PDN of type 2 diabetes (14 -16). Here, we describe PDN in leptin-deficient (ob/ob) mice, a model of obesity and mild type 2 diabetes (17,18) that is clearly characterized by manifest motor and sensory nerve conduction deficits, small sensory nerve fiber neuropathy, intraepidermal sensory nerve fiber loss, and oxidativenitrosative stress in peripheral nerve, spinal cord, and dorsal root ganglion (DRG). These neuropathic changes (except tactile allodynia) appeared amenable to pathogenetic treatment with the aldose reductase (AR) inhibitor fidarestat (19), which supports the role for increased AR activity in PDN associated with obesity and mild type 2 diabetes. RESEARCH DESIGN AND METHODS Unless otherwise stated, all chemicals were of reagent-grade quality and were purchased from Sigma Chemical (St. Louis, MO). Rabbit polyclonal anti-From the
doi:10.2337/db06-0885 pmid:17130477 fatcat:sabea46ahfh7jhot5js5jwf2n4