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11 pages, 2892 KiB

Open AccessArticle

The Effects of Insulin on Immortalized Rat Schwann Cells, IFRS1

by Tomokazu Saiki, Nobuhisa Nakamura, Megumi Miyabe, Mizuho Ito, Tomomi Minato, Kazunori Sango, Tatsuaki Matsubara and Keiko Naruse

Int. J. Mol. Sci. 2021, 22(11), 5505; https://doi.org/10.3390/ijms22115505 - 23 May 2021

Cited by 8 | Viewed by 3106

Abstract

Schwann cells play an important role in peripheral nerve function, and their dysfunction has been implicated in the pathogenesis of diabetic neuropathy and other demyelinating diseases. The physiological functions of insulin in Schwann cells remain unclear and therefore define the aim of this [...] Read more.

Schwann cells play an important role in peripheral nerve function, and their dysfunction has been implicated in the pathogenesis of diabetic neuropathy and other demyelinating diseases. The physiological functions of insulin in Schwann cells remain unclear and therefore define the aim of this study. By using immortalized adult Fischer rat Schwann cells (IFRS1), we investigated the mechanism of the stimulating effects of insulin on the cell proliferation and expression of myelin proteins (myelin protein zero (MPZ) and myelin basic protein (MBP). The application of insulin to IFRS1 cells increased the proliferative activity and induced phosphorylation of Akt and ERK, but not P38-MAPK. The proliferative potential of insulin-stimulated IFRS1 was significantly suppressed by the addition of LY294002, a PI3 kinase inhibitor. The insulin-stimulated increase in MPZ expression was significantly suppressed by the addition of PD98059, a MEK inhibitor. Furthermore, insulin-increased MBP expression was significantly suppressed by the addition of LY294002. These findings suggest that both PI3-K/Akt and ERK/MEK pathways are involved in insulin-induced cell growth and upregulation of MPZ and MBP in IFRS1 Schwann cells. Full article

(This article belongs to the Special Issue Pathogenesis and Molecular Treatment Strategies of Diabetic Neuropathy)

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17 pages, 3054 KiB

Open AccessArticle

Exendin-4 Promotes Schwann Cell Survival/Migration and Myelination In Vitro

by Shizuka Takaku, Masami Tsukamoto, Naoko Niimi, Hideji Yako and Kazunori Sango

Int. J. Mol. Sci. 2021, 22(6), 2971; https://doi.org/10.3390/ijms22062971 - 15 Mar 2021

Cited by 12 | Viewed by 3596

Abstract

Besides its insulinotropic actions on pancreatic β cells, neuroprotective activities of glucagon-like peptide-1 (GLP-1) have attracted attention. The efficacy of a GLP-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) for functional repair after sciatic nerve injury and amelioration of diabetic peripheral neuropathy (DPN) has been [...] Read more.

Besides its insulinotropic actions on pancreatic β cells, neuroprotective activities of glucagon-like peptide-1 (GLP-1) have attracted attention. The efficacy of a GLP-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) for functional repair after sciatic nerve injury and amelioration of diabetic peripheral neuropathy (DPN) has been reported; however, the underlying mechanisms remain unclear. In this study, the bioactivities of Ex-4 on immortalized adult rat Schwann cells IFRS1 and adult rat dorsal root ganglion (DRG) neuron–IFRS1 co-culture system were investigated. Localization of GLP-1R in both DRG neurons and IFRS1 cells were confirmed using knockout-validated monoclonal Mab7F38 antibody. Treatment with 100 nM Ex-4 significantly enhanced survival/proliferation and migration of IFRS1 cells, as well as stimulated the movement of IFRS1 cells toward neurites emerging from DRG neuron cell bodies in the co-culture with the upregulation of myelin protein 22 and myelin protein zero. Because Ex-4 induced phosphorylation of serine/threonine-specific protein kinase AKT in these cells and its effects on DRG neurons and IFRS1 cells were attenuated by phosphatidyl inositol-3′-phosphate-kinase (PI3K) inhibitor LY294002, Ex-4 might act on both cells to activate PI3K/AKT signaling pathway, thereby promoting myelination in the co-culture. These findings imply the potential efficacy of Ex-4 toward DPN and other peripheral nerve lesions. Full article

(This article belongs to the Special Issue Pathogenesis and Molecular Treatment Strategies of Diabetic Neuropathy)

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15 pages, 1179 KiB

Open AccessArticle

Increased Oxidative Stress Underlies Abnormal Pain Threshold in a Normoglycemic Japanese Population

by Sho Osonoi, Hiroki Mizukami, Chieko Itabashi, Kanichiro Wada, Kazuhiro Kudoh, Akiko Igawa, Saori Ogasawara, Yasuyuki Ishibashi, Makoto Daimon, Soroku Yagihashi and Shigeyuki Nakaji

Int. J. Mol. Sci. 2020, 21(21), 8306; https://doi.org/10.3390/ijms21218306 - 5 Nov 2020

Cited by 9 | Viewed by 2281

Abstract

Normal-high HbA1c levels are a risk factor for attenuated pain sensation in normoglycemic subjects. It is unclear, however, what mechanisms underlie the pathogenesis of attenuated pain sensation in such a population. We, therefore, explored the relationship between oxidative stress (OS) and pain sensation [...] Read more.

Normal-high HbA1c levels are a risk factor for attenuated pain sensation in normoglycemic subjects. It is unclear, however, what mechanisms underlie the pathogenesis of attenuated pain sensation in such a population. We, therefore, explored the relationship between oxidative stress (OS) and pain sensation in a rural Japanese population. A population-based study of 894 individuals (average age 53.8 ± 0.5 years) and 55 subjects with impaired fasting glucose (IFG) were enrolled in this study. Individuals with diabetes were excluded. Relationships between pain threshold induced by intraepidermal electrical stimulation (PINT) and clinico-hematological parameters associated with OS were evaluated. Univariate linear regression analyses revealed age, BMI, HbA1c, the OS biomarker urine 8-hydroxy-2′-deoxyguanosine (8-OHdG), systolic blood pressure, and decreased Achilles tendon reflex on the PINT scores. Adjustments for age, gender, and multiple clinical measures confirmed a positive correlation between PINT scores and urine 8-OHdG (β = 0.09, p < 0.01). Urine 8-OHdG correlated positively with higher HbA1c levels and age in the normoglycemic population. Unlike in the normoglycemic population, both inflammation and OS were correlated with elevated PINT scores in IFG subjects. OS may be a major contributing factor to elevated PINT scores in a healthy Japanese population. Full article

(This article belongs to the Special Issue Pathogenesis and Molecular Treatment Strategies of Diabetic Neuropathy)

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13 pages, 2737 KiB

Open AccessArticle

Direct Comparison of Therapeutic Effects on Diabetic Polyneuropathy between Transplantation of Dental Pulp Stem Cells and Administration of Dental Pulp Stem Cell-Secreted Factors

by Saki Kanada, Eriko Makino, Nobuhisa Nakamura, Megumi Miyabe, Mizuho Ito, Masaki Hata, Taisuke Yamauchi, Noritaka Sawada, Shun Kondo, Tomokazu Saiki, Tomomi Minato, Ken Miyazawa, Shigemi Goto, Tatsuaki Matsubara and Keiko Naruse

Int. J. Mol. Sci. 2020, 21(17), 6064; https://doi.org/10.3390/ijms21176064 - 23 Aug 2020

Cited by 15 | Viewed by 3438

Abstract

Stem cell transplantation is a potential novel therapy for diabetic polyneuropathy. Dental pulp stem cells (DPSCs) are attractive stem cell sources because DPSCs can be isolated from extracted teeth and cryopreserved while retaining viability. In this study, we directly compared the efficacy of [...] Read more.

Stem cell transplantation is a potential novel therapy for diabetic polyneuropathy. Dental pulp stem cells (DPSCs) are attractive stem cell sources because DPSCs can be isolated from extracted teeth and cryopreserved while retaining viability. In this study, we directly compared the efficacy of the transplantation of DPSCs and the administration of the secreted factors from DPSCs (DPSC-SFs) on diabetic polyneuropathy. Eight weeks after streptozotocin injection, DPSCs (1.0 × 10⁶ cells/rat) or DPSC-SFs (1.0 mL/rat) were administered into the unilateral hindlimb skeletal muscles of diabetic Sprague–Dawley rats. DPSC transplantation and DPSC-SF administration did not affect blood glucose levels and body weights in the diabetic rats. Both DPSC transplantation and DPSC-SF administration significantly ameliorated sciatic nerve conduction velocity and sciatic nerve blood flow, accompanied by increases in muscle bundle size, vascular density in the skeletal muscles and intraepidermal nerve fiber density in the diabetic rats, while there was no difference between the results for DPSCs and DPSC-SFs. These results suggest that the efficacy of both DPSC transplantation and DPSC-SF administration for diabetic polyneuropathy four weeks after transplantation/administration was mainly due to the multiple secretomes secreted from transplanted DPSCs or directly injected DPSC-SFs in the early phase of transplantation/administration. Full article

(This article belongs to the Special Issue Pathogenesis and Molecular Treatment Strategies of Diabetic Neuropathy)

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Review

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13 pages, 583 KiB

Open AccessReview

Recent Advances in Biomarkers and Regenerative Medicine for Diabetic Neuropathy

by Yoshikai Fujita, Tatsufumi Murakami and Akihiro Nakamura

Int. J. Mol. Sci. 2021, 22(5), 2301; https://doi.org/10.3390/ijms22052301 - 25 Feb 2021

Cited by 22 | Viewed by 4047

Abstract

Diabetic neuropathy is one of the most common complications of diabetes. This complication is peripheral neuropathy with predominant sensory impairment, and its symptoms begin with hyperesthesia and pain and gradually become hypoesthesia with the loss of nerve fibers. In some cases, lower limb [...] Read more.

Diabetic neuropathy is one of the most common complications of diabetes. This complication is peripheral neuropathy with predominant sensory impairment, and its symptoms begin with hyperesthesia and pain and gradually become hypoesthesia with the loss of nerve fibers. In some cases, lower limb amputation occurs when hypoalgesia makes it impossible to be aware of trauma or mechanical stimuli. On the other hand, up to 50% of these complications are asymptomatic and tend to delay early detection. Therefore, sensitive and reliable biomarkers for diabetic neuropathy are needed for an early diagnosis of this condition. This review focuses on systemic biomarkers that may be useful at this time. It also describes research on the relationship between target gene polymorphisms and pathological conditions. Finally, we also introduce current information on regenerative therapy, which is expected to be a therapeutic approach when the pathological condition has progressed and nerve degeneration has been completed. Full article

(This article belongs to the Special Issue Pathogenesis and Molecular Treatment Strategies of Diabetic Neuropathy)

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14 pages, 2525 KiB

Open AccessReview

Aldose Reductase and the Polyol Pathway in Schwann Cells: Old and New Problems

by Naoko Niimi, Hideji Yako, Shizuka Takaku, Sookja K. Chung and Kazunori Sango

Int. J. Mol. Sci. 2021, 22(3), 1031; https://doi.org/10.3390/ijms22031031 - 21 Jan 2021

Cited by 40 | Viewed by 8454

Abstract

Aldose reductase (AR) is a member of the reduced nicotinamide adenosine dinucleotide phosphate (NADPH)-dependent aldo-keto reductase superfamily. It is also the rate-limiting enzyme of the polyol pathway, catalyzing the conversion of glucose to sorbitol, which is subsequently converted to fructose by sorbitol dehydrogenase. [...] Read more.

Aldose reductase (AR) is a member of the reduced nicotinamide adenosine dinucleotide phosphate (NADPH)-dependent aldo-keto reductase superfamily. It is also the rate-limiting enzyme of the polyol pathway, catalyzing the conversion of glucose to sorbitol, which is subsequently converted to fructose by sorbitol dehydrogenase. AR is highly expressed by Schwann cells in the peripheral nervous system (PNS). The excess glucose flux through AR of the polyol pathway under hyperglycemic conditions has been suggested to play a critical role in the development and progression of diabetic peripheral neuropathy (DPN). Despite the intensive basic and clinical studies over the past four decades, the significance of AR over-activation as the pathogenic mechanism of DPN remains to be elucidated. Moreover, the expected efficacy of some AR inhibitors in patients with DPN has been unsatisfactory, which prompted us to further investigate and review the understanding of the physiological and pathological roles of AR in the PNS. Particularly, the investigation of AR and the polyol pathway using immortalized Schwann cells established from normal and AR-deficient mice could shed light on the causal relationship between the metabolic abnormalities of Schwann cells and discordance of axon-Schwann cell interplay in DPN, and led to the development of better therapeutic strategies against DPN. Full article

(This article belongs to the Special Issue Pathogenesis and Molecular Treatment Strategies of Diabetic Neuropathy)

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13 pages, 452 KiB

Open AccessReview

Collateral Glucose-Utlizing Pathwaya in Diabetic Polyneuropathy

by Hiroki Mizukami and Sho Osonoi

Int. J. Mol. Sci. 2021, 22(1), 94; https://doi.org/10.3390/ijms22010094 - 24 Dec 2020

Cited by 35 | Viewed by 5443

Abstract

Diabetic polyneuropathy (DPN) is the most common neuropathy manifested in diabetes. Symptoms include allodynia, pain, paralysis, and ulcer formation. There is currently no established radical treatment, although new mechanisms of DPN are being vigorously explored. A pathophysiological feature of DPN is abnormal glucose [...] Read more.

Diabetic polyneuropathy (DPN) is the most common neuropathy manifested in diabetes. Symptoms include allodynia, pain, paralysis, and ulcer formation. There is currently no established radical treatment, although new mechanisms of DPN are being vigorously explored. A pathophysiological feature of DPN is abnormal glucose metabolism induced by chronic hyperglycemia in the peripheral nerves. Particularly, activation of collateral glucose-utilizing pathways such as the polyol pathway, protein kinase C, advanced glycation end-product formation, hexosamine biosynthetic pathway, pentose phosphate pathway, and anaerobic glycolytic pathway are reported to contribute to the onset and progression of DPN. Inhibitors of aldose reductase, a rate-limiting enzyme involved in the polyol pathway, are the only compounds clinically permitted for DPN treatment in Japan, although their efficacies are limited. This may indicate that multiple pathways can contribute to the pathophysiology of DPN. Comprehensive metabolic analysis may help to elucidate global changes in the collateral glucose-utilizing pathways during the development of DPN, and highlight therapeutic targets in these pathways. Full article

(This article belongs to the Special Issue Pathogenesis and Molecular Treatment Strategies of Diabetic Neuropathy)

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15 pages, 4205 KiB

Open AccessReview

Blood–Nerve Barrier (BNB) Pathology in Diabetic Peripheral Neuropathy and In Vitro Human BNB Model

by Yukio Takeshita, Ryota Sato and Takashi Kanda

Int. J. Mol. Sci. 2021, 22(1), 62; https://doi.org/10.3390/ijms22010062 - 23 Dec 2020

Cited by 21 | Viewed by 5058

Abstract

In diabetic peripheral neuropathy (DPN), metabolic disorder by hyperglycemia progresses in peripheral nerves. In addition to the direct damage to peripheral neural axons, the homeostatic mechanism of peripheral nerves is disrupted by dysfunction of the blood–nerve barrier (BNB) and Schwann cells. The disruption [...] Read more.

In diabetic peripheral neuropathy (DPN), metabolic disorder by hyperglycemia progresses in peripheral nerves. In addition to the direct damage to peripheral neural axons, the homeostatic mechanism of peripheral nerves is disrupted by dysfunction of the blood–nerve barrier (BNB) and Schwann cells. The disruption of the BNB, which is a crucial factor in DPN development and exacerbation, causes axonal degeneration via various pathways. Although many reports revealed that hyperglycemia and other important factors, such as dyslipidemia-induced dysfunction of Schwann cells, contributed to DPN, the molecular mechanisms underlying BNB disruption have not been sufficiently elucidated, mainly because of the lack of in vitro studies owing to difficulties in establishing human cell lines from vascular endothelial cells and pericytes that form the BNB. We have developed, for the first time, temperature-sensitive immortalized cell lines of vascular endothelial cells and pericytes originating from the BNB of human sciatic nerves, and we have elucidated the disruption to the BNB mainly in response to advanced glycation end products in DPN. Recently, we succeeded in developing an in vitro BNB model to reflect the anatomical characteristics of the BNB using cell sheet engineering, and we established immortalized cell lines originating from the human BNB. In this article, we review the pathologic evidence of the pathology of DPN in terms of BNB disruption, and we introduce the current in vitro BNB models. Full article

(This article belongs to the Special Issue Pathogenesis and Molecular Treatment Strategies of Diabetic Neuropathy)

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26 pages, 2259 KiB

Open AccessReview

Diabetes Mellitus-Related Dysfunction of the Motor System

by Ken Muramatsu

Int. J. Mol. Sci. 2020, 21(20), 7485; https://doi.org/10.3390/ijms21207485 - 11 Oct 2020

Cited by 38 | Viewed by 9450

Abstract

Although motor deficits in humans with diabetic neuropathy have been extensively researched, its effect on the motor system is thought to be lesser than that on the sensory system. Therefore, motor deficits are considered to be only due to sensory and muscle impairment. [...] Read more.

Although motor deficits in humans with diabetic neuropathy have been extensively researched, its effect on the motor system is thought to be lesser than that on the sensory system. Therefore, motor deficits are considered to be only due to sensory and muscle impairment. However, recent clinical and experimental studies have revealed that the brain and spinal cord, which are involved in the motor control of voluntary movement, are also affected by diabetes. This review focuses on the most important systems for voluntary motor control, mainly the cortico-muscular pathways, such as corticospinal tract and spinal motor neuron abnormalities. Specifically, axonal damage characterized by the proximodistal phenotype occurs in the corticospinal tract and motor neurons with long axons, and the transmission of motor commands from the brain to the muscles is impaired. These findings provide a new perspective to explain motor deficits in humans with diabetes. Finally, pharmacological and non-pharmacological treatment strategies for these disorders are presented. Full article

(This article belongs to the Special Issue Pathogenesis and Molecular Treatment Strategies of Diabetic Neuropathy)

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