The leptin-deficient (ob/ob) mouse : A new animal model of peripheral neuropathy of type 2 diabetes and obesity

• Published in: Diabetes (New York, N.Y.) Vol. 55; no. 12; pp. 3335 - 3343
• Main Authors: DREL, Viktor R, MASHTALIR, Nazar, ILNYTSKA, Olga, SHIN, Jeho, FEI LI, LYZOGUBOV, Valeriy V, OBROSOVA, Irina G
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.12.2006
• Subjects: Animals; Biological and medical sciences; Cranial nerves. Spinal roots. Peripheral nerves. Autonomic nervous system. Gustation. Olfaction; Diabetes; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - genetics; Diabetes. Impaired glucose tolerance; Diabetic Neuropathies - genetics; Diabetic Neuropathies - pathology; Diabetic neuropathy; Diagnosis; Disease Models, Animal; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Glucose; Laboratory animals; Leptin - deficiency; Leptin - genetics; Medical sciences; Metabolic diseases; Mice; Mice, Knockout; Mice, Obese - genetics; Morphology; Nerve Fibers - pathology; Nervous system (semeiology, syndromes); Neural Conduction; Neurology; Obesity; Obesity - genetics; Physiology; Risk factors; Sciatic Nerve - physiopathology; Spinal cord; Type 2 diabetes; Endocrinopathy; Type 2 diabetes; Animal model; Obesity; Nervous system diseases; Rodentia; Nutrition disorder; Metabolic diseases; Adipokine; Peripheral neuropathy; Vertebrata; Mammalia; Mouse; Animal; Leptin; Peripheral nerve disease; Nutritional status
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db06-0885

Whereas functional, metabolic, neurotrophic, and morphological abnormalities of peripheral diabetic neuropathy (PDN) have been extensively explored in streptozotocin-induced 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 ( approximately 11 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 ( approximately 78%) 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 . kg(-1) . 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 fidarestat-treated 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.