Preserved Expression of Skin Neurotrophic Factors in Advanced Diabetic Neuropathy Does Not Lead to Neural Regeneration despite Pancreas and Kidney Transplantation

Abstract

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes with potential severe consequences. Its pathogenesis involves hyperglycemia-linked mechanisms, which may include changes in the expression of neurotrophic growth factors. We analyzed the expression of 29 factors potentially related to nerve degeneration and regeneration in skin biopsies from 13 type 1 diabetic pancreas and kidney recipients with severe DPN including severe depletion of intraepidermal nerve fibers (IENF) in lower limb skin biopsies (group Tx1 1st examination). The investigation was repeated after a median 28-month period of normoglycemia achieved by pancreas transplantation (group Tx1 2nd examination). The same tests were performed in 13 stable normoglycemic pancreas and kidney recipients 6–12 years posttransplantation (group Tx2), in 12 matched healthy controls (group HC), and in 12 type 1 diabetic subjects without severe DPN (group DM). Compared to DM and HC groups, we found a significantly higher (p < 0.05–0.001) expression of NGF (nerve growth factor), NGFR (NGF receptor), NTRK1 (neurotrophic receptor tyrosine kinase 1), GDNF (glial cell-derived neurotrophic factor), GFRA1 (GDNF family receptor alpha 1), and GFAP (glial fibrillary acidic protein) in both transplant groups (Tx1 and Tx2). Enhanced expression of these factors was not normalized following the median 28-month period of normoglycemia (Tx1 2nd examination) and negatively correlated with IENF density and with electrophysiological indices of DPN (vibration perception threshold, electromyography, and autonomic tests). In contrast to our expectation, the expression of most of 29 selected factors related to neural regeneration was comparable in subjects with severe peripheral nerve fiber depletion and healthy controls and the expression of six factors was significantly upregulated. These findings may be important for better understanding the pathophysiology of nerve regeneration and for the development of intervention strategies.

Molecular and cellular correlates of human nerve regeneration: ADCYAP1/PACAP enhance nerve outgrowth

“…Whereas some studies report a decrease in neutrophin levels ( Anand et al , 1996 ; Uceyler et al , 2015 ), others found increased levels ( Kennedy et al , 1998 ; Diemel et al , 1999 ) compared to healthy controls. Of note, a recent study reported higher levels of neurotrophin family mRNA in patients with diabetic neuropathy following pancreas/kidney transplantation compared to diabetic patients and healthy controls ( Saudek et al , 2018 ). In accordance with our findings however, serial skin evaluation before and after glucose homeostasis did not reveal changes in neurotrophin expression profiles.…”

Recent Advances in Biomolecular Patho-Mechanistic Pathways behind the Development and Progression of Diabetic Neuropathy

“…NGF synthesis is inhibited in the epidermis of diabetic mice, and NGF supplementation exacerbates neuropathic alterations in small fibers and autonomic disease [202]. Elevated levels of the neurotrophic elements did not result in a discernible regeneration of the peripheral sensory fibers in a study that investigated the expression of NGF and other factors in the skin following kidney and pancreas transplantation in individuals with DN [203]. These results demonstrate the urgent need to understand more about the cellular components of DN.…”

Interplay of BDNF and GDNF in the Mature Spinal Somatosensory System and Its Potential Therapeutic Relevance

“…The interactions of BDNF and GDNF in nociceptive pathways impose a change of approach toward combinational therapies [246], including the delivery of both trophic factors and/or small molecules acting on downstream targets, aiming to restore an altered balance. On the other hand, the successful development of combinational therapies based on a homeostatic approach implies the availability of diagnostic tools to non-invasively explore the neurotrophic content at both central and peripheral levels in different types of painful neuropathies [247][248][249].…”