The Leptin-Deficient (ob/ob) Mouse

Abstract

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) diabetes. 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 ...

Autonomic dysregulation in ob/ob mice is improved by inhibition of angiotensin-converting enzyme

“…As previously described [14,15], blood glucose levels were increased in ob/ob compared to ob/+ mice at 16 weeks of age. Day and night mean arterial pressure (MAP) and heart rate (HR) are shown in Figure 1.…”

A peroxynitrite decomposition catalyst counteracts sensory neuropathy in streptozotocin-diabetic mice

“…Accumulation of nitrotyrosine [NT, a footprint of peroxynitrite-and other reactive nitrogen species (RNS)-induced protein nitration] has been documented in vascular endothelium (Pacher et al, 2005;Szabo et al, 2002b), myocardium (Pacher et al, 2005), retina (Cheung et al, 2005;Obrosova et al, 2005c), and kidneys (Drel et al, 2006b) of streptozotocin-diabetic rats and mice as well as cutaneous microvascular endothelium (Szabo et al, 2002b), myocardium (Frustaci et al, 2000), and kidneys (Thuraisingham et al, 2000) of human subjects with diabetes. Increased NT immunoreactivity has also been demonstrated in peripheral nervous system i.e., peripheral nerve, spinal cord and dorsal root ganglion (DRG) neurons, of STZ-diabetic rats (Cheng and Zochodne, 2003;Obrosova et al, 2005a) and STZ-diabetic (Ho et al, 2006;Obrosova et al, 2005b), ob/ob (Drel et al, 2006a), and high-fat diet fed mice (Obrosova et al, 2007b), and epineurial vessels of STZ-diabetic, ZDF diabetic fatty, and Zucker fatty rats (Coppey et al, 2001; Obrosova et al, 2005a,b;Oltman et al, 2005). Enhanced nitrosative stress has been reported in human subjects with peripheral diabetic neuropathy (Hoeldtke, 2003).…”

Rats bred for low and high running capacity display alterations in peripheral tissues and nerves relevant to neuropathy and pain

“…Models of type 2 diabetes presenting with common signs of metabolic syndrome such as increased body weight, fat mass, and blood glucose, often also show systemic inflammation and heightened sensitivity (Drel et al., 2006). Previous work examining the role of inflammation in altered sensitivity shows that with profoundly increased inflammation there can be an alteration in both thermal and mechanical sensation (Andrew & Greenspan, 1999; Kidd & Urban, 2001).…”