OBJECTIVE-Mesenchymal stem cells (MSCs) have been reported to secrete various cytokines that exhibit angiogenic and neurosupportive effects. This study was conducted to investigate the effects of MSC transplantation on diabetic polyneuropathy (DPN) in rats.RESEARCH DESIGN AND METHODS-MSCs were isolated from bone marrow of adult rats and transplanted into hind limb skeletal muscles of rats with an 8-week duration of streptozotocin (STZ)-induced diabetes or age-matched normal rats by unilateral intramuscular injection. Four weeks after transplantation, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) productions in transplanted sites, current perception threshold, nerve conduction velocity (NCV), sciatic nerve blood flow (SNBF), capillary number-to-muscle fiber ratio in soleus muscles, and sural nerve morphometry were evaluated.RESULTS-VEGF and bFGF mRNA expression were significantly increased in MSC-injected thigh muscles of STZ-induced diabetic rats. Furthermore, colocalization of MSCs with VEGF and bFGF in the transplanted sites was confirmed. STZ-induced diabetic rats showed hypoalgesia, delayed NCV, decreased SNBF, and decreased capillary number-to-muscle fiber ratio in soleus muscles, which were all ameliorated by MSC transplantation. Sural nerve morphometry showed decreased axonal circularity in STZ-induced diabetic rats, which was normalized by MSC transplantation. D iabetic polyneuropathy (DPN) is the most common complication of diabetes. It is estimated that ϳ20 -30% of diabetic patients are affected by symptomatic DPN (1). Generally, DPN develops symmetrically in a length-dependent fashion, with dying back or dropout of the longest nerve fibers; both myelinated and unmyelinated, large and small are affected. Diabetic patients suffer from various symptoms of DPN, such as spontaneous pain, hyperalgesia, and diminished sensation (2). It has been shown that tight glycemic control is effective in slowing the progression of DPN but cannot completely prevent it (3). Therefore, additional therapeutic strategies are required. CONCLUSIONS-TheseNeural cell degeneration and decreased nerve blood flow (NBF) have been recognized as pathophysiologically characteristic features of DPN (4). Therefore, therapeutic agents that could act as both neurotrophic and angiogenic factors would be useful for the treatment of DPN even at an advanced stage. We previously demonstrated that local administration of basic fibroblast growth factor (bFGF) by intramusclar injection with crosslinked gelatin hydrogel improved the impaired nerve functions of streptozotocin (STZ)-induced diabetic rats, including amelioration of decreased NBF, hypoalgesia, and the delayed motor nerve conduction velocity (MNCV) on the treated side of sciatictibial nerves and that these effects were maintained for at least 30 days (5). Schratzberger et al. (6) showed that vascular endothelial growth factor (VEGF) gene transfer significantly increased the NCV and NBF as well as the vascular densities in muscle and peripheral nerv...

OBJECTIVEThe therapeutic potential of exendin-4, an agonist of the glucagon-like peptide-1 receptor (GLP-1R), on diabetic polyneuropathy (DPN) in streptozotocin (STZ)-induced diabetic mice was investigated.RESEARCH DESIGN AND METHODSThe presence of the GLP-1R in lumbar dorsal root ganglion (DRG) was evaluated by immunohistochemical analyses. DRG neurons were dissected from C57BL6/J mice and cultured with or without Schwann cell–conditioned media in the presence or absence of GLP-1 (7–37) or exendin-4. Then neurite outgrowth was determined. In animal-model experiments, mice were made diabetic by STZ administration, and after 12 weeks of diabetes, exendin-4 (10 nmol/kg) was intraperitoneally administered once daily for 4 weeks. Peripheral nerve function was determined by the current perception threshold and motor and sensory nerve conduction velocity (MNCV and SNCV, respectively). Sciatic nerve blood flow (SNBF) and intraepidermal nerve fiber densities (IENFDs) also were evaluated.RESULTSThe expression of the GLP-1R in DRG neurons was confirmed. GLP-1 (7–37) and exendin-4 significantly promoted neurite outgrowth of DRG neurons. Both GLP-1R agonists accelerated the impaired neurite outgrowth of DRG neurons cultured with Schwann cell–conditioned media that mimicked the diabetic condition. At the doses used, exendin-4 had no effect on blood glucose or HbA1c levels. Hypoalgesia and delayed MNCV and SNCV in diabetic mice were improved by exendin-4 without affecting the reduced SNBF. The decreased IENFDs in sole skins of diabetic mice were ameliorated by exendin-4.CONCLUSIONSOur findings indicate that exendin-4 ameliorates the severity of DPN, which may be achieved by its direct actions on DRG neurons and their axons.

1 This study has investigated the e ects of JTT-501, a peroxisome proliferator-activated receptor (PPAR)-a and PPAR-g agonist, on the pathogenesis of diabetic complications in the Zucker diabetic fatty (ZDF) rats, a model of type 2 diabetes. Comparison is made with troglitazone, a PPAR-g agonist. 2 The ZDF rats exhibited hyperglycaemia and hyperlipidaemia, and developed diabetic complications such as cataract, nephropathy, and neuropathy. Treatment with JTT-501 from the prediabetic stage controlled glycaemia and lipidaemia, and prevented the development of diabetic complications. Troglitazone was less e ective in controlling serum cholesterol and neuropathy. 3 ZDF rats developed diabetic osteopenia with reduced bone turnover, and this was prevented by JTT-501 and troglitazone, possibly mediated by increased bone turnover and bone formation. 4 Since JTT-501 controlled glycaemia and lipidaemia in ZDF rats and prevented several diabetic complications, it is suggested that treatment with JTT-501, which activates both PPAR-a and PPAR-g, could provide a valuable therapeutic approach against diabetic complications in type 2 diabetes.

Relief from painful diabetic neuropathy is an important clinical issue. We have previously shown that the transplantation of cultured endothelial progenitor cells or mesenchymal stem cells ameliorated diabetic neuropathy in rats. In this study, we investigated whether transplantation of freshly isolated bone marrow-derived mononuclear cells (BM-MNCs) alleviates neuropathic pain in the early stage of streptozotocin-induced diabetic rats. Two weeks after STZ injection, BM-MNCs or vehicle saline were injected into the unilateral hind limb muscles. Mechanical hyperalgesia and cold allodynia in SD rats were measured as the number of foot withdrawals to von Frey hair stimulation and acetone application, respectively. Two weeks after the BM-MNC transplantation, sciatic motor nerve conduction velocity (MNCV), sensory nerve conduction velocity (SNCV), sciatic nerve blood flow (SNBF), mRNA expressions and histology were assessed. The BM-MNC transplantation significantly ameliorated mechanical hyperalgesia and cold allodynia in the BM-MNC-injected side. Furthermore, the slowed MNCV/SNCV and decreased SNBF in diabetic rats were improved in the BM-MNC-injected side. BM-MNC transplantation improved the decreased mRNA expression of NT-3 and number of microvessels in the hind limb muscles. There was no distinct effect of BM-MNC transplantation on the intraepidermal nerve fiber density. These results suggest that autologous transplantation of BM-MNCs could be a novel strategy for the treatment of painful diabetic neuropathy.

The positive rate of anti-BP180NC16a antibody was lower in BP patients with DPP4I than without DPP4I, regardless of type 2 diabetes mellitus. The antibody titer was low in both the overall and type 2 diabetes mellitus populations. The prevalence of BP in 9,304 patients receiving DPP4Is was 0.0859%, which is higher than that in the general population. As DPP4Is are common diabetes treatments, we must be aware of the risk of BP.