Investigation of Diabetes-Induced Histological Changes in the Peripheral Sensory Neurons

Diabetic peripheral neuropathy (DPN) is the most common type of neuropathy, which is characterised by the degeneration of the peripheral nerves. The symptoms of DPN begin distally, in the lower limbs, then progress proximally to the upper limbs, producing the characteristic "stockings and gloves" distribution. Patients with DPN experience positive symptoms, including tingling, pinprick sensation, and pain, which affect 30% of diabetic patients, while up to 50% experience negative symptoms, such as numbness and a loss of sensation. These sensory deficits increase the risk of developing foot ulcers and gangrene; of the patients who are affected by these problems, 25% are at risk of developing amputation. This highlights the significant impact of sensory loss on the quality of life of DPN patients. However, the precise mechanism underlying sensory deficit remains unclear. Dorsal root ganglia (DRG) contain the sensory neurons and are particularly vulnerable to damage due to diabetes. In this study, we investigated histological changes in the sensory neurons in the lumbar DRG of 32-week-old db/db mice, focusing on changes that might cause sensory deficit related to DPN. Sympathetic sprouting into the DRG has been linked to pain in nerve injury models. Thus, we investigated whether the sympathetic sprouting occurred in the db/db mice, which might contribute to pain in DPN. No sympathetic sprouting was detected in the DRG of the db/db mice. However, a slight increase in the TH-positive neurons, accounting for 3.69% and 4.42% in the L4 and L5 DRG, respectively, were found. Then, we further investigated previous data from our lab, which showed a reduction in the large-diameter neurons in cultured DRG from the db/db mice. Here, we examined changes in the number and soma size of large-diameter neurons (labelled neurofilament 200) and small-diameter neurons (labelled peripherin) in the db/db mice (in vivo). Our findings revealed a 12.46% reduction in large-diameter neurons, with a decrease in the size of their soma diameter. No change was observed in small-diameter neurons. In addition, we were the first to characterise the presence of cytoplasmic vacuoles in large-diameter neurons, with vacuolated neurons being 11.27% more prevalent in the db/db mice. The number of vacuoles increased in diabetic mice, ranging between 5 and 8 per neuron. However, the origin of these vacuoles could not be determined using cellular markers. The findings of this study offer insights into the structural changes within the specific population of the DRG sensory neurons, which are particularly vulnerable in DPN. These large-diameter neurons are responsible for detecting touch and vibration, so their loss might explain sensory deficit in DPN, and so contribute towards a therapeutic approach that targets these neurons to minimise sensory deficit.