PERIPHERAL NEUROPATHY IN TRANSGENIC DIABETIC MICE - RESTORATION OF C-FIBER FUNCTION WITH HUMAN RECOMBINANT NERVE GROWTH-FACTOR

Mice (Ins.D(d)1) with hypoinsulinemic diabetes were created by increas ed expression of syngeneic major histocompatibility complex (MHC) clas s I protein in pancreatic beta-cells. The diabetic state was character ized in these mice by high glucose concentrations and islet pathology. To determine whether a neuropathy would develop, motor and sensory co nduction velocities (CV) were determined in the sciatic nerves of 2-, 4-, and 7-month-old control and diabetic littermate male mice. Recordi ng bipolar electrodes were placed in the plantar muscles of the hind f oot of anesthetized (ketamine/xylazine) mice. Bipolar stimulating elec trodes mere positioned near the sciatic nerve at the sciatic notch or near the tibial nerve at the ankle. Motor CV from cu-motor fibers and sensory CV from proprioceptive Aa nerves were measured and expressed a s meters per second (m/s). Group data are reported as mean +/- SE and compared by analysis of variance. The CVs from nondiabetic mice (contr ols) were not different across the three ages and averaged 41.3 +/- 1. 7 m/s for motor and 38.7 +/- 1.7 m/s for sensory. The motor CVs from d iabetic mice at 2 and 4 months were similar to controls. Sensory CVs w ere unchanged at 2 months but were lower at 4 months (18.9 +/- 2.4 m/s ). Both sensory (23.9 +/- 2.1 m/s) and motor (18.9 +/- 1.8 m/s) CVs we re significantly reduced at 7 months, which is indicative of a polyneu ropathy. NGF has well-known trophic effects on sympathetic and small s ensory neurons. To determine whether NGF could influence this neuropat hy, 6-month-old control and diabetic mice were divided into the follow ing groups: 1) control + vehicle, 2) diabetic + vehicle, and 3) diabet ic + NGF (1 mg/kg, 3 x week, s.c.). After 1 month of treatment, motor and sensory CVs were determined. In some mice, the branches of the sci atic nerve were exposed and in situ recordings from the sural nerve we re performed to determine compound C-fiber CV, integral, and amplitude . Sensory CV, determined via Hoffmann's reflex (H-reflex) (A-fiber), w as decreased in diabetic compared with control animals as expected (P < 0.05), and NGF did not alter this parameter. Continuing diabetes red uced the amplitude (0.9 +/- 0.2 vs. 3.2 +/- 0.7 mV x 10(-2); P < 0.05) and integral (6.9 +/- 1.9 mV/ms vs. 18.8 +/- 4,4 mV/ms; P < 0.05) of the C-fiber response versus control, suggesting fiber loss. NGF treatm ent normalized C-fiber amplitude (2.9 +/- 0.8 mV x 10(-2)) and integra l(21.2 +/- 6.5 mV/ms) in animals with established diabetes, with no ef fect on blood glucose. The C-fiber CV was similar in all groups, indic ating that the animals had some normally conducting small fiber sensor y nerves. These studies characterized a motor and sensory polyneuropat hy in transgenic diabetic mice and are the first to demonstrate direct ly that NGF treatment can protect or restore abnormal sensory C-fiber function.